UCB 20 April 2017 Statistical Analysis Plan Brivaracetam N01199 Confidential Page 1 of 47 STATISTICAL ANALYSIS PLAN (SAP) Study: N01199 Product: Brivaracetam An open-label, multi-center, follow-up trial to evaluate the long-term safety and efficacy of brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to a maximum of 200mg/day in subjects aged 16 years or older suffering from epilepsy SAP/Amendment Number Date Final SAP SAP Amendment 1 27 January 2014 20 April 2017 Confidentiality Material Confidential This document is the property of UCB and may not – in full or in part – be passed on, reproduced, published, or otherwise used without the express permission of UCB. REDACTED Da Da COPY This document Thi Thi r r cannot nno be used to support any marketing te te 27 J 27 J authorization application and fro fro any e up e up om ep om ep extensions ety ety an an y y y y p t p t or variations thereof.
Transcript
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 1 of 47
STATISTICAL ANALYSIS PLAN (SAP)
Study: N01199
Product: Brivaracetam
An open-label, multi-center, follow-up trial to evaluate the long-term safety and efficacy of brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to a maximum of
200mg/day in subjects aged 16 years or older suffering from epilepsy
SAP/Amendment Number Date
Final SAP
SAP Amendment 1
27 January 2014
20 April 2017
Confidentiality Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, published, or otherwise used without the express permission of UCB.
REDACTED
DateREDACTED
Date
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27 January
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nd ears or older suffering from epileps
and
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any 34714) used as adjunctive treatment at a flexible dose up to a maximum of
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term safetyex
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term safety and efficacyex
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and efficacyterm safety and efficacyterm safetyex
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term safety and efficacyterm safety34714) used as adjunctive treatment at a flexible dose up to a maximum of ex
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34714) used as adjunctive treatment at a flexible dose up to a maximum of
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 2 of 47
TABLE OF CONTENTS
LIST OF ABBREVIATIONS.................................................................................................... 6
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 6 of 47
LIST OF ABBREVIATIONS
AE adverse eventAED antiepileptic drugAMD antimyoclonic drugALP Alkaline phosphataseALT alanine aminotransferaseAST aspartate aminotransferaseATC Anatomic Therapeutic ClassBMI body mass indexbpm Beats per minuteBRV BrivaracetamBUN blood urea nitrogenCR CL creatinine clearanceCRF case report formC-SSRS Columbia-Suicide Severity Rating ScaleDBP diastolic blood pressureECG electrocardiogramEDV Early Discontinuation VisitEQ-5D EuroQol 5 DimensionsER emergency roomF FemaleFDA Food and Drug AdministrationFEV Full Evaluation VisitFV Final VisitGGT Gamma-glutamyl transpeptidase HADS Hospital Anxiety and Depression ScaleHDL High-density lipoprotein HRQoL Health-Related Quality of LifeILAE International League Against EpilepsyLDL low-density lipoproteinMedDRA Medical Dictionary for Regulatory ActivitiesM MaleMEV Minimal Evaluation VisitN/A Not applicablePBO PlaceboPCST potentially clinically significant treatment-emergentPGS primary generalized seizuresPOS partial onset seizurePT preferred term QOLIE-31-P Patient Weighted Quality of Life in Epilepsy
QuestionnaireRBC Red Blood CellSAE serious adverse event
REDACTED Food and Drug Administration
REDACTED Food and Drug AdministrationFull Evaluation Visit
REDACTED
Full Evaluation VisitFinal Visit
REDACTED
Final VisitGammaREDACTED
Gamma
COPY y Discontinuation Visit
COPY y Discontinuation VisitEuroQol 5 Dimensions
COPY EuroQol 5 Dimensions
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Gamma
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 7 of 47
SAP statistical analysis planSBP systolic blood pressureSD standard deviationSEV Supplemental Entry VisitSGOT serum glutamic oxaloacetic transaminaseSGPT serum glutamic pyruvic transaminaseSOC system organ classTEAE treatment-emergent adverse eventULN Upper Limit of NormalV VisitVAS visual analog scaleWBC White Blood CellWHO-DRL World Health Organization Drug Reference ListYEV Yearly Evaluation Visit
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
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1 INTRODUCTION
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a detailed description of statistical methodology for the statistical analyses to support the final clinical study report for N01199.
2 PROTOCOL SUMMARY
2.1 Study objectives
2.1.1 Primary objective
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses with a maximum of 200mg/day in subjects suffering from epilepsy
2.1.2 Secondary objectives
To evaluate the maintenance of efficacy over time of BRV (for subjects with partial onset seizures [POS] and subjects with primary generalized seizures [PGS])
2.1.3 Exploratory objectives
Exploratory objectives for subjects with POS/PGS:
To explore medical resource use and indirect cost parameters for the first 2 years
To obtain a description of the subject’s self-reported health status for the first 2 years
To explore the effects of BRV on the subject’s Health-related Quality of Life (HRQoL), anxiety, and depression for the first 2 years
To explore any change in the subject’s socio-professional status for the first 2 years
2.2 Study variables
2.2.1 Safety variables
2.2.1.1 Primary safety variables
Occurrence of a treatment-emergent adverse event (TEAE)
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and body weight
Electrocardiogram (ECG)
Physical and neurological examinations
REDACTED To obtain a description of the subject’s self
REDACTED To obtain a description of the subject’s selfTo obtain a description of the subject’s self-To obtain a description of the subject’s self
REDACTED To obtain a description of the subject’s self-To obtain a description of the subject’s self reported health status for the first 2 y
REDACTED reported health status for the first 2 y
To explore the effects of BRV on the subject’s Health-
REDACTED To explore the effects of BRV on the subject’s Health-
n for the first 2 y
REDACTED
n for the first 2 y
change in the subject’s socioREDACTED
change in the subject’s socio
COPY use and indirect cost parameters for the first 2 y
COPY use and indirect cost parameters for the first 2 y
reported health status for the first 2 yCOPY
reported health status for the first 2 y
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reported health status for the first 2 y
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reported health status for the first 2 y
To explore the effects of BRV on the subject’s Health-
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 9 of 47
Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline of the previous study to each assessment for the first 2 years and to the last Evaluation Period assessment during the first 2 years
2.2.2 Efficacy variables
2.2.2.1 Secondary efficacy variables
For subjects with focal-onset epilepsy:
POS (type I) frequency per 28 days during the Evaluation Period
Percent reduction in POS (type I)frequency per 28 days from Baseline of the previous study to the Evaluation Period
Responder rate for POS (type I) frequency over the Evaluation Period. A responder is defined as a subject with a ≥50% reduction in seizure frequency from the Baseline Period of the previous study
2.2.2.2 Other efficacy variables
For subjects with focal-onset epilepsy:
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:
Generalized (type II) seizure days per 28 days during the Evaluation Period
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the previous study to the Evaluation Period
Responder rate for generalized (type II) seizure days over the Evaluation Period. A responder is defined as a subject with a ≥50% reduction in seizure days from the Baseline Period of the previous study
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects with generalized epilepsy:
Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) scores from Baseline of the previous study to each assessment for the first 2 years and to the last Evaluation Period assessment during the first 2 years
EuroQol 5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 2 years for the Evaluation Period and for the last assessment during the first 2 years of the Evaluation Period
REDACTED s pe
REDACTED s per 28 day
REDACTED r 28 day
Percent reduction in generalized (tyREDACTED
Percent reduction in generalized (type II) seizure dayREDACTED
pe II) seizure dayPercent reduction in generalized (type II) seizure dayPercent reduction in generalized (tyREDACTED
Percent reduction in generalized (type II) seizure dayPercent reduction in generalized (typrevious study to the Evaluation PeriodREDACTED
previous study to the Evaluation Period
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supp
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Percentage of subjects continuously
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 10 of 47
2.2.3 Pharmacoeconomic variables
Due to the inconsistencies in data captured and collection forms across LTFU studies, the following variables will be provided in subject data listings only, but will not be evaluated or descriptive summarized:
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent medical procedures, concomitant medications, hospitalizations, and emergency room [ER] visits) during the first 2 years of the Evaluation Period
Indirect costs (work days or school days lost by the subject and days subject received help from a caregiver) during the first 2 years of the Evaluation Period
Socio-professional data for each assessment for the first 2 years and for the last assessment during the first 2 years of the Evaluation Period
2.3 Study Design and Conduct
This is an open-label, long-term follow-up, multicenter, noncomparative, single-arm study of BRV. The primary objective is to evaluate the long-term safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day in subjects with epilepsy. The secondary objective is to evaluate the maintenance of efficacy of BRV. Exploratory objectives are to assess the effects of BRV on subjects’ HRQoL, obtain information on the direct and indirect costs, and explore changes in socio-professional status.
At the time of development of this SAP, the enrollment into N01199 had completed. Study N01199 enrolled subjects 16 years of age and older who had completed N01193, N01252, N01253, or N01254. Subjects from N01252 and N01254 enrolled into long-term follow-up studies, either N01125 or N01199, depending on their country of residence. Studies N01193, N01252, and N01253 enrolled subjects with focal-onset seizures with or without secondary generalization (designated as “POS subjects”). Study N01254 enrolled subjects with focal-onset epilepsy and also a smaller number of subjects with generalized epilepsy (designated as “PGS subjects”).
Subjects from double-blind, placebo-controlled studies N01193 were to enter N01199 at a dose of 20mg/day. Subjects from double-blind, placebo-controlled N01252 were to enter N01199 at a dose of 50mg/day. Subjects from double-blind, placebo-controlled N01253 were to enter N01199 at a dose of 50mg/day or 20mg/day. The starting doses for subjects from double-blind, placebo-controlled, flexible-dose N01254 were based on the blinded dose levels achieved during the Maintenance Period of N01254 but were not to exceed 100mg/day; thus, starting doses for subjects from N01254 were 20mg/day, 50mg/day, or 100mg/day, with most subjects entering N01199 at a dose of 100mg/day.
Subjects who enrolled in the study entered an Evaluation Period during which treatment with BRV was initiated. The dose of BRV could be adjusted based on the individual subject’s seizure control and tolerability. Dose increases could be made in increments of 50mg/day on a weekly basis up to a maximum of 200mg/day; dose decreases could be made in steps of 50mg/day on a weekly basis. Subjects who discontinue treatment with BRV enter a Down-
REDACTED direct and indirect costs, and explore changes in socio-
REDACTED direct and indirect costs, and explore changes in socio-
At the time of development of this SAP, the enrollment into N01199 had completed. Study
REDACTED At the time of development of this SAP, the enrollment into N01199 had completed. StudyN01199 enrolled subjects 16 years of age and older who had completed N0119
REDACTED
N01199 enrolled subjects 16 years of age and older who had completed N0119N01253, or N01254. Subjects from N01252 and N01254 enrolled into long
REDACTED
N01253, or N01254. Subjects from N01252 and N01254 enrolled into longstudies, either N01125 or N01199, depending on their countryREDACTED
studies, either N01125 or N01199, depending on their country
COPY objective is to evaluate the maintenance of efficacy
COPY objective is to evaluate the maintenance of efficacyobjectives are to assess the effects of BRV on subjects’ HRQoL, obtain in
COPY objectives are to assess the effects of BRV on subjects’ HRQoL, obtain indirect and indirect costs, and explore changes in socio-COPY
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autho
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on objectives are to assess the effects of BRV on subjects’ HRQoL, obtain in
autho
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direct and indirect costs, and explore changes in socio-
autho
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direct and indirect costs, and explore changes in socio-professional status.
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professional status.
At the time of development of this SAP, the enrollment into N01199 had completed. Study
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At the time of development of this SAP, the enrollment into N01199 had completed. StudyN01199 enrolled subjects 16 years of age and older who had completed N0119
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N01253, or N01254. Subjects from N01252 and N01254 enrolled into long
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 11 of 47
Titration Period during which the dose of BRV is decreased in steps of 50mg/day on a weekly basis with a last down titration step at 20mg/day for 1 week. Subjects who have completed the Down-Titration Period or subjects who discontinue during the Evaluation Period without entering the Down-Titration Period enter a Post-Treatment Period for a minimum of 2 weeks and a maximum of 4 weeks and subsequently, the final visit will occur.
The maximum allowable daily dose for this study was increased from 150mg/day to 200mg/day based on amendment 6 to the protocol. It is recommended that the daily dose be administered in 2 equal intakes.
Dose adjustment to concomitant AEDs may be made at any time during the study and subjects may start new AEDs. Concomitant AEDs may also be discontinued; however, special considerations apply if the discontinuation of such AEDs results in the subject receiving BRV monotherapy. Previously, in the event of excellent efficacy and tolerability of BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been attempted by the Investigator. With protocol amendment 6, conversion to monotherapy was no longer permitted; however, subjects already on BRV monotherapy are allowed to continue monotherapy treatment.
The visit schedule for this study depends on the previous study from which the subject was enrolled and the numbering of study visits differs depending on the previous study. Study visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearly Evaluation Visits (YEVs) at which a greater number of assessments are performed for all subjects from previous studies. For subjects coming from N01193, study visits at Months 1, 3, 5, 15, and 21 are minimal Evaluation Visits (MEVs) at which few assessments are generally performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from N01252, N01253, and N01254, study visits at Months 1, 3, 9, 15, 21 are MEVs. The study visit at Month 2 is an FEV. In addition, a phone call is scheduled at the end of the Down-Titration period and a Drug-Free Final Visit (FV) is scheduled at the end of the Post-Treatment Period. The study schedule just described is shown in Table 2‒1 .
REDACTED Evaluation Visits (YEVs) at which a greater number of assessments are performed for all
REDACTED Evaluation Visits (YEVs) at which a greater number of assessments are performed for all subjects from previous studies. For subjects coming from N01193, study
REDACTED subjects from previous studies. For subjects coming from N01193, study
minimal Evaluation Visits (MEVs) at which few assessments are
REDACTED
minimal Evaluation Visits (MEVs) at which few assessments are y performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from
REDACTED
y performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from N01252, N01253, and N01254, studyREDACTED
N01252, N01253, and N01254, study visits at Months 1, 3, 9, 15, 21 are MEVs. The studyREDACTED
visits at Months 1, 3, 9, 15, 21 are MEVs. The studyN01252, N01253, and N01254, study visits at Months 1, 3, 9, 15, 21 are MEVs. The studyN01252, N01253, and N01254, studyREDACTED
N01252, N01253, and N01254, study visits at Months 1, 3, 9, 15, 21 are MEVs. The studyN01252, N01253, and N01254, study
COPY depends on the previous study
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COPY visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearl
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rizati
on
subjects from previous studies. For subjects coming from N01193, studyminimal Evaluation Visits (MEVs) at which few assessments are
autho
rizati
on
minimal Evaluation Visits (MEVs) at which few assessments are y performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from au
thoriz
ation
y performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from
appli
catio
n y on BRV monotherap
appli
catio
n y on BRV monotherap
depends on the previous study
appli
catio
n
depends on the previous study from which the subject was
appli
catio
n
from which the subject was depends on the previous study from which the subject was depends on the previous study
appli
catio
n
depends on the previous study from which the subject was depends on the previous studyy visits differs depending on the previous study. Study
appli
catio
n
y visits differs depending on the previous study. Study visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearlap
plica
tion
visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearl
and the Investigator. With protocol amendment 6, conversion to monotherapy
and the Investigator. With protocol amendment 6, conversion to monotherapy
y on BRV monotherapand y on BRV monotherapy and y are allowedand are allowed
any BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been
any BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been
the Investigator. With protocol amendment 6, conversion to monotherapyany
the Investigator. With protocol amendment 6, conversion to monotherapy
exten
sions
an
exten
sions
and
exten
sions
d also be discontinued; however,
exten
sions
also be discontinued; however,
if the discontinuation of such AEDs results in the subject
exten
sions
if the discontinuation of such AEDs results in the subject , in the event of excellent efficacy ex
tensio
ns
, in the event of excellent efficacy and tolerabexten
sions
and tolerab, in the event of excellent efficacy and tolerab, in the event of excellent efficacy exten
sions
, in the event of excellent efficacy and tolerab, in the event of excellent efficacyBRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been ex
tensio
ns
BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been
or d or
d va
riatio
ns
dose be
varia
tions
dose be
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 12 of 47
Table 2‒1: Study Schedule
Subjects coming from Exploratory Study (N01193)
Subjects coming from Confirmatory Studies (N01252, N01253, N01254)
Month Visit Type of Visit Month Visit Type of Visit
All subjects should have a Visit 1 at the start of N01199. Visit 1 will typically correspond to the last visit from the previous study and should be the visit at which study drug is dispensed for N01199. However, some subjects had a delay in treatment with study medication after completion of the previous study. Such subjects may have had an additional Supplemental Entry Visit (SEV) at the time of entry into N01199.
This study will run throughout the duration of the clinical development period ofbrivaracetam, and will continue until a marketing authorization is granted by any Health Authority in an indication for the adjunctive treatment in adults with refractory POS, whether or not secondarily generalized, until the Sponsor decides to close the study, until a managed access program, named patient program, compassionate use program, or similar type of access program is established as allowed per country-specific requirement in addition to legal and regulatory guidelines, or until brivaracetam development is stopped by the Sponsor.
REDACTED
REDACTED
REDACTED
REDACTED
REDACTED
REDACTED
MEV1
REDACTED
MEV1
REDACTED
FEV
REDACTED
FEV
REDACTED
MEV2REDACTED
MEV2REDACTED COPY M10
COPY M10M11
COPY M11
COPY
COPY
This do
cumen
t or not secondarily
docu
ment
or not secondarily
docu
ment access program, named patient program, compassionate
docu
ment access program, named patient program, compassionate
access p
docu
ment
access p
cann
ot brivaracetam, and will continue until a marketing authori
cann
ot brivaracetam, and will continue until a marketing authoriAuthority
cann
ot Authority in an indication
cann
ot in an indicationAuthority in an indicationAuthority
cann
ot Authority in an indicationAuthorityor not secondarilyca
nnot
or not secondarily
be will run throughout the duration of the clinical development period of
be will run throughout the duration of the clinical development period of
brivaracetam, and will continue until a marketing authoribe
brivaracetam, and will continue until a marketing authori
used
Visit (SEV) at the time of entry
used
Visit (SEV) at the time of entry
will run throughout the duration of the clinical development period ofused
will run throughout the duration of the clinical development period of
to completion of the previous studyto completion of the previous study Visit (SEV) at the time of entry
to Visit (SEV) at the time of entry
supp
ort All subjects should have a Visit 1 at the start of N01199. Visit 1 will ty
supp
ort All subjects should have a Visit 1 at the start of N01199. Visit 1 will ty
visit from the previous study and should be the visit at which study
supp
ort
visit from the previous study and should be the visit at which studyfor N01199. However, some subjects had a delay
supp
ort
for N01199. However, some subjects had a delaycompletion of the previous studysu
pport
completion of the previous study
any
All subjects should have a Visit 1 at the start of N01199. Visit 1 will tyany
All subjects should have a Visit 1 at the start of N01199. Visit 1 will ty
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 13 of 47
2.4 Determination of Sample Size
No sample size calculation was done. Sample size was dependent upon recruitment into and completion of preceding studies. At the time of development of this SAP, the study enrollment has been completed; a total of 668 subjects were enrolled into N01199.
3 DATA ANALYSIS CONSIDERATIONS
3.1 General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical output will be carried out using SAS® Version 9.1 or higher.
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 75th percentile, minimum value, and maximum value for quantitative variables, and counts and percentages for categorical variables, will be provided. Denominators for percentages will generally be based on the set of subjects with at least 1 assessment at the time point or at least 1 assessment during the time interval being summarized.
All summaries will be descriptive; no statistical hypothesis testing is planned.
