2012N157680_09 CONFIDENTIAL The GlaxoSmithKline group of companies AMB116457 1 TITLE PAGE Division: Worldwide Development Information Type: Protocol Amendment Title: An open-label extension study of the long-term safety, tolerability and efficacy of Ambrisentan in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Compound Number: GSK1325760 Effective Date: 16-FEB-2015 Protocol Amendment Number: 07 Subject: Inoperable Chronic Thromboembolic Pulmonary Hypertension, Endothelin Receptor Antagonist. Authors: (CDBU Responsible Medical, GSK) , (RD Projects Clinical Platforms & Sciences), (R&D Projects Clinical Platforms and Sciences, Clinical Statistics), (Project Physician Lead, CVM MDC). Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. PPD PPD PPD PPD
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2012N157680_09 CONFIDENTIALThe GlaxoSmithKline group of companies AMB116457
Title: An open-label extension study of the long-term safety, tolerability and efficacy of Ambrisentan in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.
PPD PPD
PPD
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2012N157680_09 CONFIDENTIALThe GlaxoSmithKline group of companies AMB116457
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Revision Chronology
GlaxoSmithKlineDocument Number
Date Version
2012N157680_01 2013-JAN-24 Original
2012N157680_02 2013-MAR-12 Amendment No. 1
Update to maximum study sample size following changes to the Double-Blind study (AMB115811).
Correction to the IP storage conditions to change from 15-30ºC to up to 30 ºC.
Revision of pregnancy follow-up information to include partners of male subjects in the study and is consistent with the AMB115811 study
Correct to the description of several efficacy assessments and timepoints to remove the requirement to perform efficacy tests 30 days after discontinuation of IP (safety only is required for this follow-up).
2012N157680_03 2013-JUL-03 Amendment No. 2
Clarification on the study design: subject’s study participation duration:
Clarifications on inclusion criteria:
-in case of prematurely withdrawal from study AMB115811 for whatever reason, the investigator will decide whether or not the subject will receive the IP.
-add of some general inclusion criteria on reliable methods of contraception, non participation to another study and signature of the approved consent form.
Clarification on the treatment given after the end of the study.
Change in the visit window of month 1 and monthly visits ( 7 days)
Vital signs, clarification on blood pressure measurements
Clarification on the study medication storage temperatures
2012N157680_04 2013-JUL-16 Amendment No. 3
Amendment No. 3 (Specific to UK)
Clarification on the study design: subject’s study participation in the open label extension and clarification of the expected date of marketing authorization.
Clarifications on the withdrawal criteria: a subject will discontinue from the
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investigational product or from the study in case of pregnancy.
Clarification on the treatment after the end of the study.
2012N157680_05 2013-JUL-17 Amendment No. 3
Amendment No. 03 (complement specific to UK)
Clarification on the amendment 03 on the subject’s study participation in the open label extension
Clarification on the date of study end
2012N157680_06 2014-JAN-02 Amendment No. 4
Amendment No. 04 (specific to Italy)
Clarification on the population included in the open label extension study.
2012N157680_07 2014-JAN-02 Amendment No. 5
Amendment No. 05 (specific to China)
Clarification about the central laboratory location where Chinese inhibin B samples will be analysed.
2012N157680_08 2014-JUN-03 Amendment No. 6
Amendment No. 06 (specific to China)
Clarification about the central laboratory location where Chinese inhibin B samples will be analysed and GSK exemption for acetaminophen test.
Correction to the IP storage temperature.
2012N157680_09 2015-FEB-16 Amendment No. 7
The purpose of this amendment is to provide clarity following GSK decision to stop the study early.
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.
Sponsor Medical Monitor Contact Information:
Dr
Tel:
Mobile :
Sponsor Serious Adverse Events (SAE) Contact Information: same as above
I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.
Investigator Name: _____________________________
Investigator Signature Date
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
2.2.1. Efficacy assessments ..................................................................182.2.2. Other ...........................................................................................18
3. INVESTIGATIONAL PLAN.....................................................................................193.1. Study Design ..............................................................................................19
4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................194.1. Number of Subjects ....................................................................................194.2. Inclusion Criteria .........................................................................................194.3. Exclusion Criteria........................................................................................20
4.3.1. Exclusion from IP.........................................................................204.4. Withdrawal Criteria .....................................................................................21
5. STUDY TREATMENTS..........................................................................................215.1. Investigational Product and Other Study Treatment....................................215.2. Treatment Assignment................................................................................225.3. Blinding.......................................................................................................225.4. Product Accountability ................................................................................235.5. Treatment Compliance................................................................................235.6. Concomitant Medications and Non-Drug Therapies....................................23
5.6.1. Permitted Medications and Non-Drug Therapies..........................235.6.2. Addition of Other Targeted PAH Therapeutic Agents...................235.6.3. Prohibited Medications and Non-Drug Therapies.........................245.6.4. Prohibited medical interventions ..................................................24
5.7. Treatment after the End of the Study ..........................................................245.8. Treatment of Study Treatment Overdose....................................................24
6. STUDY ASSESSMENTS AND PROCEDURES .....................................................256.1. Critical Baseline Assessments ....................................................................286.2. Safety .........................................................................................................28
6.2.1. Physical examination ...................................................................286.2.2. Electrocardiogram........................................................................286.2.3. Vital Signs, Body Weight..............................................................286.2.4. Change in Dose...........................................................................29
6.2.6. Liver chemistry stopping and followup criteria..............................306.2.7. Adverse Events............................................................................32
6.2.7.1. Definition of an AE......................................................336.2.7.2. Definition of a SAE .....................................................33
6.2.8. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs.........................................................35
6.2.9. Pregnancy ...................................................................................356.2.10. Time Period and Frequency of Detecting AEs and SAEs.............356.2.11. Prompt Reporting of Serious Adverse Events and Other
Events to Sponsor .......................................................................366.2.11.1. Regulatory reporting requirements for SAEs ..............37
6.3. Efficacy assessments .................................................................................376.3.1. 6 minute walking distance (6MWD) test .......................................376.3.2. Clinical worsening of CTEPH.......................................................376.3.3. Addition of Other Targeted PAH Therapeutic Agents...................386.3.4. Change in Dose of Ambrisentan ..................................................386.3.5. Subject Global Assessment (SF-36 short form) ...........................386.3.6. WHO functional class...................................................................386.3.7. N-terminal pro-B type natriuretic peptide (NT-Pro BNP)...............386.3.8. Cardiopulmonary hemodynamic assessments.............................386.3.9. Borg CR10 Scale (BCR10S)........................................................38
6.4. Health Outcomes........................................................................................396.4.1. SF-36 Health Survey ...................................................................39
7. DATA MANAGEMENT ...........................................................................................39
8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................398.1. Hypotheses.................................................................................................398.2. Study Design Considerations......................................................................40
8.3. Data Analysis Considerations .....................................................................408.3.1. Analysis Populations....................................................................408.3.2. Analysis Data Sets.......................................................................408.3.3. Treatment Comparisons ..............................................................40
8.3.3.1. Primary Comparisons of Interest ................................408.3.3.2. Other Comparisons of Interest....................................41
8.3.4. Interim Analysis ...........................................................................418.3.5. Key Elements of Analysis Plan ....................................................41
9. STUDY CONDUCT CONSIDERATIONS ...............................................................439.1. Posting of Information on Publicly Available Clinical Trial Registers............439.2. Regulatory and Ethical Considerations, Including the Informed
Consent Process ........................................................................................43
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9.3. Quality Control (Study Monitoring) ..............................................................439.4. Quality Assurance.......................................................................................449.5. Study and Site Closure ...............................................................................449.6. Records Retention ......................................................................................449.7. Provision of Study Results to Investigators, Posting of Information
on Publicly Available Clinical Trials Registers and Publication ....................459.8. Independent Data Monitoring Committee (IDMC) .......................................46
11. APPENDICES ........................................................................................................5011.1. Appendix 1: Cardiopulmonary Hemodynamic Sub-study ............................5011.2. Appendix 2: List of Highly Effective Methods for Avoidance of