Unless otherwise noted, summaries will present BRV overall, which will include all subjects exposed to BRV during the study.
Subject data listings will be provided and will present source data and key derived variables for statistical analyses.
3.2 Analysis time points
3.2.1 First and last dose of BRV
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first dose of BRV during N01199 (ie, not the first dose of BRV from the previous study in which subjects participated in prior to N01199). Unless otherwise noted, all references to the last known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods (ie, not necessarily the last dose of BRV during the Evaluation Period).
3.2.2 Relative day
Relative day will be calculated as the current date minus the date of first dose of study drugfor days prior to the first dose of study drug, and the current date minus the date of first dose of study drug plus 1 for days on or after the day first dose of study drug and prior to or on the day of last study drug dose (eg, the day of first dose will be Day 1 and the day prior to first dose will be Day -1), ie, Day 1 representing the day of first dose of BRV, the previous day is Day -1 and each day prior to that is Day -2, Day -3, etc; subsequent relative days to Day 1 will be Day 2, Day 3, etc. For days after the last dose of BRV, relative day will be calculated as the current date minus the date of last dose of BRV and including a ‘+’ to denote post treatment days (eg, the day after the last dose of BRV will be Day +1). Relative day will not be calculated for partial or missing dates.
REDACTED Subject data listings will be provided and will present source data and key
REDACTED Subject data listings will be provided and will present source data and key
sis time points
REDACTED
sis time points
First and last dose of BRVREDACTED
First and last dose of BRV
COPY Unless otherwise noted, summaries will present BRV overall, which will incl
COPY Unless otherwise noted, summaries will present BRV overall, which will incl
Subject data listings will be provided and will present source data and keyCOPY
Subject data listings will be provided and will present source data and key
This do
cumen
t Day
docu
ment Day
docu
ment
will be Day
docu
ment
will be Dayas the current date minus the date of last dose of BRV and including a ‘+’ to denote post
docu
ment
as the current date minus the date of last dose of BRV and including a ‘+’ to denote post
cann
ot of last study
cann
ot of last studydose will be Day
cann
ot dose will be DayDay ca
nnot
Day -cann
ot
-1 and each daycann
ot
1 and each day
be drug plus 1 for days on or after the daybe drug plus 1 for days on or after the day
of last studybe
of last study
used
will be calculated as the current date minus the date of first dose of study
used
will be calculated as the current date minus the date of first dose of studys prior to the first dose of studyus
ed
s prior to the first dose of study drug plus 1 for days on or after the day
used
drug plus 1 for days on or after the day
to Relative day
to Relative day
will be calculated as the current date minus the date of first dose of studyto will be calculated as the current date minus the date of first dose of studysu
pport
RV in this SAP refer to the last dose of BRV taken across
supp
ort RV in this SAP refer to the last dose of BRV taken across
(ie, not necessarily the last dose of BRV during the Evaluation Period).
supp
ort
(ie, not necessarily the last dose of BRV during the Evaluation Period).
supp
ort
Relative daysupp
ort
Relative day
any subjects participated in prior to N01199). Unless otherwise noted, all references to the last
any subjects participated in prior to N01199). Unless otherwise noted, all references to the last
RV in this SAP refer to the last dose of BRV taken across any
RV in this SAP refer to the last dose of BRV taken across
marketi
ng First and last dose of BRV
marketi
ng First and last dose of BRV
Unless otherwise noted, all references
marketi
ng
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first
marketi
ng
to the first dose of BRV in this SAP refer to the first dose of BRV during N01199 (ie, not the first dose of BRV from the previous study
marketi
ng
dose of BRV during N01199 (ie, not the first dose of BRV from the previous studysubjects participated in prior to N01199). Unless otherwise noted, all references to the last mark
eting
subjects participated in prior to N01199). Unless otherwise noted, all references to the last
autho
rizati
on
Subject data listings will be provided and will present source data and key
autho
rizati
on
Subject data listings will be provided and will present source data and key
First and last dose of BRVautho
rizati
on
First and last dose of BRV
appli
catio
n All summaries will be descriptive; no statistical hypothesis testing is planned.
appli
catio
n All summaries will be descriptive; no statistical hypothesis testing is planned.
Unless otherwise noted, summaries will present BRV overall, which will incl
appli
catio
n
Unless otherwise noted, summaries will present BRV overall, which will incl
Subject data listings will be provided and will present source data and keyap
plica
tion
Subject data listings will be provided and will present source data and key
and
1 assessment at the time point or at
and
1 assessment at the time point or at
All summaries will be descriptive; no statistical hypothesis testing is planned.an
d
All summaries will be descriptive; no statistical hypothesis testing is planned.
any and percentages for categorical variables, will be provided. Denominators for percentages
any and percentages for categorical variables, will be provided. Denominators for percentages
1 assessment at the time point or at any 1 assessment at the time point or at ex
tensio
ns
25th percentile,
exten
sions
25th percentile,
75th percentile, minimum value, and maximum value for quantitative variables, and counts ex
tensio
ns
75th percentile, minimum value, and maximum value for quantitative variables, and counts and percentages for categorical variables, will be provided. Denominators for percentages ex
tensio
ns
and percentages for categorical variables, will be provided. Denominators for percentages
or sis and generation of tables, figures, subject data listings, and statistical
or sis and generation of tables, figures, subject data listings, and statistical va
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 14 of 47
3.2.3 Study Entry Visit
The study Entry Visit (EV) corresponds to assessments performed at the time of entry into N01199. There are 3 groups of subjects to consider:
1. Subjects who immediately entered N01199 after completing the Treatment Periods for N01193, N01252, N01253, and N01254.
2. Subjects who entered the Down-Titration Period of the previous study and entered N01199 during the Down-Titration Period.
3. Subjects who did not immediately enter N01199 and had a gap in treatment with study drug between the previous study and N01199.
Subjects in Categories 1 and 2
Subjects in categories 1 and 2 will generally not have any interruption in study drug dosing during the transition to N01199. For such subjects, selected assessments from the following visits from the previous study will be summarized at EV:
Study Visit (Time Point)
N01193 Visit 4 (Week 7)
N01252/N01253 Visit 7 (Week 12)
N01254 Visit 8 (Week 16)
The following assessments were to be performed for all subjects at the above time points: laboratory parameters, vital signs, and ECGs; the results for these assessments will be summarized at EV. Other assessments were to be performed at the above time points but will not be summarized. QOLIE-31-P, HADS, EQ-5D and social-professional data were only assessed at the above time points for studies N01252, N01253, and N01254.
The body weight recorded at the above study visits for the previous studies will be summarized for EV.
Subjects in Category 3
Some subjects in category 3 have data available from an SEV at the time of entry into N01199. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized at EV. If one or more of these assessments were not performed at SEV, or if a subject in category 3 does not have an SEV, then the subject will be excluded from EV for the assessments that were not performed, regardless of the duration of time the subject was not receiving the study drug after the previous study.
QOLIE-31-P, HADS, EQ-5D, and socio-professional data will not be summarized at EV for subjects in category 3 regardless of the duration of time the subject was not receiving study drug after the previous study.
REDACTED Visit 8 (Week 16)
REDACTED Visit 8 (Week 16)
The following assessments were to be performed for all
REDACTED The following assessments were to be performed for all
parameters, vital signs, and ECGs; the results for these assessments will be
REDACTED
parameters, vital signs, and ECGs; the results for these assessments will be summarized at EV. Other assessments were to be performed at the above time points but will REDACTED
summarized at EV. Other assessments were to be performed at the above time points but will -P, HADS, EQ-5DREDACTED
-P, HADS, EQ-5D
COPY Visit 7 (Week 12)
COPY Visit 7 (Week 12)
Visit 8 (Week 16)COPY
Visit 8 (Week 16)
This do
cumen
t QOLIE
docu
ment QOLIE
subjects in category
docu
ment
subjects in category
cann
ot assessments that were not performed, regardless of the duration of time the subject was not
cann
ot assessments that were not performed, regardless of the duration of time the subject was not receiving the stud
cann
ot receiving the stud
QOLIEca
nnot
QOLIE
be at EV. If one or more of these assessments were not performed at SEV, or if a subject in
be at EV. If one or more of these assessments were not performed at SEV, or if a subject in
be 3 does not have an SEV, then the subject will be excluded from EV for the be 3 does not have an SEV, then the subject will be excluded from EV for the
assessments that were not performed, regardless of the duration of time the subject was not be
assessments that were not performed, regardless of the duration of time the subject was not
used
N01199. Laboratory
used
N01199. Laboratoryat EV. If one or more of these assessments were not performed at SEV, or if a subject in us
ed
at EV. If one or more of these assessments were not performed at SEV, or if a subject in 3 does not have an SEV, then the subject will be excluded from EV for the
used
3 does not have an SEV, then the subject will be excluded from EV for the
to Some subjects in category 3 have data available from an SEV at the time of entryto Some subjects in category 3 have data available from an SEV at the time of entryN01199. Laboratoryto
N01199. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized to parameters, vital signs, and ECGs collected at SEV will be summarized N01199. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized N01199. Laboratoryto
N01199. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized N01199. Laboratory
supp
ort
Subjects in Category 3
supp
ort
Subjects in Category 3
Some subjects in category 3 have data available from an SEV at the time of entrysupp
ort
Some subjects in category 3 have data available from an SEV at the time of entry
any weight recorded at the above study
any weight recorded at the above studymark
eting
summarized at EV. Other assessments were to be performed at the above time points but will
marketi
ng summarized at EV. Other assessments were to be performed at the above time points but will
-P, HADS, EQ-5D
marketi
ng
-P, HADS, EQ-5Dassessed at the above time points for studies N01252, N01253, and N01254.
marketi
ng
assessed at the above time points for studies N01252, N01253, and N01254.
weight recorded at the above studymarketi
ng
weight recorded at the above study
autho
rizati
on
Visit 8 (Week 16)
autho
rizati
on
Visit 8 (Week 16)
The following assessments were to be performed for all
autho
rizati
on
The following assessments were to be performed for all parameters, vital signs, and ECGs; the results for these assessments will be
autho
rizati
on
parameters, vital signs, and ECGs; the results for these assessments will be summarized at EV. Other assessments were to be performed at the above time points but will au
thoriz
ation
summarized at EV. Other assessments were to be performed at the above time points but will
appli
catio
n and
during the transition to N01199. For such subjects, selected assessments from t
and
during the transition to N01199. For such subjects, selected assessments from tany y interruption in study
any y interruption in study
during the transition to N01199. For such subjects, selected assessments from tany
during the transition to N01199. For such subjects, selected assessments from tex
tensio
ns th study
exten
sions
th study
y interruption in studyexten
sions
y interruption in study
or th studyor th studyva
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 15 of 47
3.2.4 Study periods
The study is divided into 3 periods: Evaluation Period, Down-Titration Period, and Post-Treatment Period. A subject is classified as “discontinued” if the subject has a termination case report form (CRF) or has an early discontinuation visit (EDV). A subject is classified as “completed” if this subject completes the full extent of the study as defined in the protocol at database lock.
A “discontinued” subject can be potentially slotted into the 3 periods of the study. The following algorithms will be used to slot the subject appropriately into the Evaluation Period, Down-Titration Period, and Post-Treatment Period.
For Evaluation Period, the start date is the date of first dose of BRV, and the following algorithm is used to determine the end date:
If the subject enters the Down-Titration Period, then the date of EDV is the end date;
If the subject does not enter the Down-Titration Period but meets 1 of the following criteria, the Evaluation Period ends on date of last dose of BRV:
Without an EDV but having a termination CRF,
With an EDV and having a termination CRF,
With an EDV and the date of EDV prior to the database lock date and having no termination CRF.
A subject is considered entering Down-Titration Period only if the subject has an EDV and at least 1 dose of study drug after the date of EDV, the start date of Down-Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period ends on date of last dose of BRV. A subject without an EDV but having a termination CRF or with an EDV but without any dosing of study drug after the EDV will not have the Down-Titration Period, and no artificial Down-Titration Period will be created for analysis.
A subject is considered entering the Post-Treatment Period if the subject has at least 1 contact (scheduled visit, unscheduled visit, or telephone contact) after the date of last dose of BRV. The Post-Treatment Period starts 1 day after date of last dose of BRV irrespective of entering the Down-Titration Period, and there is no end date.
A “completed” subject can potentially have Evaluation Period, Down-Titration Period, or Post-Treatment Period. At the time of study termination by the Sponsor, subjects will discontinue the study drug following the down titration process or will be converted without titration to commercial BRV where available; alternatively, subjects may be initiated without down-titration in a managed access program, named patient program, compassionate use program, or similar type of access program as allowed per country specific requirements in addition to legal and regulatory guidelines.
REDACTED With an EDV and the date of EDV prior to the database lock date and
REDACTED With an EDV and the date of EDV prior to the database lock date and having no termination CRF.
REDACTED having no termination CRF.
A subject is considered entering Down
REDACTED
A subject is considered entering Downdose of studyREDACTED
dose of study
COPY a termination CRF,
COPY a termination CRF,
With an EDV and having a termination CRF,COPY
With an EDV and having a termination CRF,
This do
cumen
t discontinue the study
docu
ment discontinue the study
titration to commercial BRV where available; alternatively
docu
ment
titration to commercial BRV where available; alternatively
cann
ot A “complete
cann
ot A “complete
cann
ot Post
cann
ot Post-
cann
ot -Treatment Period. At the time of studyca
nnot
Treatment Period. At the time of studydiscontinue the studyca
nnot
discontinue the study
be irrespective of entering the Down
be irrespective of entering the Downus
ed t (scheduled visit, unscheduled visit, or telephone contact) after the date of last
used
t (scheduled visit, unscheduled visit, or telephone contact) after the date of last dose of BRV. The Post
used
dose of BRV. The Postirrespective of entering the Downus
ed
irrespective of entering the Down
to A subject is considered entering the Post
to A subject is considered entering the Post
t (scheduled visit, unscheduled visit, or telephone contact) after the date of last to t (scheduled visit, unscheduled visit, or telephone contact) after the date of last su
pport
Titration Period, and no artificial Down
supp
ort Titration Period, and no artificial Down
supp
ort
ys
supp
ort
ysis.
supp
ort
is.
A subject is considered entering the Postsupp
ort
A subject is considered entering the Post
any ut without any
any ut without any
Titration Period, and no artificial Downany
Titration Period, and no artificial Down
marketi
ng A subject is considered entering Down
marketi
ng A subject is considered entering Down
dose of study
marketi
ng
dose of study drug after the date of EDV, the start date of Down-
marketi
ng
drug after the date of EDV, the start date of Down-dose of study drug after the date of EDV, the start date of Down-dose of study
marketi
ng
dose of study drug after the date of EDV, the start date of Down-dose of studyTitration Period is set as 1 day
marketi
ng
Titration Period is set as 1 day after the date of EDV, and the Down-
marketi
ng
after the date of EDV, and the Down-Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period is set as 1 day
marketi
ng
Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period is set as 1 dayends on date of last dose of BRV. A subject without an EDV but having a termination mark
eting
ends on date of last dose of BRV. A subject without an EDV but having a termination ut without anymark
eting
ut without any
autho
rizati
on With an EDV and having a termination CRF,
autho
rizati
on With an EDV and having a termination CRF,
With an EDV and the date of EDV prior to the database lock date and
autho
rizati
on
With an EDV and the date of EDV prior to the database lock date and having no termination CRF.
autho
rizati
on
having no termination CRF.
A subject is considered entering Downautho
rizati
on
A subject is considered entering Down
appli
catio
n Titration Period but meets 1 of the
appli
catio
n Titration Period but meets 1 of the following criteria, the Evaluation Period ends on date of last dose of BRV:
appli
catio
n following criteria, the Evaluation Period ends on date of last dose of BRV:
a termination CRF,
appli
catio
n
a termination CRF,
With an EDV and having a termination CRF,appli
catio
n
With an EDV and having a termination CRF,
and
Titration Period but meets 1 of the and
Titration Period but meets 1 of the
any Titration Period, then the date of EDV is the
any Titration Period, then the date of EDV is the ex
tensio
ns
For Evaluation Period, the start date is the date of first dose of BRV, and the
exten
sions
For Evaluation Period, the start date is the date of first dose of BRV, and the
Titration Period, then the date of EDV is the exten
sions
Titration Period, then the date of EDV is the
or to slot the subject appropriately into the Evaluation Period,
or to slot the subject appropriately into the Evaluation Period, va
riatio
ns
to slot the subject appropriately into the Evaluation Period, varia
tions
to slot the subject appropriately into the Evaluation Period,
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 16 of 47
3.2.5 Monthly time intervals
A month is defined as 30 days and time intervals based on monthly durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The following definitions of 3-month and 6-month intervals are based on 30-day months where the date of first dose of BRV is Day 1:
Interval Duration DefinitionMonths 1-3 Days 1-90Months 4-6 Days 91-180Months 7-9 Days 181-270Months 10-12 Days 271-360
Months 1-6 Days 1-180Months 7-12 Days 181-360Months 13-18 Days 361-540Months 19-24 Days 541-720
Subsequent 3- and 6-month intervals are defined in a similar manner.
Six-month intervals are defined for the evaluation of direct and indirect cost parameters. Statistical summaries for direct and indirect cost parameters will only present results through the first 2 years of treatment. Three-month intervals will be used for analysis of efficacy outcomes and AEs.
End date is the date of last dose of BRV.
For the analysis of efficacy outcomes, a subject is included in the analysis for a 3-month interval if the end date is on or after the last day of the 3-month interval and the subject diary was completed for at least 1 day during the 3-month interval.
For the analysis of AEs, a subject is included in the analysis for a 3-month interval if the end date is on or after the first day of the 3-month interval.
3.2.6 Last Value on BRV Treatment
Last Value for QOLIE-31-P, HADS, EQ-5D, and socio-professional data is the lastassessment strictly after the date of first dose of BRV and up to and including the YEV at the end of the second year and any EDVs for subjects who did not complete through the YEV at the end of the second year.
Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All scheduled and unscheduled assessments within this time period will be considered. Last Value will be determined separately for each laboratory parameter.
REDACTED Statistical summaries for direct and indirect cost parameters will only
REDACTED Statistical summaries for direct and indirect cost parameters will only
month intervals will be used for anal
REDACTED month intervals will be used for anal
End date is the date of last dose of BRV.
REDACTED
End date is the date of last dose of BRV.
COPY month intervals are defined for the evaluation of direct and indirect cost paramete
COPY month intervals are defined for the evaluation of direct and indirect cost paramete
Statistical summaries for direct and indirect cost parameters will onlyCOPY Statistical summaries for direct and indirect cost parameters will only
month intervals will be used for analCOPY
month intervals will be used for anal
This do
cumen
t Last Value for clinical laboratory
docu
ment Last Value for clinical laboratory
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All
docu
ment
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All
cann
ot assessment strictly
cann
ot assessment strictlyend of the second year and any EDVs for subjects who did not complete through the YEV at
cann
ot end of the second year and any EDVs for subjects who did not complete through the YEV at
cann
ot the end of the second
cann
ot the end of the second
be Last Value for QOLIE
be Last Value for QOLIE
assessment strictlybe
assessment strictlyus
ed Last Value on BRV Treatment
used
Last Value on BRV Treatment
Last Value for QOLIEused
Last Value for QOLIE
to Last Value on BRV Treatmentto Last Value on BRV Treatmentsu
pport
was completed for at least 1 day
supp
ort was completed for at least 1 day
is of AEs, a subject is included in the anal
supp
ort
is of AEs, a subject is included in the analdate is on or after the su
pport
date is on or after the first daysupp
ort
first day
any interval if the end date is on or after the
any interval if the end date is on or after the
was completed for at least 1 dayany
was completed for at least 1 day during the 3any during the 3was completed for at least 1 day during the 3was completed for at least 1 dayany
was completed for at least 1 day during the 3was completed for at least 1 daymark
eting
outcomes, a subject is included in the analmark
eting
outcomes, a subject is included in the analinterval if the end date is on or after the mark
eting
interval if the end date is on or after the
autho
rizati
on month intervals are defined for the evaluation of direct and indirect cost paramete
autho
rizati
on month intervals are defined for the evaluation of direct and indirect cost paramete
Statistical summaries for direct and indirect cost parameters will only
autho
rizati
on Statistical summaries for direct and indirect cost parameters will only
month intervals will be used for anal
autho
rizati
on
month intervals will be used for anal
appli
catio
n -month intervals are defined in a similar manner.
appli
catio
n -month intervals are defined in a similar manner.
month intervals are defined for the evaluation of direct and indirect cost parameteappli
catio
n
month intervals are defined for the evaluation of direct and indirect cost parameteStatistical summaries for direct and indirect cost parameters will only
appli
catio
n
Statistical summaries for direct and indirect cost parameters will only
and a
ny ex
tensio
ns or
varia
tions
there
of.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 17 of 47
3.2.7 Exposure duration and exposure duration cohorts
At the final analysis, the overall duration of exposure (or On Treatment Period) will be calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day.