Pregnancy in Women of Childbearing Potential ..........................................5111.3. Appendix 3: 6 Minute Walk Distance Test...................................................5211.4. Appendix 4: Borg CR10 Scale ....................................................................5511.5. Appendix 5: SF-36 Quality of Life Questionnaire.......................................5711.6. Appendix 6: Liver Chemistry Stopping and Followup Criteria......................6311.7. Appendix 7: Country Specific Requirements ...............................................6411.8. Appendix 8: Protocol Amendment Changes................................................65
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LIST OF ABBREVIATIONS
ABS AmbrisentanADME Absorption, distribution, metabolism, and eliminationAE Adverse eventALT Alanine aminotransferaseAST Aspartate aminotransferaseAUC Area under the plasma concentration-time curveBid Twice dailybig ET-1 Proendothelin-1BDIBCR10S
Borg dyspnea indexBorg CR10 Scale
BMI Body mass indexBNPBSA
B-type natriuretic peptideBody surface area
BSEP Bile salt export pumpBUNCBP
Blood urea nitrogenChildbearing potential
CCB Calcium channel blockers CEC Clinical Endpoint CommitteeCI Cardiac IndexCmax Maximum plasma concentrationCONMED Concomitant medicationCRF Case report formCRO Clinical research organizationCT Computed axial tomography scanCTD Connective tissue diseaseCYP Cytochrome P450CTEPHDB
EMA European Medicines AuthorityEOS End of StudyERA Endothelin receptor antagonistET-1 Endothelin-1ETA Endothelin receptor type AETB Endothelin receptor type BEU European UnionFAV Final Assessment Visit FC Functional ClassFDA Food and Drug AdministrationFEV1 Forced expiratory volume in 1 second
HIV Human Immunodeficiency VirusHMG-CoA 5-hydroxy-3-methylglutaryl-coenzyme AHRQL Health Related Quality of LifeIB Investigator’s BrochureICF Informed Consent FormICH International Conference on HarmonisationIDMC Independent Data Monitoring CommitteeIEC Independent Ethics CommitteeINR International normalized ratioIP Investigational productiPAH Idiopathic pulmonary arterial hypertensionITT Intent to treatIUD Intrauterine deviceIVRS Interactive Voice Response SystemIRB Institutional Review BoardIvKM
IntravenousKaplan Meier
LFT Liver function testLOCF Last-observation-carried-forwardLVEDP Left ventricle end diastolic pressureMedDRA Medical Dictionary for Regulatory Activitiesm Metermg Milligrammin MinutemmHg Millimeters mercurymPAP Mean pulmonary artery pressureMRP2 Multidrug resistance-associated protein 2NDA New Drug ApplicationNO Nitric oxideNT-pro-BNP N-terminal pro-B-type natriuretic peptideNTCP Sodium-taurocholate co-transporter proteinNYHA New York Heart AssociationOATP Organic anion transporter polypeptideodOLE
Once dailyOpen Label Extension
PAH Pulmonary arterial hypertensionPAH-CTD Pulmonary arterial hypertension associated with connective
Tissue diseasePAPPBO
Pulmonary artery pressurePlacebo
PCWP Pulmonary capillary wedge pressurePDE-5 Phosphodiesterase type 5
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PEA Pulmonary EndarterectomyPGI2 ProstacyclinP-gp P-glycoproteinPH Pulmonary hypertensionpo By mouth, orallyPP Per ProtocolPT Prothrombin timePVOD Pulmonary veno-occlusive diseasePVR Pulmonary vascular resistanceQoL Quality of LifeRAP Right atrial pressureRHC Right heart catheterizationRoW Rest of WorldSAE Serious adverse eventSaO2 Arterial oxygen saturationSF-36 SF-36 Health SurveySOC System Organ ClassSPC Summary of Product CharacteristicsSUSAR Suspected Unexpected Serious Adverse Reactiontid Three times dailyTLC Total lung capacityTtCW Time to Clinical WorseningTtCF Time to Clinical FailureUGT Uridine glucuronosyltransferaseULN Upper limit of normalUS United StatesV/Q Scan Ventilation-perfusion scan WHO World Health Organization6MWD 6-minute walk distance
Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of companies
FLOLAN Borg CR10 scaleLetairisnQuery AdvisorSF-36TracleerVolibris
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PROTOCOL SUMMARY
Rationale
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition resulting in increased pulmonary vascular resistance, progressive pulmonary hypertension (PH) and right heart failure. CTEPH is associated with considerable morbidity and mortality and forms group IV of the current World Health Organization (WHO) classification system for PH [Galiè, 2009]. The true incidence of CTEPH is not known, with studies suggesting as many a 3.8% of patients develop the condition after an acute pulmonary embolism, though in up to 60% of cases of CTEPH no history acute PE can be identified.
The preferred treatment for CTEPH is surgical disobliteration of the pulmonary arteries by pulmonary endarterectomy (PEA). European PAH guidelines recommend that CTEPH be treated in an expert centre and that PAH specific therapies may play a role in the management of inoperable CTEPH. However, given the limited data, the guidelines conclude that further studies are necessary to obtain data on the efficacy and safety of PAH therapies in patients with CTEPH, and these patients should be treated within clinical trials whenever possible [Galiè, 2009].
Ambrisentan (VOLIBRIS tablets) is an endothelin receptor antagonist (ERA) marketed in the European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in the United States as Letairis by Gilead Sciences Inc. Ambrisentan is indicated for the treatment of adult patients with PAH to improve exercise capacity, decrease the symptoms of PAH, and delay clinical worsening.
The primary purpose of this study is to provide clinically relevant information on the long term safety of Ambrisentan in subjects with inoperable CTEPH. This study is only open to patients who have participated in Study AMB115811, a randomised, multicenter study comparing the effect on 6 Minute Walking Distance (6MWD) of Ambrisentan or placebo in subjects with inoperable CTEPH, and in whom continued treatment with Ambrisentanis warranted.
Objective(s)
The primary objective of this study is to evaluate the long term safety and tolerability of Ambrisentan in subjects with inoperable CTEPH who have participated in AMB115811. The secondary objective is to obtain supportive efficacy data (change from baseline in efficacy parameters) on the use of Ambrisentan in CTEPH.
Study Design
This is an open label, long term extension to Study AMB115811 and given the decision to stop study AMB115811, this study will also be stopped. All subjects will continue until their next scheduled study visit, at which time they will be informed and have an End of study visit and then follow up visit. Then they will be transitioned to local standard of care. Patients that have no local access to any alternative
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treatment and who in their physician’s opinion have responded to ambrisentan treatment may be eligible for continued treatment with ambrisentan, which could be through a compassionate program, according to the local regulatory environment and these subjects may continue in the study until this is secured.If compassionate use or similar programs are not allowed per local regulations (i.e. continued treatment with ambrisentan no possible per local laws and regulations), then subjects will be transitioned onto local standard of care.
Study Endpoints/Assessments
Primary
The primary objective is the long-term safety and tolerability of Ambrisentan in the CTEPH population (see Safety).
oedema, ascites and signs of deep vein thrombosis); Vital Signs (including body mass index at the entry visit only); The time to change in dose of Ambrisentan or other targeted PAH therapeutic
agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events).
Secondary
Efficacy
The change from Study AMB115811 baseline and week 16 visits in the 6 minute walking distance (6MWD) test evaluated every three months;
The change from Study AMB115811 baseline and week 16 visits in WHO functional class every three months;
The change from Study AMB115811 baseline and week 16 visits in Borg CR10 Scale (BCR10S) immediately following exercise, every three months;
Clinical worsening of CTEPH as defined by the time from randomization to the first occurrence of
Death lung transplantation hospitalization for worsening CTEPH atrial septostomy addition of parenteral prostanoids appearance of two or more CTEPH worsening events*;
*Worsening events to consider:
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1. A decrease from baseline of at least 20 percent in the distance walked during the six-minute walk test;
2. An increase of one or more WHO Functional Class; 3. Worsening right ventricular failure (e.g., as indicated by increased jugular
venous pressure, new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and TDI of the tricuspid annulus);
4. Rapidly progressing cardiogenic, hepatic, or renal failure; 5. Refractory systolic hypotension (systolic blood pressure less than 85
mmHg).
Clinical Worsening events will be independently adjudicated.
The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to the following reasons:- Deterioration of clinical condition;- Lack of beneficial effect with previous therapy (not reaching set treatment
goals); The time to change in dose of Ambrisentan or other targeted PAH therapeutic
agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition;
The change from Study AMB115811 baseline and week 16 visits in Subject Global Assessment every three months using the Short Form 36 Health Survey (SF-36)
Change from Study AMB115811 baseline and week 16 visits in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration every three months.
Other
The change from Study AMB115811 baseline and week 16 visits cardiopulmonary hemodynamic assessments data in subjects in whom hemodynamic data is considered part of the standard of care (see Appendix 1).
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by intraluminal thrombus organization, fibrous stenosis of pulmonary artery, and subsequent vascular remodeling in small unobstructed vessels, resulting in increased pulmonary vascular resistance, progressive pulmonary hypertension (PH) and right heart failure. CTEPH is associated with considerable morbidity and mortality and forms group IV of the current World Health Organization (WHO) classification system for PH.
The true incidence of CTEPH is not known, with studies suggesting as many a 3.8% of patients develop the condition after an acute pulmonary embolism, though in up to 60% of cases of CTEPH no history acute PE can be identified. Incomplete clot lysis, with subsequent organization of the obstructing material into vessel walls, causes continued obstruction to pulmonary vascular blood flow. A peripheral vasculopathy with microvascular changes indistinguishable from idiopathic pulmonary arterial hypertension can then occur even in the areas of the pulmonary vascular bed that have been unaffected by thromboembolism. The pathogenesis is poorly understood, though Endothelin-1 (ET-1) has been shown to be significantly raised in patients with CTEPH.
1.1.2. Current treatment options
The preferred treatment for CTEPH is surgical disobliteration of the pulmonary arteries by pulmonary endarterectomy (PEA). The current reported perioperative mortality is 5 to 10% in experienced centers, but there are significant improvements in pulmonary hemodynamics and self-reported functional class. Some patients, however, have thromboembolic disease that is too distal in the pulmonary arterial bed to be surgically accessible and/or have hemodynamic compromise out of proportion to the degree of segmental arterial obstruction present on imaging. Management of these patients was previously supportive. As very similar histopathologic changes of pulmonary arterial hypertension (PAH) are seen in patients with CTEPH, the disease-modifying therapies used in other forms of pulmonary arterial hypertension have been utilised around the world. Riociguat is the first of a new class of drugs, the sGC stimulators, which has demonstrated its efficacy in CTEPH patients. It was registered in the US (in October 2013) and Europe (in March 2014) and soon in other countries.
There is currently data from a number of non-randomised trials which appear to support the use of a number PAH-specific medications for the treatment of PAH. One randomised, placebo-controlled trial of the non-selective endothelin receptor antagonist (ERA) bosentan has been published. The trial, with independent co-primary endpoints, showed a highly significant improvement in pulmonary vascular resistance (PVR) or -22%, though this did not translate into an improvement in exercise capacity (6MWD -2.2m p=NS). The reason for this improvement in cardiac haemodynamics failing to show through in an improvement in the clinical status of the subject is unknown, though it is
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postulated that the study may have recruited subjects who were unable to show an improvement in exercise capacity, or that the study was too short.
1.2. Rationale
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition, associated with considerable morbidity and mortality. Without intervention, the prognosis of patients with CTEPH is poor and depends on the hemodynamic severity of pulmonary hypertension (Riedel, 1982, Lewczuk, 2001).