Each subject will be classified into one or more of the following exposure duration cohorts based on the duration of BRV exposure as calculated above:
All subjects ≥1 day
≥3 months ≥90 days
≥6 months ≥180 days
≥12 months ≥360 days
This categorization will continue in 6-month increments past 12 months up to a time point that will be determined based on cumulative exposure at the time of the database lock.
3.2.8 Study visit cohorts
Study visit cohorts are defined for summaries of QOLIE-31-P, HADS, and EQ-5D. Six-month, 12-month, 18-month, and 24-month cohorts are defined. Subjects will be classified into a study visit cohort if they attend the scheduled visit at the time point defined by the cohort. For example, subjects will be included in the 18-month study visit cohort if they attend the scheduled visit at 18 months (ie, FEV at Month 18). Subjects may be classified in more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included in all earlier study visit cohorts (eg, 6-month and 12-month study visit cohorts for subjects in the 18-month study visit cohort), although this may not be the case in the event of a missed visit or if an unscheduled visit is conducted in lieu of a scheduled visit.
3.3 Definition of Baseline Values
Baseline for all study outcomes will be based on baseline from the previous studies. For assessments performed at scheduled and unscheduled visits, Baseline will generally be the last result obtained or prior to the randomization visit of the previous study. Baseline will be defined separately for each hematology, blood chemistry, and urinalysis parameter.
Baseline for the evaluation of seizure frequency and seizure days will be calculated from the core study seizure diary based on the rules defined in Section 3.8.1.
3.4 Protocol deviations
The criteria for identifying important protocol deviations and the classification of importantprotocol deviations will be defined separately in the Specification of Protocol Deviations document. Whenever possible, criteria for identifying important protocol deviations will be implemented algorithmically to ensure consistency in the classification of important protocol deviations across all subjects.
REDACTED months (ie, FEV at Month
REDACTED months (ie, FEV at Monthmore than 1 cohort. Generally, subjects included in a cohort for a later visit will be included
REDACTED more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included
month and 12
REDACTED month and 12
visit cohort), although this may
REDACTED
visit cohort), although this mayvisit or if an unscheduled visit is conducted in lieu of a scheduled visit. REDACTED
visit or if an unscheduled visit is conducted in lieu of a scheduled visit.
COPY attend the scheduled visit at the time point defined by
COPY attend the scheduled visit at the time point defined bycluded in the 18
COPY cluded in the 18
months (ie, FEV at MonthCOPY
months (ie, FEV at Month
This do
cumen
t document. Whenever possible, criteria for identifying important protocol deviations will be
docu
ment document. Whenever possible, criteria for identifying important protocol deviations will be
implemented algorithmically
docu
ment
implemented algorithmically
cann
ot The criteria for identify
cann
ot The criteria for identifyprotocol deviations will be defined separatel
cann
ot protocol deviations will be defined separateldocument. Whenever possible, criteria for identifying important protocol deviations will be ca
nnot
document. Whenever possible, criteria for identifying important protocol deviations will be
be us
ed
Baseline for the evaluation of seizure frequency
used
Baseline for the evaluation of seizure frequencycore study seizure diary based on t
used
core study seizure diary based on t
Protocol deviationsused
Protocol deviations
to Baseline for the evaluation of seizure frequencyto Baseline for the evaluation of seizure frequencycore study seizure diary based on t
to core study seizure diary based on t
supp
ort assessments performed at scheduled and unscheduled visits, Baseline will generall
supp
ort assessments performed at scheduled and unscheduled visits, Baseline will generall
last result obtained or prior to the randomization vi
supp
ort last result obtained or prior to the randomization vi
for each hematology, blood chemistry
supp
ort
for each hematology, blood chemistry
Baseline for the evaluation of seizure frequencysupp
ort
Baseline for the evaluation of seizure frequency
any Baseline for all study outcomes will be based on baseline from the previous studies. For
any Baseline for all study outcomes will be based on baseline from the previous studies. For
any assessments performed at scheduled and unscheduled visits, Baseline will generallany assessments performed at scheduled and unscheduled visits, Baseline will generall
last result obtained or prior to the randomization vian
y
last result obtained or prior to the randomization vi
marketi
ng visit or if an unscheduled visit is conducted in lieu of a scheduled visit.
marketi
ng visit or if an unscheduled visit is conducted in lieu of a scheduled visit.
tion of Baseline Values
marketi
ng
tion of Baseline Values
Baseline for all study outcomes will be based on baseline from the previous studies. For marketi
ng
Baseline for all study outcomes will be based on baseline from the previous studies. For
autho
rizati
on cluded in the 18
autho
rizati
on cluded in the 18
months (ie, FEV at Month
autho
rizati
on
months (ie, FEV at Monthmore than 1 cohort. Generally, subjects included in a cohort for a later visit will be included
autho
rizati
on
more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included month and 12
autho
rizati
on
month and 12 visit cohort), although this mayau
thoriz
ation
visit cohort), although this mayvisit or if an unscheduled visit is conducted in lieu of a scheduled visit. au
thoriz
ation
visit or if an unscheduled visit is conducted in lieu of a scheduled visit.
appli
catio
n P, HADS, and EQ
appli
catio
n P, HADS, and EQmonth cohorts are defined. Subjects will be classified
appli
catio
n month cohorts are defined. Subjects will be classified
attend the scheduled visit at the time point defined by
appli
catio
n
attend the scheduled visit at the time point defined bycluded in the 18 ap
plica
tion
cluded in the 18-appli
catio
n
-month studyappli
catio
n
month study
and
P, HADS, and EQan
d
P, HADS, and EQ
any the database lock.
any the database lock.ex
tensio
ns
month increments past 12 months up to a time point exten
sions
month increments past 12 months up to a time point the database lock.
exten
sions
the database lock.
or va
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 18 of 47
3.5 Analysis populations
3.5.1 Safety Population
The Safety Analysis Set will consist of all subjects who took at least 1 dose of study drug.
Summaries of demographics and baseline characteristics, medical history, AEDs, non-AEDs, HADS, , study drug exposure, and safety outcomes will be provided for the Safety Analysis Set.
3.5.2 Efficacy Populations
Efficacy Analysis Sets will consist of all subjects who took at least 1 dose of study drug and have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy Populations are defined for subjects with focal epilepsy from N01193, N01252, N01253, and N01254 and subjects with generalized epilepsy from N01254.
A subject will be excluded from the Efficacy Analysis Set for POS or PGS if either they did not receive at least 1 dose of BRV, or the clinical database indicates that the daily seizure diary was not completed for any days on or after the first dose of BRV and on or prior to the end date of the Evaluation Period (see Section 8).
Seizure outcomes will be summarized for either the Efficacy Analysis Set for POS or the Efficacy Analysis Set for PGS. Summaries of epilepsy history, QOLIE-31-P, and EQ-5D will be provided for the Efficacy Analysis Sets for both POS and PGS.
3.6 Treatment Assignment and Treatment Groups
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally adjusted for each subject. Generally, statistical summaries will present all subjects combined as a single treatment arm unless otherwise indicated.
3.7 Coding dictionaries
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be coded using the World Health Organization Drug Reference List (WHO-DRL). Prior and concomitant medical procedures will not be coded.
3.8 Definitions of study-specific derived variables
3.8.1 Calculation of seizure frequency/days
3.8.1.1 Initial seizure data processing
Each seizure code in the clinical database will be mapped to exactly 1 of the following codes based on the 1981 International League Against Epilepsy (ILAE) classification: I, IA, IA1, IA2, IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III.
With regard to cluster seizures, investigator sites are to report the number of cluster episodes rather than reporting the estimated number of individual seizures. Therefore, no imputation will be applied for the seizure counts corresponding to reports of cluster seizures.
REDACTED is Sets for both POS and PGS.
REDACTED is Sets for both POS and PGS.
ssignment and Treatment Groups
REDACTED ssignment and Treatment Groups
in which all subjects receive BRV in doses that are optimally
REDACTED
in which all subjects receive BRV in doses that are optimallysted for each subject. Generally, statistical summaries will present all subjects combined REDACTED
sted for each subject. Generally, statistical summaries will present all subjects combined
COPY Seizure outcomes will be summarized for either the Efficacy
COPY Seizure outcomes will be summarized for either the Efficacyies of epilepsy
COPY ies of epilepsy
is Sets for both POS and PGS. COPY
is Sets for both POS and PGS.
This do
cumen
t based on the 1981 International League Against Epilepsy
docu
ment based on the 1981 International League Against Epilepsy
IA
docu
ment IA2, IA3, IA4, IB, IB1, IB2, IC, II,
docu
ment 2, IA3, IA4, IB, IB1, IB2, IC, II, ca
nnot Each seizure code in the clinical database will be mapped to exactly
cann
ot Each seizure code in the clinical database will be mapped to exactlybased on the 1981 International League Against Epilepsyca
nnot
based on the 1981 International League Against Epilepsy
be us
ed Definitions of study
used
Definitions of study
3.8.1 Calculation of seizure frequencyused
3.8.1 Calculation of seizure frequency
to Definitions of studyto Definitions of studysu
pport
and AEs will be coded using the Medical Dictionary
supp
ort and AEs will be coded using the Medical Dictionary
s (MedDRA). Medications will be coded using the World Health Organization Drug
supp
ort
s (MedDRA). Medications will be coded using the World Health Organization Drug Reference List (WHO
supp
ort
Reference List (WHO-su
pport
-DRLsu
pport
DRL
Definitions of studysu
pport
Definitions of study
any
Coding dictionaries
any
Coding dictionaries
and AEs will be coded using the Medical Dictionaryany
and AEs will be coded using the Medical Dictionarys (MedDRA). Medications will be coded using the World Health Organization Drug
any
s (MedDRA). Medications will be coded using the World Health Organization Drug
marketi
ng in which all subjects receive BRV in doses that are optimally
marketi
ng in which all subjects receive BRV in doses that are optimally
sted for each subject. Generally, statistical summaries will present all subjects combined
marketi
ng sted for each subject. Generally, statistical summaries will present all subjects combined
as a single treatment arm unless otherwise indicated.
marketi
ng
as a single treatment arm unless otherwise indicated.
Coding dictionariesmarketi
ng
Coding dictionaries
autho
rizati
on ies of epilepsy
autho
rizati
on ies of epilepsy history
autho
rizati
on historyies of epilepsy historyies of epilepsy
autho
rizati
on ies of epilepsy historyies of epilepsy
is Sets for both POS and PGS.
autho
rizati
on
is Sets for both POS and PGS.
ssignment and Treatment Groups
autho
rizati
on
ssignment and Treatment Groups
in which all subjects receive BRV in doses that are optimallyautho
rizati
on
in which all subjects receive BRV in doses that are optimallysted for each subject. Generally, statistical summaries will present all subjects combined
autho
rizati
on
sted for each subject. Generally, statistical summaries will present all subjects combined
appli
catio
n on or after the first dose of BRV and on or prior to the
appli
catio
n on or after the first dose of BRV and on or prior to the
Seizure outcomes will be summarized for either the Efficacyap
plica
tion
Seizure outcomes will be summarized for either the Efficacy Analyap
plica
tion
AnalySeizure outcomes will be summarized for either the Efficacy AnalySeizure outcomes will be summarized for either the Efficacyap
plica
tion
Seizure outcomes will be summarized for either the Efficacy AnalySeizure outcomes will be summarized for either the Efficacy historyap
plica
tion
history
and
is Set for POS or PGS if either they did
and
is Set for POS or PGS if either they did not receive at least 1 dose of BRV, or the clinical database indicates that the daily
and not receive at least 1 dose of BRV, or the clinical database indicates that the daily
on or after the first dose of BRV and on or prior to the and
on or after the first dose of BRV and on or prior to the
any
is Set for POS or PGS if either they did any
is Set for POS or PGS if either they did
exten
sions
is Sets will consist of all subjects who took at least 1 dose of study
exten
sions
is Sets will consist of all subjects who took at least 1 dose of study drug and
exten
sions
drug and is Sets will consist of all subjects who took at least 1 dose of study drug and is Sets will consist of all subjects who took at least 1 dose of study
exten
sions
is Sets will consist of all subjects who took at least 1 dose of study drug and is Sets will consist of all subjects who took at least 1 dose of studyy during the Evaluation Period. Separate Efficacy
exten
sions
y during the Evaluation Period. Separate Efficacy Populations
exten
sions
Populations y during the Evaluation Period. Separate Efficacy Populations y during the Evaluation Period. Separate Efficacy
exten
sions
y during the Evaluation Period. Separate Efficacy Populations y during the Evaluation Period. Separate Efficacy
y from N01193, N01252, N01253, and N01254 and
exten
sions
y from N01193, N01252, N01253, and N01254 and
or drug and or drug and
varia
tions
there
of.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 19 of 47
3.8.1.2 Calculation of adjusted seizure frequency
The following derivations apply only to subjects with Partial Onset Seizures.
Baseline POS frequency for seizure types I, IA, IB, IC, and for all seizure types (I+II+III) will be obtained from the Baseline Period of the previous double-blind study.
The total number of seizures for seizure types I, IA, IB, and IC, and the total number of seizures for all seizure types (I+II+III) will be calculated overall, by 3-month time intervals, and over the cohort interval for each exposure duration cohort.
All seizure diary during evaluation period will be considered for these calculations.
Twenty-eight day adjusted seizure frequency for seizure types I, IA, IB, and IC, and for all seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and over each exposure duration cohort interval by dividing the total number of seizures for each seizure type by the number of days for which the diary was completed overall, within each 3-month interval, and within each exposure duration cohort interval, and multiplying the resulting value by 28.
3.8.1.3 Calculation of adjusted seizure days
The following derivations apply only to subjects with All Other Seizure Types, based on the 1981 ILAE classification, All Other Seizure Types include the generalized seizure types and unclassified seizure types.
Baseline seizure days for seizure types II, IIA through IIF, and for all seizure types (I+II+III) will be obtained from the Baseline Period of the previous study.
The total number of seizure days for seizure types II, IIA through IIF, and the total number of seizure days for all seizure types (I+II+III) will be calculated overall, by 3 month time intervals, and over the cohort interval for each exposure duration cohort. The same seizure diary data defined in the Section 3.8.1.2 for POS frequency will be considered.
Twenty-eight day adjusted seizure days for seizure types II, IIA through IIF, and for all seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and over each exposure duration cohort interval by dividing the total number of seizure days for each seizure type by the number of days for which the diary was completed overall (ie, over the periods defined in the Section 3.8.1.2), within each 3-month interval, and within each exposure duration cohort interval, and multiplying the resulting value by 28.
3.8.2 QOLIE-31-P
The QOLIE-31-P is an adaptation of the original QOLIE-31 (Cramer et al, 1998). The QOLIE-31-P includes 30 items grouped into 7 multi-item subscales (seizure worry [5 items], overall quality of life [2 items], emotional well-being [5 items], energy/fatigue [4 items], cognitive functioning [6 items], medication effects [3 items], and social function [5 items]) and a health status item. The QOLIE-31-P total score, subscale scores, and health status item score are calculated according to the scoring algorithm described below, with scores ranging from 0 to 100 and higher scores indicating better functioning. In addition to these 31 items,
REDACTED II, IIA through IIF, and for all seizure ty
REDACTED II, IIA through IIF, and for all seizure ty
will be obtained from the Baseline Period of the previous study
REDACTED
will be obtained from the Baseline Period of the previous study
for seizure tREDACTED
for seizure t
COPY y to subjects with All Other Seizure Types, based on the
COPY y to subjects with All Other Seizure Types, based on the pes include the generalized seizure ty
COPY pes include the generalized seizure ty
This do
cumen
t QOLIE
docu
ment QOLIE
overall quality
docu
ment
overall quality
cann
ot The QOLIE
cann
ot The QOLIEQOLIEca
nnot
QOLIE
be exposure duration cohort interval, and multiply
be exposure duration cohort interval, and multiplyus
ed the periods defined in the
used
the periods defined in the exposure duration cohort interval, and multiplyus
ed
exposure duration cohort interval, and multiply
to e b to e by the number of days for which the diary was completed overall (ie, over to y the number of days for which the diary was completed overall (ie, over the periods defined in the
to the periods defined in the
supp
ort adjusted seizure day
supp
ort adjusted seizure day
pes (I+II+III) will be calculated overall, within each 3
supp
ort
pes (I+II+III) will be calculated overall, within each 3over each exposure duration cohort interval bsu
pport
over each exposure duration cohort interval by the number of days for which the diary was completed overall (ie, over su
pport
y the number of days for which the diary was completed overall (ie, over
any ection
any ection
adjusted seizure dayany
adjusted seizure day
marketi
ng for seizure t
marketi
ng for seizure t
(I+II+III) will be calculated overall, by
marketi
ng
(I+II+III) will be calculated overall, byintervals, and over the cohort interval for each exposure durat
marketi
ng
intervals, and over the cohort interval for each exposure duratmark
eting
3.8.1.2marketi
ng
3.8.1.2
autho
rizati
on pes include the generalized seizure ty
autho
rizati
on pes include the generalized seizure ty
II, IIA through IIF, and for all seizure ty
autho
rizati
on
II, IIA through IIF, and for all seizure tywill be obtained from the Baseline Period of the previous study
autho
rizati
on
will be obtained from the Baseline Period of the previous study
for seizure tauth
oriza
tion
for seizure t
appli
catio
n
y to subjects with All Other Seizure Types, based on the ap
plica
tion
y to subjects with All Other Seizure Types, based on the pes include the generalized seizure tyap
plica
tion
pes include the generalized seizure ty
and month interval, and within each exposure duration cohort interval, and multiply
and month interval, and within each exposure duration cohort interval, and multiplyan
y y the number of days for which the diary was completed overall, within each an
y y the number of days for which the diary was completed overall, within each month interval, and within each exposure duration cohort interval, and multiplyan
y month interval, and within each exposure duration cohort interval, and multiply
exten
sions
C, and for all
exten
sions
C, and for all
-month time interval, and
exten
sions
-month time interval, and r of seizures for each ex
tensio
ns
r of seizures for each
or va
riatio
ns
month time intervals,
varia
tions
month time intervals,
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 20 of 47
the QOLIE-31-P includes 7 items assessing the degree of “distress” associated with the topic of each subscale (ie, distress items) and 1 item asking about the relative importance of each subscale topic (ie, prioritization item).
Subscale Scores
As a first step to calculating the subscale scores, the individual responses for the 30 subscale items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled values for each item are defined in Section 13.1. Each subscale score is then calculated by summing the rescaled responses for that subscale and dividing by the number of items without a missing response. A subscale score will be calculated only if at least 50% of the items within the subscale are present.
Total Score
Total score is calculated as a weighted sum of the subscale scores based on the weighting in Section 13.1. Total score will be missing if at least 1 subscale score is missing. Total score will range from 0 to 100 with a higher score reflecting better functioning.
Health Status Item
Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher score corresponding to a better health status. The health status item response is analyzed without rescaling.
Distress Items
Each subscale includes 1 distress item. The response for each distress item is an integer ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale (ie, 0, 25, 50, 75, and 100) with a higher score corresponding to greater distress.
Prioritization Item
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. The prioritization ranking is analyzed without rescaling.
3.8.3 HADS
The HADS assessment consists of 14 items that are each scored on a 4-point scale ranging from 0 to 3, with a higher score corresponding to worse anxiety or depression. The depression and anxiety scores will be calculated by summing the scores for the items corresponding to each subscale, as described in the Hospital Anxiety and Depression Scale Manual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all even-numbered items; the anxiety score is calculated as the sum of all odd-numbered items. Scores for each subscale range from 0 to 21, with higher scores corresponding to a greater level of anxiety or depression.
Missing items will be replaced by the mean of non missing items from the same subscale when calculating the above, provided at least 50% of the items (ie, at least 4 of 7 items) within the subscale are present. A subscale score will not be calculated if more than 50% of the items are missing within a subscale. This rule applies separately to the subscale scores for
REDACTED
Each subscale includes 1 distress item. The response for each distress item is an integer
REDACTED
Each subscale includes 1 distress item. The response for each distress item is an integer ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale
REDACTED
ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale th a higher score corresponding to greater distress.REDACTED
th a higher score corresponding to greater distress.
COPY Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher
COPY Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher score corresponding to a better health status. The health status item response is ana
COPY score corresponding to a better health status. The health status item response is ana
This do
cumen
t Scores for e
docu
ment Scores for e
level of anxiety or depression.
docu
ment
level of anxiety or depression.
cann
ot corresponding to each sub
cann
ot corresponding to each subManual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all
cann
ot Manual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all even
cann
ot even-
cann
ot -numbered items; the anxietyca
nnot
numbered items; the anxietyScores for eca
nnot
Scores for e
be depression and anxiety
be depression and anxiety
corresponding to each subbe
corresponding to each subus
ed from 0 to 3, with a higher score corresponding to worse anxiety
used
from 0 to 3, with a higher score corresponding to worse anxiety
used
depression and anxietyus
ed
depression and anxiety
to The HADS assessment consisto The HADS assessment consisfrom 0 to 3, with a higher score corresponding to worse anxiety
to from 0 to 3, with a higher score corresponding to worse anxiety
supp
ort The prioritization ranking is anal
supp
ort The prioritization ranking is anal
The HADS assessment consissupp
ort
The HADS assessment consis
any The response for each subscale for the prioritization item is an integer ranging from 1 to 7.
any The response for each subscale for the prioritization item is an integer ranging from 1 to 7.
The prioritization ranking is analany
The prioritization ranking is anal
marketi
ng ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale
marketi
ng ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale
th a higher score corresponding to greater distress.
marketi
ng
th a higher score corresponding to greater distress.
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. mark
eting
The response for each subscale for the prioritization item is an integer ranging from 1 to 7.
autho
rizati
on score corresponding to a better health status. The health status item response is ana
autho
rizati
on score corresponding to a better health status. The health status item response is ana
Each subscale includes 1 distress item. The response for each distress item is an integer au
thoriz
ation
Each subscale includes 1 distress item. The response for each distress item is an integer ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale au
thoriz
ation
ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale
appli
catio
n
Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher
appli
catio
n
Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher score corresponding to a better health status. The health status item response is anaap
plica
tion
score corresponding to a better health status. The health status item response is ana
and
. Total score will be missing if at least 1 subscale score is m
and
. Total score will be missing if at least 1 subscale score is mto 100 with a higher score reflecting better functioning.an
d to 100 with a higher score reflecting better functioning.an
y ale scores based on the weighting in
any ale scores based on the weighting in
. Total score will be missing if at least 1 subscale score is many
. Total score will be missing if at least 1 subscale score is missing. Total score any
issing. Total score
exten
sions
items without a missing response. A subscale score will be calculated only if at least 50% of
exten
sions
items without a missing response. A subscale score will be calculated only if at least 50% of
ale scores based on the weighting in exten
sions
ale scores based on the weighting in
or y the number of
or y the number of
items without a missing response. A subscale score will be calculated only if at least 50% of or items without a missing response. A subscale score will be calculated only if at least 50% of va
riatio
ns
y the number of varia
tions
y the number of
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 21 of 47
anxiety and depression; for example, it may be possible to calculate the depression score in cases where the anxiety score is not calculated due to non response.
3.9 Subject site transfers
Subjects may have transferred from one site to another through the course of participation in the study. Subjects that transferred from one site to another site, for whatever reason, have generally retained their subject number. However, in some cases, the subject number changed. When this is true, the most recently assigned subject number will be used for analyses and subject data listings. A record of any change in subject numbers will be presented in the Section 13.2.
4 STATISTICAL/ANALYTICAL ISSUES
4.1 Adjustments for covariates
No statistical testing is planned; therefore, this section is not applicable.
4.2 Handling of dropouts or missing data
Seizure frequency (subjects with POS) and seizure days (subjects with PGS) will be calculated over non missing diary days during each study period or time interval as described in Section 3.2.4 and Section 3.2.5 ; diary days for which seizure data were not obtained will not be considered in the calculation of seizure frequency or seizure days. Because the evaluation of efficacy is not the primary objective of this study, and because this is an uncontrolled study in a variable setting, which allows individualized optimization of dosing of BRV and concomitant AEDs, no summaries assessing the impact of missing seizure diary days are planned.
For subjects who prematurely discontinue during the Evaluation Period, the calculation of POS frequency and PGS seizure days will be based on available seizure diary while the subject was receiving BRV. The presence of such dropouts may influence the evaluation of the long-term outcomes for subjects who either do not discontinue or do not discontinue early in the study. Therefore, as described below, selected summaries will be produced by exposure duration cohorts to allow an assessment of long-term outcomes without the potentially confounding influence of earlier discontinuations.
4.3 Interim analyses and data monitoring
Interim summaries may be produced to support regulatory submissions for marketing authorization while this study is ongoing. There are no statistical concerns with such interim assessments for this study design.
4.4 Multicenter studies
Efficacy and safety outcomes will not be assessed for individual investigator sites due to the low expected number for enrollment within each investigator site.
4.5 Multiple comparisons/multiplicity
No statistical testing is planned; therefore, this section is not applicable.
REDACTED objective of this study
REDACTED objective of this study in a variable setting, which allows individualized optimization of dosing
REDACTED in a variable setting, which allows individualized optimization of dosing
AEDs, no summaries assessing the impact of missing seizure diary
REDACTED
AEDs, no summaries assessing the impact of missing seizure diary
For subjects who prematurely discontinue during the Evaluation Period, the calculation of REDACTED
For subjects who prematurely discontinue during the Evaluation Period, the calculation of
COPY s during each study
COPY s during each studys for which seizure data were not obtained will
COPY s for which seizure data were not obtained will of seizure frequency
COPY of seizure frequency
objective of this studyCOPY
objective of this study
This do
cumen
t 4.4
docu
ment 4.4
Efficacy
docu
ment
Efficacy
cann
ot authorization while this study
cann
ot authorization while this studyassessments for this study design.
cann
ot assessments for this study design.
be Interim summaries may
be Interim summaries may
authorization while this studybe
authorization while this study
used
Interim analy
used
Interim analy
Interim summaries mayused
Interim summaries may
to confounding influence of earlier discontinuations.
to confounding influence of earlier discontinuations.
Interim analyto
Interim analy
supp
ort the long-term outcomes for subjects who either do not discontinue or do not discontinue earl
supp
ort the long-term outcomes for subjects who either do not discontinue or do not discontinue earl
supp
ort . Therefore, as described below, selected summaries will
supp
ort . Therefore, as described below, selected summaries will
duration cohorts to allow an assessment of long
supp
ort
duration cohorts to allow an assessment of longconfounding influence of earlier discontinuations.su
pport
confounding influence of earlier discontinuations.
any subject was receiving BRV. The presence of such dropouts may
any subject was receiving BRV. The presence of such dropouts may
the long-term outcomes for subjects who either do not discontinue or do not discontinue earlany the long-term outcomes for subjects who either do not discontinue or do not discontinue earl
. Therefore, as described below, selected summaries will an
y
. Therefore, as described below, selected summaries will
marketi
ng
For subjects who prematurely discontinue during the Evaluation Period, the calculation of
marketi
ng
For subjects who prematurely discontinue during the Evaluation Period, the calculation of and PGS seizure day
marketi
ng
and PGS seizure days will be based on available seizure diarymark
eting
s will be based on available seizure diarysubject was receiving BRV. The presence of such dropouts maymark
eting
subject was receiving BRV. The presence of such dropouts may
autho
rizati
on of seizure frequency
autho
rizati
on of seizure frequency
objective of this study
autho
rizati
on
objective of this study in a variable setting, which allows individualized optimization of dosing
autho
rizati
on
in a variable setting, which allows individualized optimization of dosing AEDs, no summaries assessing the impact of missing seizure diary
autho
rizati
on
AEDs, no summaries assessing the impact of missing seizure diary
appli
catio
n s (subjects with PGS) will be
appli
catio
n s (subjects with PGS) will be
period or time interval as described
appli
catio
n
period or time interval as described s for which seizure data were not obtained will ap
plica
tion
s for which seizure data were not obtained will of seizure frequencyap
plica
tion
of seizure frequency or seizure dayappli
catio
n
or seizure dayof seizure frequency or seizure dayof seizure frequencyappli
catio
n
of seizure frequency or seizure dayof seizure frequency
and
No statistical testing is planned; therefore, this section is not applicable.
and
No statistical testing is planned; therefore, this section is not applicable.any No statistical testing is planned; therefore, this section is not applicable.any No statistical testing is planned; therefore, this section is not applicable.ex
tensio
ns or
varia
tions
there
of.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 22 of 47
4.6 Use of an “Efficacy Subset” of subjects
All subjects who receive at least 1 dose of study drug and have at least 1 diary record during the Evaluation Period will be included in efficacy summaries. No additional efficacy subsets are defined for this study.
4.7 Active-control studies intended to show equivalence
This section is not applicable for this study.
4.8 Examination of subgroups
Selected summaries will be provided for the following subgroups as specified within each of the following sections;
Seizure type (Partial Onset Seizures, Primary Generalized Seizures)
Geographic region (Latin America, North America, Asia/Pacific/Other). A mapping of countries to geographic regions is defined as
Geographic Region CountryNorth America Canada, United States, Puerto RicoLatin America Brazil, MexicoAsia/Pacific/Other Australia, Hong Kong, India, Israel, Japan, Singapore,
South Africa, Republic of Korea, Taiwan, Tunisia
Randomized treatment in the previous study (placebo [PBO], BRV) (TEAEs only)
5 STUDY POPULATION CHARACTERISTICS
5.1 Subject disposition
Due to differences in data format across studies, in order to facilitate summary of subject disposition, the reasons for discontinuation for individual studies will be collapsed as follows for summaries:
LTFU Category CRF ReasonADVERSE EVENT ADVERSE EVENTLACK OF EFFICACY LACK OF EFFICACY
LOSS OF EFFICACYLOST TO FOLLOW-UP LOST TO FOLLOW-UPSUBJECT CHOICE CONSENT WITHDRAWN
WITHDRAWAL OF CONSENT FOR PERSONAL REASONS NOT RELATED TO AESWITHDRAWAL OF CONSENT FOR PERSONAL REASONS NOT RELATED TO AES OR LACK OF EFFICACY
OTHER PROTOCOL VIOLATIONOTHER REASONOTHER
REDACTED South Africa, Republic of Korea, Taiwan, Tunisia
REDACTED South Africa, Republic of Korea, Taiwan, Tunisia
REDACTED Randomized treatment in the previous study
REDACTED Randomized treatment in the previous study
STUDY POPULA
REDACTED
STUDY POPULATION CHA
REDACTED
TION CHA
Subject dispositionREDACTED
Subject disposition
COPY Hong Kong, India, I
COPY Hong Kong, India, I
South Africa, Republic of Korea, Taiwan, TunisiaCOPY
South Africa, Republic of Korea, Taiwan, TunisiaCOPY
COPY
This do
cumen
t
docu
ment c
anno
t SUBJECT CHOI
cann
ot SUBJECT CHOIbe
LOST TO FOLLOW
be LOST TO FOLLOW
be
SUBJECT CHOIbe
SUBJECT CHOIbe us
ed
LOST TO FOLLOWused
LOST TO FOLLOWus
ed to
CACYto CACYsu
pport
supp
ort
ADVERSE EVENT supp
ort
ADVERSE EVENT supp
ort
CACYsu
pport
CACYsu
pport
any the reasons for discontinuation for individual studies will be collapsed as follows
any the reasons for discontinuation for individual studies will be collapsed as follows mark
eting
Subject disposition
marketi
ng
Subject disposition
Due to differences in data format across studies, mark
eting
Due to differences in data format across studies, the reasons for discontinuation for individual studies will be collapsed as follows mark
eting
the reasons for discontinuation for individual studies will be collapsed as follows
autho
rizati
on Hong Kong, India, I
autho
rizati
on Hong Kong, India, I
South Africa, Republic of Korea, Taiwan, Tunisia
autho
rizati
on
South Africa, Republic of Korea, Taiwan, Tunisia
autho
rizati
on
Randomized treatment in the previous study
autho
rizati
on
Randomized treatment in the previous study (placebo [PBO], BRV) (TEAEs only
autho
rizati
on
(placebo [PBO], BRV) (TEAEs onlyRandomized treatment in the previous study (placebo [PBO], BRV) (TEAEs onlyRandomized treatment in the previous study
autho
rizati
on
Randomized treatment in the previous study (placebo [PBO], BRV) (TEAEs onlyRandomized treatment in the previous study
TION CHAautho
rizati
on
TION CHA
appli
catio
n Canada, United States, Puerto Rico
appli
catio
n Canada, United States, Puerto Rico
appli
catio
n
appli
catio
n
Hong Kong, India, Iappli
catio
n
Hong Kong, India, Iappli
catio
n and
an
d any
egion (Latin America, North America, Asia/Pacific/Other). A mapping of an
y egion (Latin America, North America, Asia/Pacific/Other). A mapping of ex
tensio
ns Selected summaries will be provided for the following subgroups as specified within each of
exten
sions
Selected summaries will be provided for the following subgroups as specified within each of or
Selected summaries will be provided for the following subgroups as specified within each of or
Selected summaries will be provided for the following subgroups as specified within each of
varia
tions
there
of.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 23 of 47
LTFU Category CRF ReasonMISSING If subject discontinued the study and the termination CRF is
not available
Only 1 primary reason for discontinuation should have been reported. In the event that more than 1 reason is specified in the clinical database, both reasons will be summarized and a footnote will be added to the summary table to indicate that at least 1 subject is counted for multiple reasons for discontinuation.
An overall summary of disposition will be provided for all enrolled subjects (ie, all subjects who signed informed consent). The following will be summarized:
The number of subjects in the Safety Analysis Set
The number of subjects excluded from the Safety Analysis Set
The number of subjects who have completed the study
The number of subjects who have discontinued from the study, including the reason for discontinuation. If subject discontinued the study and the termination CRF is not available, the reason for discontinuation will be reported as “MISSING”.
Additionally, an overall summary of disposition will present the following for subjects in the Safety Analysis Set:
The number of subjects completing the study (final analysis only)
The overall number of subjects discontinuing and the number of subjects discontinuing by primary reason for discontinuation. If subject discontinued the study and the termination CRF is not available, the reason for discontinuation will be reported as “MISSING”.
Overall subject disposition will also be summarized by geographic region and seizure typefor the Safety Analysis Set.
The number of subjects within each geographic region and the number of subjects with each seizure type will be summarized for the Safety Analysis Set.
Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 24, 36, 48, and 60 months of treatment with BRV will be provided. This analysis will be based on the duration of exposure to BRV as defined in Section 3.2.7. Subjects who have permanently discontinued will be analyzed as events on the last day of treatment with study drug; subjects who complete the study will be censored on the last day of treatment with study drug.
The date of first subject in (date of earliest Visit 1), date of last subject out (date of last scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in each analysis set or seizure type will be summarized overall and by investigator site. Subjects who transferred sites will be summarized according to their original site.
5.2 Protocol Deviations
The number and percentage of subjects with at least 1 important protocol deviation will be summarized overall and by category of protocol deviation for the Safety Analysis Set.
REDACTED The number of subjects completing the study
REDACTED The number of subjects completing the study
The overall number of subjects discontinuing and the number
REDACTED
The overall number of subjects discontinuing and the number reason for discontinuation. I
REDACTED
reason for discontinuation. If subject discontinued the studyREDACTED
f subject discontinued the studyCRF is not available, the reason for discontinuation will be reported as “MISSIREDACTED
CRF is not available, the reason for discontinuation will be reported as “MISSI
COPY of disposition will present the following for subjects in the
COPY of disposition will present the following for subjects in the
This do
cumen
t scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in
docu
ment scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in
each anal
docu
ment
each analSubjects who transferr
docu
ment
Subjects who transferr
cann
ot who complete the stud
cann
ot who complete the stud
cann
ot The date of first subject in (date of earl
cann
ot The date of first subject in (date of earlscheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in ca
nnot
scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in
be discontinued will be analy
be discontinued will be analy
who complete the studbe
who complete the studus
ed months of treatment with BRV will be provided. This anal
used
months of treatment with BRV will be provided. This analduration of exposure to BRV as defined in Section
used
duration of exposure to BRV as defined in Sectiondiscontinued will be analyus
ed
discontinued will be analy
to Meier estimates of the percenta
to Meier estimates of the percenta
months of treatment with BRV will be provided. This analto months of treatment with BRV will be provided. This analsu
pport
The number of subjects within each geographic region and the number of subjects with each
supp
ort The number of subjects within each geographic region and the number of subjects with each
will be summarized for the Safety
supp
ort
will be summarized for the Safety
Meier estimates of the percentasupp
ort
Meier estimates of the percentamonths of treatment with BRV will be provided. This anal
supp
ort
months of treatment with BRV will be provided. This anal
any
The number of subjects within each geographic region and the number of subjects with each any
The number of subjects within each geographic region and the number of subjects with each
marketi
ng f subject discontinued the study
marketi
ng f subject discontinued the study
CRF is not available, the reason for discontinuation will be reported as “MISSI
marketi
ng
CRF is not available, the reason for discontinuation will be reported as “MISSI
marketi
ng
Overall subject disposition will also be summarized
marketi
ng
Overall subject disposition will also be summarized
autho
rizati
on
The number of subjects completing the study
autho
rizati
on
The number of subjects completing the study (final analy
autho
rizati
on
(final analyThe number of subjects completing the study (final analyThe number of subjects completing the study
autho
rizati
on
The number of subjects completing the study (final analyThe number of subjects completing the study
The overall number of subjects discontinuing and the number
autho
rizati
on
The overall number of subjects discontinuing and the numberf subject discontinued the studyau
thoriz
ation
f subject discontinued the study
appli
catio
n who have discontinued from the study
appli
catio
n who have discontinued from the study
and the termination CRF is not
appli
catio
n and the termination CRF is not available, the reason for discontinuation will be reported
appli
catio
n available, the reason for discontinuation will be reported as “MISSING”.
appli
catio
n as “MISSING”.
of disposition will present the following for subjects in the ap
plica
tion
of disposition will present the following for subjects in the
and who have discontinued from the study and who have discontinued from the study, including the reason for and , including the reason for
and the termination CRF is not an
d
and the termination CRF is not
any e
xtens
ions o
r l be provided for all enrolled subjects (ie, all subjects or
l be provided for all enrolled subjects (ie, all subjects varia
tions
l be provided for all enrolled subjects (ie, all subjects varia
tions
l be provided for all enrolled subjects (ie, all subjects
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 24 of 47
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
6.1 Demographics
Demographics summaries will be based on demographic data from follow-up studies for subjects who enrolled in a follow-up study that collected demographic data. Otherwise, demographics summaries will be based on demographic data collected in the previous double-blind study.
Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety Analysis Set. Demographic data will be summarized overall and by subgroup for seizure typeand geographic region.
Racial group was not collected in a consistent manner across studies. For this reason, racial group will be collapsed as follows for statistical summaries:
• Category • CRF Racial Group
• American Indian/Alaskan Native
• American Indian/Alaskan Native
• Asian • Asian, Asian/Pacific Islander, Indian/Pakistani
• Black • Black, African-American
• Native Hawaiian or Other Pacific Islander
• Native Hawaiian or Other Pacific Islander
• White • White, Caucasian, Hispanic
• Other/Mixed • Other, Other/Mixed, Mixed Race
moreover, the overall racial group will be collapsed as follows for statistical summaries:
Category Racial Group from Previous StudyWhite White, Caucasian, HispanicBlack Black, African-AmericanAsian Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander,
Indian/PakistaniOther American Indian/Alaskan Native, Other, Other/Mixed
All subjects should be classified into one of the above categories.
Racial group, ethnicity (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup (Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all studies; these variables will be provided in subject data listings if available in the clinical data from the previous study but will not be summarized.
(Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all
docu
ment
(Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all studies; these variabl
docu
ment
studies; these variabl
cann
ot All subjects
cann
ot All subjects
Racial group, ethnicitcann
ot
Racial group, ethnicit
be us
ed Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander,
used
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, to Black, Africanto Black, African
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, to
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander,
supp
ort
Racial Group from
supp
ort
Racial Group from
supp
ort
White, Caucasian, Hispanicsu
pport
White, Caucasian, HispanicBlack, Africansu
pport
Black, African
any moreover, the overall racial group will be collapsed as follows for statistical summaries:any moreover, the overall racial group will be collapsed as follows for statistical summaries:mark
eting
•
marketi
ng
• White, Caucasian, Hispanic
marketi
ng
White, Caucasian, Hispanic
•marketi
ng
•
autho
rizati
on
Asian, Asian/Pacific Islander, Indian/Pakistani
autho
rizati
on
Asian, Asian/Pacific Islander, Indian/Pakistani
Black, African
autho
rizati
on
Black, African
Native Hawaiian or Other Pacific Islanderautho
rizati
on
Native Hawaiian or Other Pacific Islander
appli
catio
n CRF Racial Group
appli
catio
n CRF Racial Group
Indian/Alaskan Nativeap
plica
tion
Indian/Alaskan Native
and Racial group was not collected in a consistent manner across studies. For this reason, racial
and Racial group was not collected in a consistent manner across studies. For this reason, racial an
y Racial group was not collected in a consistent manner across studies. For this reason, racial an
y Racial group was not collected in a consistent manner across studies. For this reason, racial
exten
sions
ears), gender, racial group and overall racial
exten
sions
ears), gender, racial group and overall racial mass index (BMI) (kg/m
exten
sions
mass index (BMI) (kg/m ), and BMI
exten
sions
), and BMI
will be summarized for the Safet
exten
sions
will be summarized for the Safet
subgroup for ex
tensio
ns
subgroup for
or ears), gender, racial group and overall racial or ears), gender, racial group and overall racial va
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 25 of 47
6.2 Medical and procedure history
6.2.1 Medical history diseases
The summary of medical history will be based on the medical history at the time of entry into the previous study.
The number and percentage of subjects with a medical history condition, including both resolved and ongoing conditions at the time of entry into the previous study, will be summarized overall and by primary MedDRA system organ class (SOC) and preferred term (PT) for the Safety Analysis Set.
6.2.2 Procedure history and concomitant procedures
Medical procedures are not coded and will only be provided in subject data listings.
6.3 History of epilepsy
All of the following are summarized using data collected at the time of entry into the previous studies or from the Baseline Period of the previous studies.
6.3.1 Etiology of epilepsy
The number and percentage of subjects with each type of etiology as specified on the CRF (genetic, congenital, etc) from the previous studies will be summarized for the Efficacy Analysis Sets for POS and PGS. A subject will be counted as having a particular etiology if that etiology was either confirmed or suspected based on the investigator's assessment.
6.3.2 Epileptic seizure profile
The number and percentage of subjects experiencing each seizure type at any time prior to study entry will be summarized for the Efficacy Analysis Sets for POS and PGS. The following seizure types will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA through IIF, III, and IV. A subject with a history of a more specific seizure type will be counted in all higher levels of seizure types (eg, a subject with a history of IB1 seizures will be counted for seizure types I, IB, and IB1).
6.3.3 Classification of epileptic syndrome
The number and percentage of subjects with each epileptic syndrome will be summarized for the Efficacy Analysis Sets for POS and PGS. This summary will include the number and percentage of subjects within the following categories: localization-related epilepsy; idiopathic, symptomatic, and cryptogenic localization-related epilepsy; generalized epilepsy; and idiopathic, symptomatic, and cryptogenic generalized epilepsy.
6.3.4 Focus localization
The number and percentage of subjects with each category of focus localization (unknown, frontal, temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set for POS for subjects from N01252, N01253, and N01254. Subjects may be counted in more than 1 category of focus localization. Focus localization data was not collected in N01193.
REDACTED sis Sets for POS and PGS. A subject will be counted as having a particular etiology
REDACTED sis Sets for POS and PGS. A subject will be counted as having a particular etiology was either confirmed or suspected based on the investigator's assessment.
REDACTED was either confirmed or suspected based on the investigator's assessment.
pileptic seizure profile
REDACTED
pileptic seizure profile
The number and percentage of subjects experiencing each seizure tREDACTED
The number and percentage of subjects experiencing each seizure t will be summarized for the Efficacy
REDACTED
will be summarized for the Efficacy
COPY The number and percentage of subjects with each ty
COPY The number and percentage of subjects with each type of etiology
COPY pe of etiologyThe number and percentage of subjects with each type of etiologyThe number and percentage of subjects with each ty
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COPY enital, etc) from the previous studies will be summarized for the Efficacy
sis Sets for POS and PGS. A subject will be counted as having a particular etiologyCOPY
sis Sets for POS and PGS. A subject will be counted as having a particular etiology
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ment 6.3.4
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cann
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be percentage of subjects within
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used
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percentage of subjects within used
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to The number and percentage of subjects with each epileptic syto The number and percentage of subjects with each epileptic sysu
pport
counted in all higher levels of seizure ty
supp
ort counted in all higher levels of seizure ty
ypes I,
supp
ort ypes I,
supp
ort
Classification of epileptic syndromesupp
ort
Classification of epileptic syndrome
any III, and IV. A subject with a history of a more specific seizure type will be
any III, and IV. A subject with a history of a more specific seizure type will be
counted in all higher levels of seizure tyany counted in all higher levels of seizure ty
ypes I, an
y
ypes I,
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ng The number and percentage of subjects experiencing each seizure t
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ng
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ng
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eting
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autho
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on enital, etc) from the previous studies will be summarized for the Efficacy
autho
rizati
on enital, etc) from the previous studies will be summarized for the Efficacy
sis Sets for POS and PGS. A subject will be counted as having a particular etiology
autho
rizati
on
sis Sets for POS and PGS. A subject will be counted as having a particular etiology was either confirmed or suspected based on the investigator's assessment.
autho
rizati
on
was either confirmed or suspected based on the investigator's assessment.
The number and percentage of subjects experiencing each seizure tautho
rizati
on
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appli
catio
n
pe of etiologyap
plica
tion
pe of etiologyenital, etc) from the previous studies will be summarized for the Efficacyap
plica
tion
enital, etc) from the previous studies will be summarized for the Efficacy
and summarized using data collected at the time of entry
and summarized using data collected at the time of entryan
y summarized using data collected at the time of entryan
y summarized using data collected at the time of entry
exten
sions
be provided in subject data listings.
exten
sions
be provided in subject data listings.
or va
riatio
ns
tem organ class (SOC) and preferred term varia
tions
tem organ class (SOC) and preferred term
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 26 of 47
6.3.5 History of epileptic seizures
History of epileptic seizures, including the number and percentage of subjects with a history of status epilepticus and quantitative summaries of epilepsy duration, age at onset of first seizure, and percent of life with epilepsy, will be summarized for the Efficacy Analysis Sets for POS and PGS
6.3.6 Seizure types experienced during baseline of the previous study
The number and percentage of subjects experiencing each seizure type during the Baseline Period will be summarized for the Efficacy Analysis Sets for POS and PGS based on the Baseline seizure diary data from the previous studies. The following seizure types will be summarized: I, IA, IB, IC, II, and IIA through IIF, and III as well.
Subjects will be counted for all higher levels of seizure type categories corresponding to the seizure types or seizure sub-types reported on the CRF.
6.4 Medications
Medications recorded on the Concomitant Medications CRF and the Concomitant Medications (AEDs only) CRF will be classified as either AEDs or non-AEDs based on the preferred drug name search criteria, which are documented outside of the SAP.
The medication is not an AED if it does not meet the search criteria based on preferred drug name, regardless of which CRF is used for reporting the medication. However, further review will be performed for medications that are recorded on the Concomitant Medications (AEDs only) CRF but are not included in the AEDs search criteria;
For non-benzodiazepine medications, if the medication meets the search criteria for an AED based on preferred drug name, then the medication will be classified as an AED regardless of indication and regardless of which CRF the medication is recorded on;
Benzodiazepines (BZD) taken more than once a week (for any indication) will be considered as a concomitant AED.
After medications are classified as AEDs or non-AEDs, the standard date imputation algorithms for start and stop date of the medication and first dose and last dose of BRV in the study will be applied. If an AED was taken at any time during dosing with BRV, then the AED is classified as a concomitant AED.
6.4.1 Non-AEDs taken at study entry
The number and percentage of subjects taking non-AED medications at study entry for the previous double-blind study will be summarized by WHO-DRL primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and preferred drug name for the Safety Analysis Set.
REDACTED drug name, regardless of which CRF is used for reporting the medication. However,
REDACTED drug name, regardless of which CRF is used for reporting the medication. However, further review will be performed for medications that are recorded on the Concomitant
REDACTED further review will be performed for medications that are recorded on the Concomitant
y) CRF but are not included in the AEDs search
REDACTED
y) CRF but are not included in the AEDs search
-benzodiazepine medications, if the medication meets the search criteria for an REDACTED
-benzodiazepine medications, if the medication meets the search criteria for an AED based on preferred drug name, then the medication will be classified as an AED REDACTED
AED based on preferred drug name, then the medication will be classified as an AED
COPY preferred drug name search criteria, which are documented outside of the SAP.
COPY preferred drug name search criteria, which are documented outside of the SAP.
The medication is not an AED if it does not meet the search criteriCOPY
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drug name, regardless of which CRF is used for reporting the medication. However,
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supp
ort
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ort Benzodiazepines (BZD) taken more than once a week (for an
supp
ort Benzodiazepines (BZD) taken more than once a week (for an
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ort
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ort
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any
any
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marketi
ng -benzodiazepine medications, if the medication meets the search criteria for an
marketi
ng -benzodiazepine medications, if the medication meets the search criteria for an
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marketi
ng
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ng
regardless of indication and regardless of which CRF the medication is reco
autho
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on The medication is not an AED if it does not meet the search criteri
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on The medication is not an AED if it does not meet the search criteri
drug name, regardless of which CRF is used for reporting the medication. However,
autho
rizati
on
drug name, regardless of which CRF is used for reporting the medication. However, further review will be performed for medications that are recorded on the Concomitant
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on
further review will be performed for medications that are recorded on the Concomitant y) CRF but are not included in the AEDs search
autho
rizati
on
y) CRF but are not included in the AEDs search
-benzodiazepine medications, if the medication meets the search criteria for an autho
rizati
on
-benzodiazepine medications, if the medication meets the search criteria for an
appli
catio
n Medications recorded on the Concomitant Medications CRF and the Concomitant
appli
catio
n Medications recorded on the Concomitant Medications CRF and the Concomitant Medications (AEDs only) CRF will be classified as either AEDs or non
appli
catio
n Medications (AEDs only) CRF will be classified as either AEDs or nonpreferred drug name search criteria, which are documented outside of the SAP.
appli
catio
n
preferred drug name search criteria, which are documented outside of the SAP.
The medication is not an AED if it does not meet the search criteriappli
catio
n
The medication is not an AED if it does not meet the search criteri
and
Medications recorded on the Concomitant Medications CRF and the Concomitant and
Medications recorded on the Concomitant Medications CRF and the Concomitant
any e
xtens
ions pes will be
exten
sions
pes will be
pe categories corresponding to the ex
tensio
ns
pe categories corresponding to the
or ysis Sets for POS and PGS based on the or ysis Sets for POS and PGS based on the pes will be
or pes will be
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tions
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riatio
ns
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f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 27 of 47
6.4.2 Number of previous AEDs
The number and percentage of subjects taking an AED within 5 years and discontinued prior to entry into the previous double-blind study will be summarized by WHO-DRL preferred drug name for the POS and PGS Efficacy Analysis Sets based on the following categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.
6.4.3 History of previous AED use
The number and percentage of subjects taking an AED within 5 years and discontinued prior to entry into the previous double-blind study will be summarized overall and by WHO-DRLpreferred drug name for the POS and PGS Efficacy Analysis Sets.
6.4.4 AEDs taken at study entry
The number and percentage of subjects taking AEDs at study entry for the previous double-blind study will be summarized by WHO-DRL preferred drug name for the POS and PGS Efficacy Analysis Sets.
6.4.5 Concomitant AEDs
A concomitant AED is an AED which was taken during administration of BRV in N01199 study, regardless of the start and stop date of the AED. The number and percentage of subjects taking concomitant AEDs will be summarized by WHO-DRL preferred drug namefor the POS and PGS Efficacy Analysis Sets.
7 MEASUREMENTS OF TREATMENT COMPLIANCE
Study drug compliance will not be assessed due to the complexities associated with the calculation and interpretation of study drug compliance for this study. Study drug dosing will be provided in subject data listings.
8 EFFICACY ANALYSES
In general, all study outcomes based on seizure frequency will be summarized for the Efficacy Analysis Set for POS and all study outcomes based on seizure days will be summarized for the Efficacy Analysis Set for PGS.
The derivations of 28-day adjusted seizure frequency and 28-day adjusted seizure days are described in detail in Section 3.8.1.2 and Section 3.8.1.3, respectively.
All summaries of efficacy data are descriptive; no statistical testing will be performed.
8.1 Statistical analyses of secondary efficacy variables
The following variables are summarized for the Efficacy Population for POS.
8.1.1 Partial onset seizure frequency
Twenty-eight day adjusted POS frequency will be summarized with quantitative descriptive statistics for all subjects for the Baseline Period, the On Treatment Period, and by 3-month
REDACTED ant AEDs will be summarized by
REDACTED ant AEDs will be summarized bysis Sets.
REDACTED sis Sets.
SUREMENTS OF TREA
REDACTED
SUREMENTS OF TREA
drug compliance will not be assessed due to the complexities associated with the REDACTED
drug compliance will not be assessed due to the complexities associated with the
COPY A concomitant AED is an AED which was taken during administration of BRV
COPY A concomitant AED is an AED which was taken during administration of BRV, regardless of the start and stop date of the AED. The number and percentage of
COPY , regardless of the start and stop date of the AED. The number and percentage of
ant AEDs will be summarized byCOPY
ant AEDs will be summarized by
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ment 8.1
The following variables are
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ment
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cann
ot All summaries of efficacy data are descriptive; no statistical testing will be performed.
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ot All summaries of efficacy data are descriptive; no statistical testing will be performed.
8.1 cann
ot
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be described in detail in us
ed summarized for the Efficacy
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ort CY
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ng
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be provided in subject data listings.
autho
rizati
on , regardless of the start and stop date of the AED. The number and percentage of
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rizati
on , regardless of the start and stop date of the AED. The number and percentage of
ant AEDs will be summarized by
autho
rizati
on
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SUREMENTS OF TREAautho
rizati
on
SUREMENTS OF TREA
appli
catio
n
A concomitant AED is an AED which was taken during administration of BRVap
plica
tion
A concomitant AED is an AED which was taken during administration of BRV, regardless of the start and stop date of the AED. The number and percentage of ap
plica
tion
, regardless of the start and stop date of the AED. The number and percentage of
and
for the previous double-
and
for the previous double- preferred drug nam
and preferred drug name for the POS and PGS
and e for the POS and PGS
any for the previous double-any for the previous double-
e for the POS and PGS an
y
e for the POS and PGS
exten
sions
ears and discontinued prior
exten
sions
ears and discontinued prior WHO
exten
sions
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or ears and discontinued prior or ears and discontinued prior va
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 28 of 47
time intervals over the On Treatment Period. The summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval and by 3-month time intervals for each exposure duration cohort.
8.1.2 Percent reduction in POS frequency
Percent reduction in POS frequency from Baseline to the On Treatment Period will be calculated as follows, where On Treatment Period Frequency is the 28-day adjusted POS frequency during On Treatment Period and Baseline Period Frequency is the 28-day adjusted POS frequency during the Baseline Period of the previous study.
FrequencyPeriodBaseline
FrequencyPeriodTreatment On FrequencyPeriodBaseline100Reduction%
A similar calculation applies to each 3-month time interval over the On Treatment Period and for the cohort interval for each exposure duration cohort.
Percent reduction from Baseline for POS frequency will be summarized with quantitative descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On Treatment Period. The summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval and by 3-month time intervals for each exposure duration cohort. Percent reduction from Baseline for POS frequency will be summarized in the same manner by geographic region.
8.1.3 Responder rate for POS frequency
Responders over the On Treatment Period are defined as subjects with a 50% or greater reduction in 28-day adjusted POS frequency from Baseline to the On Treatment Period. A similar calculation applies to each 3-month time interval over the On Treatment Period and for the cohort interval for each exposure duration cohort.
The number and percentage of responders for POS frequency will be summarized for the On Treatment Period, and by 3-month time intervals over the On Treatment Period. The summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be provided over the full cohort interval and by 3-month time intervals for each exposure duration cohort. Responder rates for POS frequency will be summarized in the same manner by geographic region.
8.2 Analysis of other efficacy variables
8.2.1 Subjects with partial onset seizures
All of the following variables are summarized for the Efficacy Analysis Set for POS.