The only potentially curative treatment is surgical removal of the obstructive material by pulmonary Endarterectomy (PEA) (Jamieson, 2003). However, a substantial percentage of patients with CTEPH are not operable, and 10% to 15% of operated patients suffer from persistent pulmonary hypertension (Auger, 2009).
Given that the histopathologic changes seen in CTEPH, the evidence that ET-1 levels are raised, and the clinical evidence (mainly uncontrolled) that these patients may benefit from PAH-targeted therapies (Bresser, 2004, Suntharalingam, 2008, Hughes, 2006, Jaïs,2008). It is hypothesised that even after the registration of riociguat there is still an unmet medical need in CTEPH disease; therefore the study success will be an opportunity for inoperable CTEPH subjects to benefit from ambrisentan, a PAH specific treatment belonging to another pathway.
2. OBJECTIVE(S)
The primary objective of this study is to evaluate the long term safety and tolerability of Ambrisentan in subjects with inoperable CTEPH who have participated in AMB115811. The secondary objective is to obtain supportive efficacy data on the use of Ambrisentanin CTEPH.
2.1. Primary
The primary objective is the long-term safety and tolerability of Ambrisentan in the CTEPH population (see Safety).
oedema, ascites and signs of deep vein thrombosis); Vital Signs (including body mass index at the entry visit only); The time to change in dose of Ambrisentan or other targeted PAH therapeutic
agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events).
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2.2. Secondary
2.2.1. Efficacy assessments
6 minute walking distance (6MWD) test evaluated every three months; WHO functional class every three months; Borg CR10 Scale (BCR10S) immediately following exercise, every three months; Clinical worsening of CTEPH as defined by the time from randomization to the
first occurrence of Death lung transplantation hospitalization for worsening CTEPH atrial septostomy addition parenteral prostanois appearance of two or more CTEPH worsening events*] (TTCW);
*Worsening events to consider:
1. A decrease from baseline of at least 20 percent in the distance walked during the six-minute walk test;
2. An increase of one or more WHO Functional Class; 3. Worsening right ventricular failure (e.g., as indicated by increased jugular
venous pressure, new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and TDI of the tricuspid annulus);
4. Rapidly progressing cardiogenic, hepatic, or renal failure; 5. Refractory systolic hypotension (systolic blood pressure less than 85
mmHg). Addition of another targeted PAH therapeutic agents (prostanoids, PDE-5
inhibitors) due to the following reasons:- Deterioration of clinical condition;- Lack of beneficial effect with previous therapy (not reaching set treatment
goals); Change in dose of Ambrisentan or other targeted PAH therapeutic agents
(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition;
Subject Global Assessment every three months using the Short Form 36 Health Survey (SF-36)
N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration every three months.
2.2.2. Other
Cardiopulmonary haemodynamic assessments data in subjects in whom haemodynamic data is considered part of routine clinical practice. This will not be considered a study procedure and will not be reimbursed by the Sponsor (see Appendix 1).
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3. INVESTIGATIONAL PLAN
3.1. Study Design
This is an open label, long term extension to Study AMB115811. All subjects mayremain in the extension study for a minimum of 18 months. Beyond the 18-monthperiod, subjects may continue in the extension study until one of the following conditions is met:
Development for use in the CTEPH population is discontinued or product is not approved by the local regulatory authority
The investigator decides to discontinue the subject or subject decides to discontinue from the study.
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.
Subjects currently enrolled in AMBER 2 (AMB116457) will be transitioned to local standard of care. Patients that have no local access to any alternative treatment and who in their physician’s opinion have responded to ambrisentan treatment will be eligible for continued treatment with ambrisentan which could be through a compassionate program according to the local regulatory environment or other alternatives for treatment continuation and these subjects may continue in the study until this is secured. (see paragraph 4.4).If alternatives for continued treatment with ambrisentan are not possible per local regulations or laws then subjects will be transitioned onto local standard of care for CTEPH.
Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.
4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1. Number of Subjects
As this study is only open to subjects who have participated in AMB115811, no more than 33 subjects will be enrolled into this extension study.
4.2. Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
Have been randomized to the protocol for AMB115811 and have met the following:
a) Completed the Week 16 visit in AMB115811;b) Or prematurely withdrew from AMB115811 for whatever reason*
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*where IP has been stopped due to safety or efficacy reasons .General considerations:
c) Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of Investigational Product (reliable methods of contraception are described in Appendix 2).
As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counseled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.
d) Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.
e) Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures.
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Investigators Brochure and product label for PAH indication.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
4.3. Exclusion Criteria
4.3.1. Exclusion from IP
Subjects meeting any of the following criteria must not receive Ambrisentan, however may still be followed-up as part of the study and be treated according to best clinical practice as decided by the investigator:
1. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients
2. Female subjects who are pregnant or breastfeeding or no-longer agree to comply with using effective contraception as defined in Appendix 2
3. Subjects with ALT and/or AST ≥ 3xULN4. Subjects with bilirubin ≥ 2xULN (with>35% direct bilirubin)5. Subjects with severe renal impairment (estimated creatinine clearance <30
mL/min assessed within the previous 45 days) at the point of transition from Study AMB115811
6. Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the point of transition from study AMB115811
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7. Subject with clinically significant fluid retention in the opinion of the investigator8. Subject with clinically significant anemia in the opinion of the investigator9. Subjects who are to enter another clinical trial or be treated with another
investigational product after exiting Study AMB115811.