8.2.1.1 Specified Month seizure freedom
The numbers and percentages of subjects who are seizure free for all seizure types for any continuous 6-month interval, 12-month interval, 18-month interval, and so forth will be summarized overall for the period of time that subjects are being treated with BRV and by
REDACTED will be summarized in the same manner by
REDACTED will be summarized in the same manner by
Responder rate for POS frequency
REDACTED Responder rate for POS frequency
esponders over the On Treatment Period are defined as subjects with a 50% or greater REDACTED
esponders over the On Treatment Period are defined as subjects with a 50% or greater adjusted POS frequencyREDACTED
adjusted POS frequency
COPY over the On Treatment Period will include all subjects in the
COPY over the On Treatment Period will include all subjects in the is Set. Similar summaries will be provided for the full cohort interval
COPY is Set. Similar summaries will be provided for the full cohort interval
3-month time intervals for each exposure duration cohort. Percent reduction from COPY 3-month time intervals for each exposure duration cohort. Percent reduction from
will be summarized in the same manner byCOPY
will be summarized in the same manner by
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ment All of the following varia
8.2.1.1
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ment
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ot 8.2.1
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ot 8.2.1
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ot
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be us
ed intervals for each exposure duration cohort. Responder rates for POS frequency will be
used
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used
summarized in the same manner bus
ed
summarized in the same manner b
to Set. Similar summaries will be provided over the full cohort interval and
to Set. Similar summaries will be provided over the full cohort interval andintervals for each exposure duration cohort. Responder rates for POS frequency will be to intervals for each exposure duration cohort. Responder rates for POS frequency will be
supp
ort The number and percentage of responders for POS frequency
supp
ort The number and percentage of responders for POS frequency
y 3
supp
ort y 3-month time intervals over the On Treatment Period. The
supp
ort -month time intervals over the On Treatment Period. The
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ort
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-month time intervals over the On Treatment Period. The an
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ng esponders over the On Treatment Period are defined as subjects with a 50% or greater
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ng
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ng
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ng
-month time interval over the On Treatment Period and
marketi
ng
-month time interval over the On Treatment Period and for the cohort interval for each exposure duration cohort.mark
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autho
rizati
on 3-month time intervals for each exposure duration cohort. Percent reduction from
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rizati
on 3-month time intervals for each exposure duration cohort. Percent reduction from
will be summarized in the same manner by
autho
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on
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Responder rate for POS frequency
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on
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esponders over the On Treatment Period are defined as subjects with a 50% or greater autho
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on
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appli
catio
n will be summarized with quantitative
appli
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n 3-month time intervals over the On
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n
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and
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will be summarized with quantitative
any -month time interval over the On Treatment Period and
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tensio
ns
exten
sions
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sions
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or adjusted
or adjusted va
riatio
ns
adjusted POS
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ns
adjusted
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f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 29 of 47
Exposure Duration Cohort. The overall summary will present the number and percentage of subjects who reported no seizures for the specified duration of seizure freedom and the seizure diary was completed for at least 90% of days within the seizure-free interval. Subjects whose duration of BRV treatment was less than the specified duration of seizure freedom will be considered failures for seizure-freedom. Summaries by exposure duration cohort will present the number and percentage of subjects who reported no seizures for the specified duration of seizure freedom at any time during the cohort interval (eg, through the end of Month 6 for the 6-month cohort) and the seizure diary was completed for at least 90% of days within the seizure-free interval. Percentages are relative to the number of subjects within each Exposure Duration Cohort.
A subject is seizure free for a 6-month interval if the subject did not report any seizures in the 6-month interval and the seizure diary was completed for at least 90% of days within the seizure-free interval. The percentage of days for which seizure diary was completed within a given 6-month interval will be calculated as follows based on a 30-day month:
A similar calculation applies for 12-month seizure freedom based on 360 days, 18-month seizure freedom based on 540 days, and so forth.
8.2.2 Subjects with All Other Seizure Types
The following variables are summarized for the Efficacy Analysis Set for PGS.
8.2.2.1 All other type seizure days
Twenty-eight day adjusted all other type seizure days will be summarized with quantitative descriptive statistics in the same manner as 28-day adjusted POS frequency.
8.2.2.2 Percent reduction in All other type seizure days
Percent reduction in all other type seizure days from Baseline will be calculated in the same manner as percent reduction in POS frequency as described in Section 8.1.2. This variable will be summarized in the same manner as percent reduction in POS frequency.
8.2.2.3 Responder outcome for all other type seizure days
Responder outcome for all other type seizure days will be derived in a manner similar to the responder outcome for POS frequency as described in Section 8.1.3. This variable will be summarized in the same manner as 50% responder outcome for POS frequency.
8.2.2.4 Specified month seizure freedom
Specified month seizure freedom for subjects in the PGS Efficacy Analysis Set will be derived in a manner similar to specified month seizure freedom for the POS Efficacy Analysis Set as described in Section 8.2.1.1. This variable will be summarized in the same manner as specified month seizure freedom for subjects in the POS Efficacy Analysis Set.
REDACTED The following variables are summarized for the Efficacy
REDACTED The following variables are summarized for the Efficacy
l other type seizure day
REDACTED
l other type seizure day
adjusted all other tyREDACTED
adjusted all other type seizure dayREDACTED
pe seizure day adjusted all other type seizure day adjusted all other tyREDACTED
adjusted all other type seizure day adjusted all other tystatistics in the same manner as 28-REDACTED
statistics in the same manner as 28-
COPY ll Other Seizure TyCOPY ll Other Seizure Ty
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be responder outcome for POS frequency
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pe seizure day
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and
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and
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ns
report any
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report any seizures in the report any
was completed for at least 90% of dayex
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ns
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tensio
ns
s within the was completed within a ex
tensio
ns
was completed within a
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f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 30 of 47
8.2.3 QOLIE-31-P
The scoring algorithm for QOLIE-31-P is described in Section 13.1. QOLIE-31-P will be summarized for the POS and PGS Efficacy Analysis Sets. QOLIE-31-P is assessed at the following time points for subjects with POS and subjects with PGS (except for mentallyimpaired subjects and subjects coming from N01193): Month 2, Month 6, Month 12, Month 18, and Month 24. QOLIE-31-P is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of the second year. Prior to protocol amendment 6, QOLIE-31-P may have been assessed for more than 2 years after study entry for some subjects. These additional assessments will not be summarized but will be provided in the subject data listings.
Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, Overall Quality of Life, and Health Status will be summarized for Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. For each time point, summary statistics will be presented for the baseline scores for subjects with a change from baseline at the time point in addition to summaries of the observed values and changes from baseline at each time point. Only subjects with a non-missing change from baseline will be summarized at each time point.
For summaries of observed values at each time point, only subjects with a change from Baseline value at that time point will be summarized. Additionally, the mean and SD for each Baseline score will be provided at each post-Baseline time point for subjects included in the summary of change from Baseline.
Similar summaries will be provided for QOLIE-31-P distress items Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, and Overall Quality of Life.
The rankings of prioritization items (Seizure Worry, Daily Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, Overall Quality of Life) will be summarized by visit for the first 2 years of the Evaluation Period, and for Last Value for the first 2 years of the Evaluation Period for the Efficacy populations for POS and PGS. Only observed values will be summarized and only the number of nonmissing values and the means for each item will be presented.
8.2.4 EQ-5D
EQ-5D (EuroQol Group, 2000) will be summarized for the POS and PGS Efficacy Analysis Sets. EQ-5D is assessed at the following time points (except for mentally impaired subjects and subjects coming from N01193): Month 2, Month 6, Month 12, Month 18, and Month 24. EQ-5D is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of the second year. Prior to protocol amendment 6, EQ-5D may have been assessed for more than 2 years after study entry for some subjects. These additional assessments will not be summarized but will be provided in subject data listings.
REDACTED Baseline value at that time point will be summarized. Additionally
REDACTED Baseline value at that time point will be summarized. AdditionallyBaseline score will be provided at each post
REDACTED Baseline score will be provided at each post-Baseline time point for subjects included in the
REDACTED -Baseline time point for subjects included in the
Similar summaries will be provided for QOLIEREDACTED
Similar summaries will be provided for QOLIE/Fatigue, Emotional WellREDACTED
/Fatigue, Emotional Well
COPY For summaries of observed values at each time point, only
COPY For summaries of observed values at each time point, onlyBaseline value at that time point will be summarized. AdditionallyCOPY
Baseline value at that time point will be summarized. Additionally
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t and subjects coming from N01193): Month 2, Month 6, Month 12, Month 18, and Month 24.
docu
ment and subjects coming from N01193): Month 2, Month 6, Month 12, Month 18, and Month 24.
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docu
ment
EQthe second
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ment
the second
cann
ot 5D
cann
ot 5D (EuroQol Group
cann
ot (EuroQol Group. ca
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be
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used
values and the means for each item will be presented.
EQused
EQ
to POS and PGS. Onlyto POS and PGS. Only observed values will be summarized and onlyto observed values will be summarized and onlyPOS and PGS. Only observed values will be summarized and onlyPOS and PGS. Onlyto POS and PGS. Only observed values will be summarized and onlyPOS and PGS. Onlyvalues and the means for each item will be presented.
to values and the means for each item will be presented.
supp
ort /Fatigue, Emotional Well
supp
ort /Fatigue, Emotional Well
of Life) will be summarized by
supp
ort
of Life) will be summarized byfor Last Value for the first 2 y
supp
ort
for Last Value for the first 2 y observed values will be summarized and onlysu
pport
observed values will be summarized and only
any The rankings of prioritization items (Seizure Worry
any The rankings of prioritization items (Seizure Worry
/Fatigue, Emotional Wellany
/Fatigue, Emotional Well
marketi
ng Similar summaries will be provided for QOLIE
marketi
ng Similar summaries will be provided for QOLIE
/Fatigue, Emotional Well
marketi
ng
/Fatigue, Emotional WellMedication Effects, and Overall Qualit
marketi
ng
Medication Effects, and Overall Quality of Life.
marketi
ng
y of Life.
The rankings of prioritization items (Seizure Worrymarketi
ng
The rankings of prioritization items (Seizure Worry
autho
rizati
on For summaries of observed values at each time point, only
autho
rizati
on For summaries of observed values at each time point, only
Baseline value at that time point will be summarized. Additionally
autho
rizati
on
Baseline value at that time point will be summarized. Additionally-Baseline time point for subjects included in the
autho
rizati
on
-Baseline time point for subjects included in the
Similar summaries will be provided for QOLIEautho
rizati
on
Similar summaries will be provided for QOLIE
appli
catio
n statistics will be presented for the baseline scores for subjects
appli
catio
n statistics will be presented for the baseline scores for subjects
with a change from baseline at the time point in addition to summaries of the observed values
appli
catio
n with a change from baseline at the time point in addition to summaries of the observed values subjects with a non
appli
catio
n subjects with a non
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catio
n
For summaries of observed values at each time point, only subjects with a change from appli
catio
n
subjects with a change from For summaries of observed values at each time point, only subjects with a change from For summaries of observed values at each time point, onlyappli
catio
n
For summaries of observed values at each time point, only subjects with a change from For summaries of observed values at each time point, only
and sis Sets for POS and PGS.
and sis Sets for POS and PGS.
statistics will be presented for the baseline scores for subjects and statistics will be presented for the baseline scores for subjects
with a change from baseline at the time point in addition to summaries of the observed values an
d
with a change from baseline at the time point in addition to summaries of the observed values
any of Life, and Health Status will be summarized for
any of Life, and Health Status will be summarized for
sis Sets for POS and PGS. any
sis Sets for POS and PGS.
exten
sions
additional assessments will not be summarized but will be provided in the subject data
exten
sions
additional assessments will not be summarized but will be provided in the subject data
Seizure Worry
exten
sions
Seizure WorryBeing, Cognitive Function, ex
tensio
ns
Being, Cognitive Function, of Life, and Health Status will be summarized for ex
tensio
ns
of Life, and Health Status will be summarized for
or additional assessments will not be summarized but will be provided in the subject data or additional assessments will not be summarized but will be provided in the subject data va
riatio
ns
P may
varia
tions
P may
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 31 of 47
EQ-5D dimensions will be summarized for Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. The number and percentage of subjects with each response will be summarized for each dimension and time point. Percentages will be relative to the number of subjects with a response to the dimension at that time point. Additionally, for each dimension and time point, the number and percentage of subjects with each response will be summarized for baseline for subjects with an observed response at that time point. Additionally, each dimension will be summarized for the 6-Month, 12-Month, 18-Month, and 24-Month Study Visit Cohorts, including summaries for baseline for all subjects within each cohort and summaries of observed responses for all time points for each cohort.
Observed values for the EQ-5D visual analog scale (VAS) score will be summarized for Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. For each time point, summary statistics will be presented for the baseline VAS score for subjects with a change from baseline at the time point in addition to summaries of the observed values and changes from baseline at each time point. Only subjects with a non-missing change from baseline will be summarized at each time point.
EQ-5D VAS score will also summarized for the 6-Month, 12-Month, 18-Month, and 24-Month Study Visit Cohorts, including summaries of the baseline scores for all subjects within each study visit cohort and summaries of observed values and changes from baseline for each time point for each study visit cohort.
8.2.5 Direct cost parameters
Direct costs will be assessed based on concurrent medical procedures, healthcare provider consultations not foreseen by protocol, hospital stays, and ER visits.
Direct cost parameters will not be summarized but will be provided in subject data listings.
8.2.6 Indirect cost parameters
The number of school or working days lost will not be summarized but will be provided in subject data listings.
8.2.7 Socio-professional data
Socio-professional data are collected at the following time points: Month 12 and Month 24. Socio-professional data are also collected at EDVs for subjects who discontinue prior to the YEV at the end of the second year. These additional assessments will not be summarized but will be provided in subject data listings.
9 PHARMACOKINETICS AND PHARMACODYNAMICS
Plasma samples for BRV and concomitant AEDs and antimyoclonic drugs (AMDs) will no longer be obtained. No summaries of BRV or concomitant AED/AMD plasma levels will be provided; plasma levels will only be provided in subject data listings.
10 IMMUNOLOGICAL PROCEDURES
This section is not applicable for this study.
REDACTED Direct costs will be assessed based on concurrent medical procedures, healthcare provider
REDACTED Direct costs will be assessed based on concurrent medical procedures, healthcare provider
protocol, hospital stay
REDACTED
protocol, hospital stay
be summarized REDACTED
be summarized
COPY visit cohort and summaries of observed values and changes from baseline
COPY visit cohort and summaries of observed values and changes from baseline
This do
cumen
t Plasma samples for BRV and concomitant AEDs and antimy
docu
ment Plasma samples for BRV and concomitant AEDs and antimy
docu
ment
longer be obtained
docu
ment
longer be obtainedprovided; plasma levels will only
docu
ment
provided; plasma levels will only
cann
ot
Plasma samples for BRV and concomitant AEDs and antimycann
ot
Plasma samples for BRV and concomitant AEDs and antimy
be will be provided in subject be will be provided in subject us
ed -professional data are also collected at EDVs for subjects who discontinue prior to the
used
-professional data are also collected at EDVs for subjects who discontinue prior to the YEV at the end of the second yus
ed
YEV at the end of the second ywill be provided in subject us
ed
will be provided in subject
to professional data are collected at the fol
to professional data are collected at the fol
-professional data are also collected at EDVs for subjects who discontinue prior to the to -professional data are also collected at EDVs for subjects who discontinue prior to the su
pport
professional data
supp
ort
professional data
professional data are collected at the folsupp
ort
professional data are collected at the fol
any The number of school or working day
any The number of school or working daymark
eting
be summarized
marketi
ng
be summarized
marketi
ng
8.2.6 Indirect cost parameters
marketi
ng
8.2.6 Indirect cost parameters
The number of school or working daymarketi
ng
The number of school or working day
autho
rizati
on
Direct costs will be assessed based on concurrent medical procedures, healthcare provider
autho
rizati
on
Direct costs will be assessed based on concurrent medical procedures, healthcare provider protocol, hospital stay
autho
rizati
on
protocol, hospital stay
appli
catio
n Month, 18
appli
catio
n Month, 18 Visit Cohorts, including summaries of the baseline scores for all subjects
appli
catio
n Visit Cohorts, including summaries of the baseline scores for all subjects visit cohort and summaries of observed values and changes from baseline
appli
catio
n
visit cohort and summaries of observed values and changes from baseline
and
subjects with a non
and
subjects with a nonmissing change from baseline will be summarized at each time point.
and missing change from baseline will be summarized at each time point.
Month, 18an
d
Month, 18
any a change from baseline at the time point in addition to summaries of the
any a change from baseline at the time point in addition to summaries of the
subjects with a nonany subjects with a nonex
tensio
ns 5D visual analog scale (VAS) score will be summarized for
exten
sions
5D visual analog scale (VAS) score will be summarized for is Sets for POS and PGS.
exten
sions
is Sets for POS and PGS.
statistics will be presented for the baseline VAS score for ex
tensio
ns
statistics will be presented for the baseline VAS score for a change from baseline at the time point in addition to summaries of the ex
tensio
ns
a change from baseline at the time point in addition to summaries of the
or within each cohort and summaries of observed responses for all time points for each cohort.
or within each cohort and summaries of observed responses for all time points for each cohort.va
riatio
ns
Month, 18
varia
tions
Month, 18-
varia
tions
-
Visit Cohorts, including summaries for baseline for all subjects va
riatio
ns
Visit Cohorts, including summaries for baseline for all subjects within each cohort and summaries of observed responses for all time points for each cohort.va
riatio
ns
within each cohort and summaries of observed responses for all time points for each cohort.
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 32 of 47
11 SAFETY ANALYSES
Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, and pregnancy test), vital signs, body weight, ECGs, physical examination, neurological examination, mental status, and psychiatric status. Summary tables will be provided for AEs; blood chemistry, hematology, and urinalysis; vital signs; body weight; and ECGs. No summary tables will be provided for pregnancy testing, physical examination, neurological examination, mental status, or psychiatric status.
All safety summaries will be based on the Safety Analysis Set.
11.1 Extent of exposure
A daily dose will be calculated for each study day from the day of first dose of BRV to the day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be calculated as the sum of the AM and PM dose for each day.
Modal daily doses will be calculated across all study days on or after the day of first dose of BRV and up to and including the day of last dose of BRV. Modal daily dose is the most frequently taken daily dose during this period. In the event of a tie, the modal dose will be set to the lower of the tied doses. Modal daily dose will be categorized as follows:
Category Definition
5 mg/day <20mg/day20mg/day ≥20mg/day to <50mg/day 50mg/day ≥50mg/day to <100mg/day100mg/day ≥100mg/day to <150mg/day150mg/day ≥150mg/day to <200mg/day200mg/day ≥200mg/day
Subject years of exposure will be calculated by summing the exposure duration in days for all subjects being summarized, and dividing the resulting value by 365.25.
Subject years of exposure will be presented overall and by modal dose for the Safety Analysis Set. The subject years of exposure presented by modal dose will be the total subject years of exposure of subjects with that modal dose.
The number and percentage of subjects exposed to BRV will be summarized overall and by modal dose category. The number and percentage of subjects in each Exposure Duration Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.
The number and percentage of subjects within each modal dose category will be summarized for each Exposure Duration Cohorts; percentages will be relative to the total number of subjects in each Exposure Duration Cohort.
In addition to the overall summaries of the above, the above will also be summarized by subgroup for region, and seizure type (Partial Onset Seizures, All Other Seizure Types).
REDACTED to <50mg/day
REDACTED to <50mg/day
50mg/day ≥50mg/day to <100mg/day
REDACTED
50mg/day ≥50mg/day to <100mg/day100mg/day ≥100mg/day
REDACTED
100mg/day ≥100mg/day to <150mg/dayREDACTED
to <150mg/day100mg/day ≥100mg/day to <150mg/day100mg/day ≥100mg/dayREDACTED
100mg/day ≥100mg/day to <150mg/day100mg/day ≥100mg/day150mg/day ≥150mg/dayREDACTED
150mg/day ≥150mg/day
COPY
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cumen
t for each Exposure Duration Cohorts; percentages will
docu
ment for each Exposure Duration Cohorts; percentages will
docu
ment
subjects in each Exposure Duration Cohort.
docu
ment
subjects in each Exposure Duration Cohort.ca
nnot
Cohort (
cann
ot Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.
cann
ot ≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.
cann
ot The number and percentage of subjects within each modal dose category
cann
ot The number and percentage of subjects within each modal dose categoryfor each Exposure Duration Cohorts; percentages willca
nnot
for each Exposure Duration Cohorts; percentages will
be modal dose category
be modal dose category
≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.be
≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.us
ed
The number and percentage of subjects exposed to BRV will be summarized overall and bus
ed
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ed
modal dose category
to ars of exposure of subjects with that modal dose.to ars of exposure of subjects with that modal dose.supp
ort
ears of exposure will be presented overall and by
supp
ort
ears of exposure will be presented overall and bysis Set. The subje
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ars of exposure of subjects with that modal dose.supp
ort
ars of exposure of subjects with that modal dose.
any
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eting
to <150mg/day
marketi
ng to <150mg/day
150mg/day ≥150mg/day
marketi
ng
150mg/day ≥150mg/day to <200mg/day
marketi
ng
to <200mg/day150mg/day ≥150mg/day to <200mg/day150mg/day ≥150mg/day
marketi
ng
150mg/day ≥150mg/day to <200mg/day150mg/day ≥150mg/day200mg/day ≥200mg/day
marketi
ng
200mg/day ≥200mg/day
exposure will be calculated bmarketi
ng
exposure will be calculated b
autho
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autho
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autho
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thoriz
ation
to <150mg/day
appli
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n BRV and up to and including the day of last dose of BRV. Modal dail
appli
catio
n BRV and up to and including the day of last dose of BRV. Modal daily dose during this period. In the event of a tie, the modal dose will be set
appli
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n y dose during this period. In the event of a tie, the modal dose will be set
dose will be cate
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dose will be categorized as follows:
appli
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gorized as follows:
and s on or after the day
and s on or after the day
BRV and up to and including the day of last dose of BRV. Modal dailand
BRV and up to and including the day of last dose of BRV. Modal dail
any
s on or after the dayan
y s on or after the day
exten
sions
first dose of BRV to the
exten
sions
first dose of BRV to the dose will be ex
tensio
ns
dose will be
or va
riatio
ns th
ereof.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 33 of 47
11.2 Adverse events
11.2.1 Definition of treatment-emergent AE
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined as AEs which had onset prior to the date of the first dose of BRV. TEAEs are defined as AEs that had onset on or after the day of first BRV dose. AEs with an incomplete onset date will be classified as TEAEs if the month and year of onset (when only the month and year are specified) is the same as the month and year of the first BRV dose or the year of onset (when only year is specified) is the same as the year of first BRV dose.
11.2.2 General summaries of TEAEs
Pre-treatment AEs will be provided in a subject data listing; no summaries of pre treatment AEs are planned.
An overall summary of AEs will provide the overall number of TEAEs and the numbers and percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent discontinuation of study drug, with a drug-related TEAE, with a severe TEAE, with a treatment-emergent SAE, and with a drug-related treatment-emergent SAE. The number and percentage of subjects who died will also be summarized. This summary will be provided for all subjects in the Safety Analysis Set and also by subgroup for geographic region and seizure type.
The following summaries of TEAEs will be provided by MedDRA SOC and PT. All summaries are for the combined Evaluation, Down-Titration, and Post-Treatment Periods unless otherwise indicated.
Overall Incidence Summaries
Incidence of TEAEs
Incidence of TEAEs by 3-month time interval
Incidence of TEAEs by study period (Evaluation, Down-Titration, Post-Treatment)
Incidence of TEAEs for TEAEs occurring in at least 5% of subjects
Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of subjects overall
Incidence of non-serious TEAEs occurring in at least 5% of subjects
The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as noted above and also by subgroup for geographic region, seizure type, and randomized treatment from the previous double-blind study.
A subject is included in a 3-month interval if the subject was receiving BRV at any time during that interval based on their duration of exposure to BRV (eg, a subject with exposure for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of AEs by 3-month intervals will include all subjects who are classified into each time interval
REDACTED be provided by
REDACTED be provided bysummaries are for the combined Evaluation, Down
REDACTED summaries are for the combined Evaluation, Down
COPY subgroup for geographic region and
COPY subgroup for geographic region and
be provided byCOPY
be provided by
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t treatment from the previous double
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ment treatment from the previous double
A subject is included in a 3
docu
ment
A subject is included in a 3
cann
ot The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as
cann
ot The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as noted above and also byca
nnot
noted above and also bytreatment from the previous double
cann
ot
treatment from the previous double
be cidence of nonbe cidence of nonus
ed cidence of TEAEs b
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pport
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ort tudy
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pport
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pport
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any -month time interval
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tudyany
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ng
-month time interval
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appli
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n -related TEAE, with a severe TEAE, with a
appli
catio
n -related TEAE, with a severe TEAE, with a
em
appli
catio
n emergent SAE. The number and
appli
catio
n ergent SAE. The number and percentage of subjects who died will also be summarized. This summary
appli
catio
n percentage of subjects who died will also be summarized. This summary
subgroup for geographic region and ap
plica
tion
subgroup for geographic region and
and TEAE that led to permanent
and TEAE that led to permanent
-related TEAE, with a severe TEAE, with a and
-related TEAE, with a severe TEAE, with a
any er of TEAEs and the numbers and
any er of TEAEs and the numbers and
TEAE that led to permanent any
TEAE that led to permanent
exten
sions
-treatment AEs will be provided in a subject data listing; no summaries of pre treatment
exten
sions
-treatment AEs will be provided in a subject data listing; no summaries of pre treatment
or va
riatio
ns
ear of the first BRV dose or the year of onset (when va
riatio
ns
ear of the first BRV dose or the year of onset (when
thereo
f.
UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 34 of 47
as defined above. TEAEs which had onset prior to or on the date of the last dose of BRV are included in summaries by 3-month time intervals.
Maximum Intensity and Causality
Incidence of TEAEs by maximum intensity
Incidence of drug-related TEAEs
Serious Adverse Events
Incidence of treatment-emergent SAEs
Discontinuations due to TEAE
Incidence of TEAEs leading to permanent discontinuation of study drug
TEAEs of interest
AEs of interest will be identified based on MedDRA search criteria, which are documented outside of the SAP. The following summaries will be provided for AEs of interest:
Incidence of TEAEs of interest
Incidence of TEAEs of interest by 3-month time interval
For the summary by maximum intensity, each subject will be counted at most once per SOC or PT according to the maximum intensity of all AEs within that SOC or PT. Severe intensity will be assumed for AEs for which intensity is not specified.
Drug-related AEs are AEs for which the relationship to study drug is specified as Related or AEs for which relationship is not specified.
11.3 Clinical laboratory evaluations
Clinical laboratory parameters (blood chemistry, hematology, urinalysis) are assessed at all FEVs, YEVs, EDVs, and at the FV and may also be assessed at unscheduled visits.
11.3.1 Hematology and blood chemistry parameters
Observed values for each planned hematology and blood chemistry parameter will be summarized for Baseline, Study Entry, and each scheduled visit during the Evaluation Period for which laboratory parameters were assessed, Last Value, EDV, and FV. Change from Baseline will be summarized for all post-Baseline time points including EV. Only laboratory parameters planned per protocol will be summarized; results for laboratory parameters not planned per the protocol will only be provided in subject data listings.
The number and percentage of subjects with an on-treatment potentially clinically significant treatment-emergent (PCST) value, PCST low value, and PCST high value will be summarized. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number ofsubjects with an on-treatment assessment.
REDACTED of all AEs within that SOC or PT. Severe intensity
REDACTED of all AEs within that SOC or PT. Severe intensityity
REDACTED ity is not specified.
REDACTED is not specified.ity is not specified.ity
REDACTED ity is not specified.ity
related AEs are AEs for which the relationship to study
REDACTED
related AEs are AEs for which the relationship to studyAEs for which relationship is not specified.REDACTED
AEs for which relationship is not specified.
COPY -month time interval
COPY -month time interval
, each subject will be counted at most once per SOC COPY , each subject will be counted at most once per SOC
of all AEs within that SOC or PT. Severe intensityCOPY
of all AEs within that SOC or PT. Severe intensity
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t The number and percentage of subjects with an on
docu
ment The number and percentage of subjects with an on
tr
docu
ment
treatment
docu
ment
eatment
cann
ot ameters planned per protocol will be summarized; results for laboratory
cann
ot ameters planned per protocol will be summarized; results for laboratoryplanned per the protocol will only
cann
ot planned per the protocol will only
The number and percentage of subjects with an oncann
ot
The number and percentage of subjects with an on
be Baseline will be summarized for all post
be Baseline will be summarized for all post
ameters planned per protocol will be summarized; results for laboratorybe
ameters planned per protocol will be summarized; results for laboratory
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ed
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ort
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supp
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supp
ort
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ort
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any parameters (blood chemistry
any parameters (blood chemistry
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of all AEs within that SOC or PT. Severe intensity
autho
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autho
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related AEs are AEs for which the relationship to study
appli
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appli
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-month time intervalap
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tion
-month time interval
, each subject will be counted at most once per SOC appli
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, each subject will be counted at most once per SOC
and AEs of interest will be identified based on MedDRA search criteria, which are documented
and AEs of interest will be identified based on MedDRA search criteria, which are documented
outside of the SAP. The following summaries will be provided for AEs of interest:and
outside of the SAP. The following summaries will be provided for AEs of interest:
any
AEs of interest will be identified based on MedDRA search criteria, which are documented any
AEs of interest will be identified based on MedDRA search criteria, which are documented
exten
sions
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riatio
ns th
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 35 of 47
Additionally, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages for each parameter and time point will be relative to the number of subjects with a value at that time point.
PCST criteria (Sections 13.3.1 and 13.3.2) are based on Food and Drug Administration (FDA) Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions.
Creatinine clearance, when available from the central laboratory, will be provided in subject data listings only and will not be summarized.
11.3.2 Macroscopic urinalysis
Quantitative urinalysis parameters will be summarized in the same manner as hematology and blood chemistry parameters. Response categories are negative, 1+, 2+, and 3+ for the qualitative urinalysis parameters occult blood, leukocytes, glucose, protein, and ketones and negative and positive for nitrates. Outcome values for these parameters are mapped to the levels Negative, 1+, 2+, and 3+ as follows for purposes of summary tables and the determination of PCST:
Category Definition
Negative “Negative”, “NEGATIVE”, or other outcomes that clearly reflect a negative finding
1+ “1+”, “+” , “Trace”, “TRACE”, or other outcomes that clearly reflect trace amount
2+ “2+” or “++”
3+ “3+”, “+++”, or other outcomes that clearly reflect the data above 3+ (eg, “4+”, “5+” etc) or more than 4 plus signs (eg, “++++”, “+++++”etc)
For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and nitrates), the number and percentage of subjects with each response category will be summarized for Baseline, Study Entry, each scheduled visit during the Evaluation Period for which urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. Percentages for each parameter will be relative to the number of subjects with a result at each time point.
For occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high value will be summarized. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number of subjects with an on-treatment assessment.
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and
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d tes, glucose, protein, annegative and positive for nitrates. Outcome values for these parameters are mapped to the an
d negative and positive for nitrates. Outcome values for these parameters are mapped to the
any is parameters will be summarized in the same manner as hematology
any is parameters will be summarized in the same manner as hematology
Response categories are negative, 1+, 2+, and 3+ for the any
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exten
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 36 of 47
Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages for each parameter and time point will be relative to the number of subjects with a value at that time point.
11.3.3 Microscopic urinalysis
In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The sediment is then examined under a microscope. In the urinalysis laboratory test group, other than urinalysis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein, Specific Gravity, Total protein, Hemoglobin, Beta-HCG, Occult Blood, and Leukocytes, a listing of microscopic analysis parameters will be provided; no summaries of microscopic analysis findings are planned.
11.4 Vital signs, physical findings, and other observations related to safety
11.4.1 Vital signs
Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits.
Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which vital signs or body weight were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, and body weight will be summarized for all post-Baseline time points.
The number and percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number of subjects with an on-treatment assessment.
Additionally, the number and percentage of subjects with a PCST value, PCST low value, and PCST high value will be summarized for the above parameters for Study Entry, each visit during the Evaluation Period for which vital signs or body weight were scheduled to be assessed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects with a value at each time point.
PCST criteria (Section 13.3.4) are based on FDA Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions.
11.4.2 Electrocardiograms
ECGs are assessed at all YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits.
REDACTED also be assessed at Unscheduled Visits.
REDACTED also be assessed at Unscheduled Visits.
Observed values for SBP, DBP, pulse rate, and body
REDACTED Observed values for SBP, DBP, pulse rate, and body
, each visit during the Evaluation Period for which vital signs or body
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also be assessed at Unscheduled Visits.
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weight is assessed at all FEVs, YEVs, EDVs, and at
and sical findings, and other observations related
and sical findings, and other observations related an
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exten
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test group, other sis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein,
exten
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sis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein,
HCG, Occult Blood, and L
exten
sions
HCG, Occult Blood, and Leukocy
exten
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eukocysis parameters will be provided; no summaries of microscopic ex
tensio
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sis parameters will be provided; no summaries of microscopic
or sis, a small sample of urine is centrifuged to remove the liquid. The
or sis, a small sample of urine is centrifuged to remove the liquid. The
test group, other or test group, other va
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sis, a small sample of urine is centrifuged to remove the liquid. The varia
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 37 of 47
The number and percentage of subjects with no abnormality, an abnormal but not clinically significant finding, and a clinically significant finding will be summarized overall. This summary will consider all assessments after the first dose of BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the number of subjects with an on-treatment assessment.
Additionally, the number and percentage of subjects with no abnormality, an abnormal but not clinically significant finding, and a clinically significant finding will be summarized for Baseline, Study Entry, each visit during the Evaluation Period for which an ECG is scheduled to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects with an ECG assessment at each time point. Subjects are counted at most once at each time point based on the worst observed outcome across all abnormalities reported at that time point.
A subject number listing will be provided that identifies subjects with a clinically significant finding after the first dose of BRV for each type of ECG abnormality.
11.4.3 Physical examination
A listing of abnormal physical examination findings will be provided; no summaries of physical examination findings are planned.
11.4.4 Neurological examination
A listing of neurological examination findings will be provided; no summaries of neurological examination findings are planned.
11.4.5 Psychiatric and mental status
A listing of abnormal Psychiatric and Mental Status findings will be provided; no summaries of Psychiatric and Mental Status findings are planned.
11.4.6 HADS
The scoring algorithm for HADS is described in Section 3.8.3.
HADS is assessed at the following time points: Month 2, Month 6, Month 12, Month 18, and Month 24. HADS is not assessed for mentally impaired subjects and subjects from N01193. HADS is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of the second year. Prior to protocol amendment 6, HADS may have been assessed for more than 2 years after study entry for some subjects. These additional assessments will not be summarized but will be provided in subject data listings.
Observed values for HADS depression and anxiety scores will be summarized for Baseline and Last Value for the Safety Analysis Set. Additionally, observed values will be summarized for Baseline and by visit for each study visit cohort. Change from Baseline will be summarized at each visit during the Evaluation Period.
For summaries of observed values at each time point, only subjects with a change from Baseline value at that time point will be summarized. Additionally, the mean and SD for each
REDACTED A listing of neurological examination findings will be provided; no summaries of
REDACTED A listing of neurological examination findings will be provided; no summaries of neurological examination findings are planned.
REDACTED neurological examination findings are planned.
hiatric and mental status
REDACTED
hiatric and mental status
chiatric and Mental Status findings will be provided; no summaries REDACTED
chiatric and Mental Status findings will be provided; no summaries
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to Month 24. HADS is not assessed for mentally
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supp
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to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of
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to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects with an ECG assessment at each time point. Subjects are counted at most once at
exten
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subjects with an ECG assessment at each time point. Subjects are counted at most once at malities reported at that
exten
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malities reported at that
A subject number listing will be provided that identifies subjects with a clinicallyexten
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or to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of or to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of va
riatio
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ignificant finding will be summarized for
varia
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ignificant finding will be summarized for
scheduled varia
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scheduled to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of
varia
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to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of
thereo
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
Confidential Page 38 of 47
Baseline score will be provided at each post-Baseline time point for subjects included in the summary of change from Baseline.
11.4.7 Columbia-Suicide Severity Rating Scale
With global amendment 6 to the protocol, the Columbia-Suicide Severity Rating Scale (C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the study sites with regard to the identification of AEs or SAEs based on the outcome of this assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study variable is defined for this assessment and no analyses are planned for the C-SSRS within the context of this study. However, subject data listings of the data for the C-SSRS will be provided. Additional listings will be provided for the subset of subjects with suicidal ideation and the subset of subject with actual suicide attempts.
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions:
Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt questions:
12 REFERENCES
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. Epilepsia 1998, 39(1): 81-88.
EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the EuroQol group. User guide. 8th issue. April 2000.
Snaith RP, Zigmond AS. The hospital anxiety and depression scale manual. London; nferNelson Publishing Company Ltd. 1994.
REDACTED es” answer to an
REDACTED es” answer to an
REDACTED
REDACTED
REDACTED COPY
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COPY
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cumen
t Snaith RP, Zigmond AS. The hospital anxiety
docu
ment Snaith RP, Zigmond AS. The hospital anxiety
nferNelson Publishing Company
docu
ment
nferNelson Publishing Company
cann
ot EuroQol Group. EQ
cann
ot EuroQol Group. EQEuroQol group. User guide. 8th issue. April 200
cann
ot EuroQol group. User guide. 8th issue. April 200
Snaith RP, Zigmond AS. The hospital anxietyca
nnot
Snaith RP, Zigmond AS. The hospital anxiety
be Epilepsia 1998, 39(1): 81
be Epilepsia 1998, 39(1): 81
EuroQol Group. EQbe
EuroQol Group. EQ
used
Cramer JA, Perrine K, Devinsky
used
Cramer JA, Perrine K, DevinskyDevelopment and cross
be provided. Additional listings will be provided for the subset of subjects with suicidal ideation
exten
sions
provided. Additional listings will be provided for the subset of subjects with suicidal ideation
y 1 of the 5 suicidal ideation questions:exten
sions
y 1 of the 5 suicidal ideation questions:
or SSRS within the
or SSRS within the
be or
be va
riatio
ns
ecause clinical events of interest will be recorded as AEs or SAEs, no study
varia
tions
ecause clinical events of interest will be recorded as AEs or SAEs, no studySSRS within the va
riatio
ns
SSRS within the
thereo
f.
The following information (eg, ) is copyrighted and UCB does not have permission to
disclose the contents.
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UCB 20 April 2017Statistical Analysis Plan Brivaracetam N01199
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13.2 Subject site transfers
Subjects listed in this section of the appendix had changes to their subject number as a result of site transfer.