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
4.4. Withdrawal Criteria
The Independent Data Monitoring Committee (IDMC) may recommend that the Sponsor stop the study at any time if they consider that the potential risks outweigh the potential benefits (based on review of safety [adverse experiences] data every three months).On the 11 December 2014, the Independent Data Monitoring Committee (IDMC) has made the recommendation to stop the AMBER 1 study due to futility of enrolment.
A subject may also be discontinued from Investigational Product, or from the study, for the following reasons:• Liver chemistry values exceeding the threshold criteria (as outlined in Section 6.2.7);• Adverse event which in the opinion of the investigator requires withdrawal;• Pregnancy;• Consent withdrawn;• Lost to follow-up;• Protocol violation; • Termination of study by sponsor;• Investigator’s discretion (document reason in eCRF)
Subjects currently enrolled in AMBER 2 (AMB116457) will be transitioned to local standard of care. Patients that have no local access to any alternative treatment and who in their physician’s opinion have responded to ambrisentan treatment will be eligible for continued treatment with ambrisentan which could be through a compassionate program/alternative treatment according to the local regulatory environment.
Before their end of study visit, investigators will follow up with their local GSK study contact to secure alternative treatment for eligible AMBER 2 patients (i.e. patients with no other treatment option and who have had a good clinical response to treatment with ambrisentan and where this treatment is allowed under local regulations) and these subjects may remain in the study until this is secured.
5. STUDY TREATMENTS
Investigational product: Ambrisentan in the form of 5mg tablets.
5.1. Investigational Product and Other Study Treatment
The sponsor will provide Ambrisentan in the form of round, white, film-coated, immediate-release tablets, containing 5mg Ambrisentan. Subjects will be dosed orally
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(tablet must be swallowed whole) once daily. Subjects may receive 5mg, or 10 mg of Ambrisentan OD.
Investigational Product will be packaged in Ambrisentan monthly dosing packs containing a total of 35 tablets of Ambrisentan in child resistant foil blister strips.
Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.
Investigational product must be stored in a secure area under the appropriate physical conditions for the product. The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the investigational products will be responsible for ensuring that the investigational product used in the study will be securely maintained as specified by the Sponsor and in accordance with applicable regulatory requirements.
Study medication will be stored in secure (locked) areas at a temperature between 15 C and 30 C (59-86 F) and dispensed according to the protocol under the supervision of the Investigator or his/her designee. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol. Subjects will be instructed to keep dispensed treatment in a secure place, out of reach of children, and at room temperature.
Subjects will be instructed to return unused medication to the Investigator. Any unused product will be returned by the Investigator to GSK or destroyed at the site based on local regulations.
5.2. Treatment Assignment
This is an open label study. All subjects eligible to receive IP will receive Ambrisentaninitially at a dose of 5mg OD.
Based on the investigator’s best judgment, the subject may continue on 5mg OD, or be up-titrated to 10mg OD. The dose may also be adjusted back to 5mg OD at investigator discretion. Whenever the dose of Ambrisentan is changed, one of the following reasons for the change will be recorded:
Deterioration of clinical condition; Tolerability issues (e.g. adverse events); Other.
5.3. Blinding
This is an open-label study.
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5.4. Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.
5.5. Treatment Compliance
Compliance will be assessed by the investigator or designee every three months and recorded in the eCRF. Compliance is calculated based on the number of tablets dispensed and the number of tablets returned, and the days between the date dispensed and the date returned. Compliance should be assessed for each child resistant blister pack to ensure an accurate assessment. The range of compliance at the appropriate visits will be recorded on the eCRF.
5.6. Concomitant Medications and Non-Drug Therapies
5.6.1. Permitted Medications and Non-Drug Therapies
Standard medical treatment(s), other than those that are explicitly excluded below, that are required by the subject may be added or changed at any time. All prescribed treatments and changes in doses will be recorded in the eCRF. Whenever the dose of other targeted PAH therapeutic agents (e.g. prostanoid or PDE-5 inhibitor) is changed, one of the following reasons will be recorded:
• Deterioration of clinical condition;
• Tolerability issues (e.g. adverse events);
• Other.
Subjects may begin oral contraceptive therapy as per the prescribing information.
5.6.2. Addition of Other Targeted PAH Therapeutic Agents
Other targeted PAH therapeutic agents (e.g., prostanoid or PDE-5 inhibitor) may used at the discretion of the investigator (these agents will not be supplied by the sponsor). Prior to addition of a targeted PAH therapy, up-titration to AMB 10mg OD may be considered. Whenever a new treatment is used, one of the following reasons will be recorded:
Deterioration of clinical condition; Lack of beneficial effect with previous therapy (not reaching set treatment goals); Electively (preset treatment strategy independent of effects with previous
therapies).
Endothelin receptor antagonists may only be used if the subject has discontinued IP.
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5.6.3. Prohibited Medications and Non-Drug Therapies
During the study, subjects receiving IP may not receive:
• Endothelin receptor antagonists other than Ambrisentan (e.g., bosentan); • If subject receives Cyclosporine A the dose of Ambrisentan must be limited to 5mg OD
5.6.4. Prohibited medical interventions
Balloon Pulmonary Angioplasty (BPA) should not be conducted whilst the subjects remains on IP. If BPA is required, subjects should withdraw from IP.
Subjects in the study not taking IP may receive BPA. It should be recorded in the eCRF.
5.7. Treatment after the End of the Study
Subjects can remain in this study until one of the following conditions is met:
The product is approved locally for use in inoperable CTEPH patients; Development for use in the CTEPH population is discontinued or product is not
approved locally; The investigator decides to discontinue the subject or subject decides to
discontinue from the study.
The Investigator should then treat the subjects according to best standard of care available to the investigator. Subjects will be followed for 30 days post their last dose of study medication. See time and event table page 28 for the follow-up visit.
Before their end of study visit, investigators will follow up with their local GSK study contact to secure alternative treatment for eligible AMBER 2 patients (i.e. patients with no other treatment option and who have had a good clinical response to treatment with ambrisentan and where this treatment is allowed under local regulations).
GSK will continue to provide post-study medication only to subjects in territories wherethe medication is not available through normal distribution channels. The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition.
5.8. Treatment of Study Treatment Overdose
There is experience in PAH patients of Ambrisentan at daily doses of 5mg and 10mg.
In healthy volunteers, single doses of 50mg and 100mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea and nasal congestion.
Due to the mechanism of action, an overdose of Ambrisentan could potentially result in hypotension. In the case of pronounced hypotension, active cardiovascular support may be required. No specific antidote is available.
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Advice on overdose is available in the product label for PAH.
6. STUDY ASSESSMENTS AND PROCEDURES
The following measurements and evaluations will be conducted during the trial. Please refer to the Time and Events Table (Table 1) for additional details on the timing of the assessments. Every effort must be made to adhere to the protocol defined visit schedule.
The data collection tool for this study will be GSK defined eCRFs. In all cases, subject initials will not be collected nor transmitted to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures.
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Table 1 Time and Events Table
Visits (days)Procedure
Study Entry *
Monthly (7) 1,2
Month1(7)
Month 3
(7)
Month 6(7)
Month 9
(7)
Month 12
(7)
Month 15
(7)
Month 18
(7)
Month 21 &
Every 3 Monthly
(7)
Every 6 Monthly
(7)
End of study
Follow up3
Unscheduled visit
Written informedconsent
X
Inclusion/ExclusionCriteria
X
Adverse Events X X X X X X X X X X X X XSerious AdverseEvents
X X X X X X X X X X X X X
Liver Function Tests4 X X X X X X X X X X X X
Clinical ChemistryX X X X X X X X X X X
Haematology X X X X X X X X X X XUrinalysis X X X X X X X X X X XPhysical Examination
X X X X X X X X X X X
Vital Signs5 X X X X X X X X X X X12-lead ECG X X X X X XConcomitantMedication
X X X X X X X X X X X X
6 Minute WalkDistance
X X X X X X X X X X
BCR10S X X X X X X X X X XTTCW X X X X X X X X X XWHO FunctionalClass
X X X X X X X X X X
SF-36 X X X X X X X X X X
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Visits (days)Procedure
Study Entry *
Monthly (7) 1,2
Month1(7)
Month 3
(7)
Month 6(7)
Month 9
(7)
Month 12
(7)
Month 15
(7)
Month 18
(7)
Month 21 &
Every 3 Monthly
(7)
Every 6 Monthly
(7)
End of study
Follow up3
Unscheduled visit
Plasma NT-Pro BNP concentration
X X X X X X X X X X
Hemodynamic Assessment6
X
Pregnancy Test7 X X X X X X X X X X X XTesticular function8 X X X X X
DispenseInvestigationalProduct9
X X X X X X X X X
AssessInvestigationalProduct Compliance
X X X X X X X X X
1. For months that do not correspond to the every three month visits, these assessments may be performed by the subject’s local clinic and laboratory2. Safety visits will be required every month after month 1. A phone call is required to assess concomitant medications and adverse events (including serious). See Section 6.2.5.
Clinical Laboratory Tests for details of the laboratory tests required. If any additional procedures are performed during the safety visit, an unscheduled visit should be completed.3. Should be performed 30 days after last dose of IP. Only for patients who are withdrawn from Ambrisentan. May be performed by telephone.4. Includes ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase, and total bilirubin 5. Includes weight, blood pressure using standard sphygmomanometer, and heart rate. Body mass index to be only at the entry visit6. Pulmonary Vascular Resistance (PVR), Cardiac Index (CI), mean Pulmonary Arterial Pressure (mPAP), Total Pulmonary Resistance (TPR) will be transcribed into the eCRF only
if the assessment is being done as part of the subject’s standard care and can be recorded in the Log page of the eCRF. 7. Either Urine or blood monthly pregnancy tests for females of childbearing potential for the duration of the study 8. Testicular function (Total testosterone, sex hormone binding globulin SHBG – needed to calculate free testosterone), FSH, LH, and inhibin B. For males only. Every effort should
be made to collect blood samples for testicular function between 8am and 1pm 9. Doses may be adjusted upward or downward by 5 mg increments. The minimum dose may not be less than 5 mg, and the maximum dose may not be greater than10 mg per day.