CRF# Initial Site Subject # Transfer Site Subject #
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UCB 8 August 2016Statistical Analysis Plan Brivaracetam N01199
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13.3 PCST criteria
13.3.1 Hematology parametersParameter UCB Conventional Units SI Units CF
Hematocrit For 1 m to < 6 m: 25% For 1 m to < 6 m: 0.25 0.01
For 6 m to < 2 y: 27% For 6 m to < 2 y: 0.27
For 2 y to < 4 y: 29% For 2 y to < 4 y: 0.29
For 4 y to < 12 y: 32% (Female[F]); 35% (Male [M]) For 4 y to < 12 y: 0.32 (F); 0.35 (M)
For 12 y: 32% (F); 37% (M) For 12 y: 0.32 (F); 0.37 (M)Hemoglobin For 6 m: 9.7 g/dL For 6 m: 97 g/L 10
For 6 m to < 12 y: 10.0 g/dL For 6 m to < 12 y: 100 g/L
For 12 y: 9.5 g/dL (F); 11.5 g/dL (M) For 12 y: 95 g/L (F); 115 g/L (M)Platelets 75 x 109/L or 700 x 109/L 75 x 109/L or 700 x 109/L Not applicable (N/A)
White Blood Cell (WBC)
For 17 y: < 3.0 x 109/L or > 20 x 109/L; For 17 y: < 3.0 x 109/L or > 20 x 109/L; N/A
For 17 y: < 2.8 x 109/L or > 16 x 109/L; For 17 y: < 2.8 x 109/L or > 16 x 109/L;Red Blood Cell (RBC)
For 17 y: < 2.5 x 106/mm3 For 17 y: < 2.5 x 1012/L 1
For 17 y: < 2.0 x 106/mm3 (F); < 2.5 x 106/mm3 (M) For 17 y: < 2.0 x 1012/L (F); < 2.5 x 1012/L (M)Eosinophils 10% or 0.7 x 109/L 0.10 or 0.7 x 109/L 0.01 or N/A
Neutrophils 15% or 1.0 x 109/L 0.15 or 1.0 x 109/L 0.01 or N/A
Basophils 5% or 0.4 x 109/L 0.05 or 0.4 x 109/L 0.01 or N/A
Monocytes 20% or 1.5 x 109/L 0.20 or 1.5 x 109/L 0.01 or N/A
Lymphocytes For 1 m to < 6 m: 22% or 80% For 1 m to < 6 m: 0.22 or 0.80 0.01
2.1 x 109/L or 8.5 x 109/L 2.1 x 109/L or 8.5 x 109/L N/A
For 6 m to < 2 y: 15% or 80% For 6 m to < 2 y: 0.15 or 0.80 0.01
1.5 x 109/L or 7.5 x 109/L 1.5 x 109/L or 7.5 x 109/L N/A
For 2 y to < 12 y: 12% or 80% For 2 y to < 12 y: 0.12 or 0.80 0.01
1.0 x 109/L or 7.5 x 109/L 1.0 x 109/L or 7.5 x 109/L N/A
For 12 y to 17 y: 10% or 80% For 12 y to 17 y: 0.10 or 0.80 0.01
0.5 x 109/L or 5.5 x 109/L 0.5 x 109/L or 5.5 x 109/L N/A
For 17 y: 10% or 80% For 17 y: 0.10 or 0.80 0.01
0.5 x 109/L or 4.5 x 109/L 0.5 x 109/L or 4.5 x 109/L N/A
REDACTED
REDACTED
/mm
REDACTED
/mm3
REDACTED
3 (M)
REDACTED
(M)
REDACTED
REDACTED COPY For 6 m to < 12 y:
COPY For 6 m to < 12 y:
For
COPY For
COPY
COPY COPY
COPY
COPY
COPY
COPY
COPY
This do
cumen
t can
not 17 y:
cann
ot 17 y:
cann
ot
cann
ot be
17 y:
be 17 y: us
ed
used
1.0 x 10
used
1.0 x 10
17 y: used
17 y: us
ed
10% or used
10% or
to 12% or to 12% or
1.0 x 10to
1.0 x 10
supp
ort /L or
supp
ort /L or
supp
ort
supp
ort
80%
supp
ort
80%
1.5 x 10supp
ort
1.5 x 109
supp
ort
9/L or supp
ort
/L or
12% or su
pport
12% or su
pport
any
any
8.5 x 10any
8.5 x 10
marketi
ng (M)
marketi
ng (M)
marketi
ng
marketi
ng
marketi
ng
marketi
ng
marketi
ng au
thoriz
ation
75 x 10
autho
rizati
on 75 x 10
For
autho
rizati
on
For
autho
rizati
on
autho
rizati
on
For
autho
rizati
on
For
autho
rizati
on
autho
rizati
on
autho
rizati
on
autho
rizati
on
autho
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on
(M) autho
rizati
on
(M) autho
rizati
on ap
plica
tion
appli
catio
n
appli
catio
n
For 6 m to < 12 y:
appli
catio
n
For 6 m to < 12 y:
12 y: appli
catio
n
12 y:
75 x 10ap
plica
tion
75 x 109appli
catio
n
9appli
catio
n and
0.29
and 0.29
and 0.32 (F); and 0.32 (F);
any 0.27
any 0.27
0.29any
0.29
exten
sions
SI Units
exten
sions
SI Units
exten
sions
exten
sions
or va
riatio
ns th
ereof.
UCB 8 August 2016Statistical Analysis Plan Brivaracetam N01199
Confidential Page 43 of 47
13.3.2 Blood chemistry parameters
Parameter UCB Conventional Units SI Units CFAST (SGOT) > 3 times of ULN > 3 times of ULN N/AALT (SGPT) > 3 times of ULN > 3 times of ULN N/AALP For 17 y: > 2 times of ULN, if normal range
adjusted to the age range; For 17 y: > 2 times of ULN, if normal range
adjusted to the age range; N/A
For 17 y: > 3 times of ULN For 17 y: > 3 times of ULNGGT > 3 times of ULN, if baseline value < 3 times of ULN > 3 times of ULN, if baseline value < 3 times of ULN N/ABUN > 30 mg/dL > 10.71 mmol/L 0.357Urea > 60 mg/dL > 10.02 mmol/L 0.167Creatinine For 17 y: > 1.5 mg/dL; For 17 y: > 132.6 umol/L; 88.4
For 17 y: > 2.0 mg/dL For 17 y: > 176.8 umol/LCreatinine clearance (calc)
For 12 y: 70 ml/min (Schwartz)(a) For 12 y: 70 ml/min (Schwartz)(a) N/A
For 12 y: 70 ml/min (Cockroft)(b) For 12 y: 70 ml/min (Cockroft)(b)
Total bilirubin
> 2.0 mg/dL > 34.2 umol/L 17.1
Glucose 50 mg/dL or 180 mg/dL 2.775 mmol/L or 9.99 mmol/L 0.0555
Total Protein For 1 m to 6 m: 3.6 g/dL or 7.8 g/dL For 1 m to 6 m: 36 g/L or 78 g/L 10
For 6 m to 17 y: 4.7 g/dL or 9.5 g/dL For 6 m to 17 y: 47 g/L or 95 g/L
For 17 y: 4.5 g/dL or 9.0 g/dL For 17 y: 45 g/L or 90 g/LAlbumin For 17 y: 2.4 g/dL or 6.5 g/dL For 17 y: 24 g/L or 65 g/L 10
For 17 y: 2.5 g/dL or 6.5 g/dL For 17 y: 25 g/L or 65 g/LGlobulin For 17 y: 1.2 g/dL or 5.0 g/dL For 17 y: 12 g/L or 50 g/L 10
For 17 y: 1.5 g/dL or 5.0 g/dL For 17 y: 15 g/L or 50 g/LSodium For 17 y: 120 mEq/L or 155 mEq/L For 17 y: 120 mmol/L or 155 mmol/L 1
For 17 y: 115 mEq/L or 155 mEq/L For 17 y: 115 mmol/L or 155 mmol/LPotassium For 17 y: 3.0 mEq/L or 6.5 mEq/L For 17 y: 3.0 mmol/L or 6.5 mmol/L 1
For 17 y: 3.0 mEq/L or 5.8 mEq/L For 17 y: 3.0 mmol/L or 5.8 mmol/LCalcium For 17 y: 7 mg/dL or 11.5 mg/dL For 17 y: 1.75 mmol/L or 2.875 mmol/L 0.25
For 17 y: 7 mg/dL or 15.5 mg/dL For 17 y: 1.75 mmol/L or 3.875 mmol/L
REDACTED
REDACTED
REDACTED
REDACTED COPY For
COPY For
COPY For
COPY For
COPY
COPY
COPY
This do
cumen
t can
not 17 y:
cann
ot 17 y:
cann
ot 17 y:
cann
ot 17 y:
cann
ot be
be
used
used
115 mEq/L or
used
115 mEq/L or
used
used
to 120 mEq/L or to 120 mEq/L or
115 mEq/L or to
115 mEq/L or
supp
ort 2.5 g/dL or
supp
ort 2.5 g/dL or
supp
ort 6.5 g/dL
supp
ort 6.5 g/dL
1.2 g/dL or
supp
ort
1.2 g/dL or
supp
ort
supp
ort
1.5 g/dL or supp
ort
1.5 g/dL or
120 mEq/L or su
pport
120 mEq/L or su
pport
any
9.0 g/dL
any
9.0 g/dL
6.5 g/dLany 6.5 g/dLany
6.5 g/dLany
6.5 g/dL
marketi
ng
marketi
ng
7.8 g/dL
marketi
ng
7.8 g/dL
marketi
ng
9.5 g/dL
marketi
ng
9.5 g/dL
9.0 g/dLmarketi
ng
9.0 g/dLmarketi
ng au
thoriz
ation
For
autho
rizati
on For
For
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on
For
autho
rizati
on
autho
rizati
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For
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on
For
autho
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on
autho
rizati
on
autho
rizati
on
autho
rizati
on ap
plica
tion ULN, if baseline value
appli
catio
n ULN, if baseline value 10.71 mmol/L
appli
catio
n 10.71 mmol/L
appli
catio
n 10.02 mmol/L
appli
catio
n 10.02 mmol/L
appli
catio
n
appli
catio
n
17 y:
appli
catio
n
17 y:
appli
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n
For appli
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For appli
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17 y: appli
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n
17 y: appli
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adjusted to the age range;
and adjusted to the age range;
>an
d >ULN, if baseline value an
d ULN, if baseline value an
d any
times of
any times of
adjusted to the age range; any
adjusted to the age range;
3 an
y
3
exten
sions
SI Units
exten
sions
SI Units
exten
sions
exten
sions
exten
sions
times of exten
sions
times of exten
sions
or va
riatio
ns th
ereof.
UCB 8 August 2016Statistical Analysis Plan Brivaracetam N01199
Confidential Page 44 of 47
Uric Acid For < 12 y: 8 mg/dL For < 12 y: 475.84 umol/L 59.48
For 12 y: 8 mg/dL (F); 9.5 mg/dL (M) For 12 y: 475.84 umol/L (F); 565.06 umol/L (M)
n ight (kg)] / (72 x serum creatinine),age) x body weight (kg)] / (72 x serum creatinine)] x 0.85
appli
catio
n age) x body weight (kg)] / (72 x serum creatinine)] x 0.85
ALT=alanine aminotransferase; ALP=Alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood ur
appli
catio
n
ALT=alanine aminotransferase; ALP=Alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood ur
appli
catio
n
density lipoprotein; SGOT=serum glutamic oxaloacetic transaminase; ap
plica
tion
density lipoprotein; SGOT=serum glutamic oxaloacetic transaminase;
and
and a
ny ex
tensio
ns 475.84 umol/L
exten
sions
475.84 umol/L
475.84 umol/L (F);
exten
sions
475.84 umol/L (F);
exten
sions
or or va
riatio
ns th
ereof.
UCB 8 August2016Statistical Analysis Plan Brivaracetam N01199
Confidential Page 45 of 47
13.3.3 Urinalysis
Qualitative urine parameters are generally reported by a descriptive score, which differs among laboratories. For data analysis purpose, a four-point scale is used. Five-point, six-point, or seven-point scales will be collapsed into a four-point scale first. A value is considered possibly clinically significant treatment emergent abnormal if an upward shift of at least 2 degrees from the baseline occurs under investigational treatment. To collapse the results in a five-point scale into a four-point scale, the lowest two positive results will be combined (see example below). For results reported with a scale of more than five-point, please consult your study physician for how to collapse into four-point scale.
Original Five-point Scale Four-point Scale
Negative/None Negative/NoneTrace/Rare/Mild/A Few Trace/1+/Rare/Mild/A Few1+2+/Mod 2+/Mod3+/Sev 3+/Sev
13.3.4 Vital signs and body weight
Pulse rate For 1 m to 12 m: <110 bpm and a decrease of > 20 bpm from baseline or > 180 bpm and an increase of > 20 bpm from baseline
For 12 m to 3 y: < 90 bpm and a decrease of > 20 bpm from baseline or > 150 bpm and an increase of > 20 bpm from baseline
For 3 y to 12 y: < 65 bpm and a decrease of > 20 bpm from baseline or > 130 bpm and an increase of > 20 bpm from baseline
For 12 y to 17 y: < 60 bpm and a decrease of > 20 bpm from baseline or > 120 bpm and an increase of > 20 bpm from baseline
For 17 y: < 50 bpm and a decrease of > 30 bpm from baseline or > 120 bpm and an increase of > 30 bpm from baseline
bpm=Beats per minute.
REDACTED 180 bpm and an increase of
REDACTED 180 bpm and an increase of
For 12 m to
REDACTED
For 12 m to
REDACTED
baseline or
REDACTED
baseline or baselineREDACTED
baseline
COPY <110 bpm and a decrease of >
COPY <110 bpm and a decrease of >
COPY 180 bpm and an increase of COPY 180 bpm and an increase of COPY
This do
cumen
t can
not
cann
ot
cann
ot bpm=Beats per minute.
cann
ot bpm=Beats per minute.
be us
ed to
supp
ort
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ort an
y baselineany baselineany
any m
arketi
ng
marketi
ng
For 3
marketi
ng
For 3
marketi
ng
y to
marketi
ng
y to baseline or mark
eting
baseline or
autho
rizati
on <110 bpm and a decrease of >
autho
rizati
on <110 bpm and a decrease of >
180 bpm and an increase of
autho
rizati
on
180 bpm and an increase of
3 y
autho
rizati
on
3 y:
autho
rizati
on
: < 90 bpm and a decrease of >
autho
rizati
on
< 90 bpm and a decrease of >> au
thoriz
ation
> 150 bpm and an increase of autho
rizati
on
150 bpm and an increase of
appli
catio
n
<110 bpm and a decrease of >appli
catio
n
<110 bpm and a decrease of >180 bpm and an increase of
appli
catio
n
180 bpm and an increase of ap
plica
tion a
nd an
y exte
nsion
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ariati
ons
point, varia
tions
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thereo
f.
UCB 8 August2016Statistical Analysis Plan Brivaracetam N01199
Confidential Page 46 of 47
Systolic blood pressure For 1 m to 12 m: < 60 mmHg and a decrease of > 20 mmHg from baseline or > 110 mmHg and an increase of > 30 mmHg from baseline
For 12 m to 6 y: < 70 mmHg and a decrease of > 20 mmHg from baseline or > 120 mmHg and an increase of > 30 mmHg from baseline
For 6 y to 13 y: < 70 mmHg and a decrease of > 20 mmHg from baseline or > 130 mmHg and an increase of > 30 mmHg from baseline
For 13 y and 17 y: < 90 mmHg and a decrease of > 20 mmHg from baseline or > 140 mmHg and an increase of > 30 mmHg from baseline
For 17 y: < 90 mmHg and a decrease of > 30 mmHg from baseline or > 180 mmHg and an increase of > 40 mmHg from baseline
Diastolic blood pressure For 1 m to 12 m: < 40 mmHg and a decrease of > 15 mmHg from baseline or > 60 mmHg and an increase of > 20 mmHg from baseline
For 12 m to 6 y: < 45 mmHg and a decrease of > 15 mmHg from baseline or > 80 mmHg and an increase of > 20 mmHg from baseline
For 6 y to 13 y: < 50 mmHg and a decrease of > 15 mmHg from baseline or > 85 mmHg and an increase of > 20 mmHg from baseline
For 13 y to 17 y: < 55 mmHg and a decrease of > 20 mmHg from baseline or > 90 mmHg and an increase of > 30 mmHg from baseline
For 17 y: < 50 mmHg and a decrease of > 20 mmHg from baseline or > 105 mmHg and an increase of > 30 mmHg from baseline
Weight For 17 y: < 3% or 97% of the normal body weight growth curve ranges for the age at date of weight assessment (a) and gender;
For 17 y: change of 7% of baseline weight(a) Once the subject reaches 17 years of age use the body curve criteria of a 17 year old regardless of their age in the study.
REDACTED
REDACTED 6 y
REDACTED 6 y: < 45 mmHg and a decrease of > 15 mmHg
REDACTED : < 45 mmHg and a decrease of > 15 mmHg
from baseline or > 80 mmHg and an increase of
REDACTED from baseline or > 80 mmHg and an increase of
mmHg from baseline
REDACTED
mmHg from baseline
For 6 REDACTED
For 6 y to REDACTED
y to
COPY 12 m: < 40 mmHg and a decrease of > 15 mmHg
COPY 12 m: < 40 mmHg and a decrease of > 15 mmHg from baseline or > 60 mmHg and an increase of
COPY from baseline or > 60 mmHg and an increase of > 20 mmHg from baseline
COPY > 20 mmHg from baseline
This do
cumen
t
docu
ment c
anno
t Weight
cann
ot Weight be
be
used
to su
pport
supp
ort an
y For 13 any For 13
from baseline or > 90 mmHg and an increase of an
y from baseline or > 90 mmHg and an increase of an
y mark
eting
y to
marketi
ng
y to
marketi
ng
marketi
ng
13 y
marketi
ng
13 yfrom baseline or > 85 mmHg and an increase of
marketi
ng
from baseline or > 85 mmHg and an increase of > 20 mmHg from baselinemark
eting
> 20 mmHg from baseline
autho
rizati
on > 20 mmHg from baseline
autho
rizati
on > 20 mmHg from baseline
: < 45 mmHg and a decrease of > 15 mmHg
autho
rizati
on
: < 45 mmHg and a decrease of > 15 mmHg from baseline or > 80 mmHg and an increase of
autho
rizati
on
from baseline or > 80 mmHg and an increase of mmHg from baselineau
thoriz
ation
mmHg from baseline
appli
catio
n baseline or > 180 mmHg and an increase of > 40 mmHg from
appli
catio
n baseline or > 180 mmHg and an increase of > 40 mmHg from
appli
catio
n
12 m: < 40 mmHg and a decrease of > 15 mmHg
appli
catio
n
12 m: < 40 mmHg and a decrease of > 15 mmHg from baseline or > 60 mmHg and an increase of ap
plica
tion
from baseline or > 60 mmHg and an increase of > 20 mmHg from baselineap
plica
tion
> 20 mmHg from baselineappli
catio
n and
: < 90 mmHg and a decrease of > 30 mmHg from
and : < 90 mmHg and a decrease of > 30 mmHg from
baseline or > 180 mmHg and an increase of > 40 mmHg from and baseline or > 180 mmHg and an increase of > 40 mmHg from
any
: < 90 mmHg and a decrease of > 30 mmHg from any
: < 90 mmHg and a decrease of > 30 mmHg from
exten
sions
: < 90 mmHg and a decrease of > 20
exten
sions
: < 90 mmHg and a decrease of > 20
mmHg from baseline or > 140 mmHg and an increase of
exten
sions
mmHg from baseline or > 140 mmHg and an increase of
or va
riatio
ns
: < 70 mmHg and a decrease of > 20 mmHg va
riatio
ns
: < 70 mmHg and a decrease of > 20 mmHg va
riatio
ns th
ereof.
UCB 8 August2016Statistical Analysis Plan Brivaracetam N01199
Confidential Page 47 of 47
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN
Rational for the amendment
The primary purpose for the amendment is (1) remove rules and definitions based on data cutoffs for interim analyses; (2) remove the summary analysis for direct cost parameter and indirect cost parameters, and as well as Socio-professional data.
Change #1 (global)
Removed all rules and definitions based on data cutoffs for interim analyses throughout SAP.
Change #2
Section 8.2.5 Direct cost parameters, Section 8.2.6 Indirect cost parameters, Section 8.2.7 Socio-professional data
Removed all direct/indirect cost parameters and socio-professional data summary analysis.
Change #3
Removed signature page. Using e-signature approval process through Mikado.
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