* The subject’s final visit in study AMB115811 will be utilised upon entry into this study (Study AMB116457).
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6.1. Critical Baseline Assessments
The subject’s final visit in study AMB115811 will be utilised upon entry into this study (Study AMB116457). The following assessments will be performed, and the information will be automatically entered into the study CRF:
Efficacy: 6 MWD, Borg CR10S, WHO FC, SF-36, Cardiac Haemodynamics, TTCW, NT-proBNP
Laboratory Tests: Clinical Chemistry, Haematology, Urinalysis, Liver function tests, Pregnancy Test (Females of CBP only), Testicular Function (males only)
6.2. Safety
6.2.1. Physical examination
Physical examinations will be performed at the month 1 visit and subsequently every three months while the subject is in the study, at the time the subject exits the study (including weight, jugular venous pressure, liver size, peripheral oedema, ascites and signs of deep vein thrombosis). Note: BMI and BSA to be calculated centrally using height (recorded in AMB115811) and weight collected in the eCRF.
6.2.2. Electrocardiogram
A 12-lead ECG will be performed every six months while the subject is in the study, at the time the subject exits the study. Any changes since Baseline felt to be significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs in the eCRF.
6.2.3. Vital Signs, Body Weight
Vital signs (including heart rate and blood pressure) will be collected at each clinic visit. One measurement of blood pressure and heart rate after the subject has been sitting quietly for at least 5 minutes should be taken. This same procedure should be followed throughout the study.
Vital signs, and weight will be collected at each clinic visit.
All measures of blood pressure will be performed using standard sphygmomanometry. If possible, the same sphygmomanometer and arm should be used. Procedural details are provided in the study procedures manual.
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6.2.4. Change in Dose
Change in dose of Ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to a tolerability issue (e.g. adverse events) will be considered a safety assessment.
6.2.5. Clinical Laboratory Tests
A central laboratory (Quest Diagnostics) will be used for the one month visit, and the three and six monthly visit laboratory assessments. Results from local laboratories can be used for the monthly assessments that do not correspond with the one month or the three-or six-month clinic visits. If local laboratories are used, the results will be forwarded to the study site.
6.2.5.1. Safety Tests
The following tests are required at the time the subject exits the study and at intervals listed below.
Liver Function: serum alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), alkaline phosphatase, gamma glutamyl transferase (GGT), and total bilirubin monthly.
Urinalysis: including a microscopic examination of the urine sediment. Additional laboratory tests may be performed by a local laboratory or the central
laboratory if clinically relevant abnormal values are obtained at any time during the course of the study. Local laboratory reports must be immediately reviewed by the investigator. Laboratory normal ranges will be collected
Chemistry: lactate dehydrogenase (LDH), creatine phosphokinase (CPK), creatinine, sodium, magnesium, potassium, chloride, bicarbonate (CO2), phosphorus-inorganic, calcium, blood urea nitrogen (BUN), uric acid, glucose, total protein, and albumin every three months.
Haematology: haemoglobin, hematocrit, red cell count, red cell indices (mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], and mean corpuscular haemoglobin concentration [MCHC]), white blood cell count (total and differential), reticulocyte count, and platelet count every three months.
Pregnancy: Either urine or blood monthly pregnancy tests for female subjects of child bearing potential.
The following test will be performed in males only at baseline and every 6 months and will be performed by a central laboratory. Every effort should be made to collect blood samples for testicular function between 8am and 1pm:
Testicular Function: Total testosterone, Sex hormone binding globulin (SHBG needed to calculate free testosterone), FSH, LH and inhibin B
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6.2.6. Liver chemistry stopping and followup criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 6:
1. ALT 3xULN and bilirubin 2xULN (with>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks
4. ALT 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:
Immediately withdraw investigational product
Report the event to GSK within 24 hours of learning its occurrence
Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed
Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below.
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Withdraw the subject from the study (unless further safety follow up is required) after completion of the liver chemistry monitoring as described below.
Do not re-challenge with investigational product.
In addition, for criterion 1:
Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring
A specialist or hepatology consultation is recommended
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks:
Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety
Can continue investigational product
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline
If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.
For criteria 1-5, make every attempt to carry out the liver event follow up assessmentsdescribed below:
Viral hepatitis serology including:
Hepatitis A IgM antibody;
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);
Hepatitis C RNA;
Cytomegalovirus IgM antibody;
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Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);
Hepatitis E IgM antibody
Blood sample for PK analysis, obtained within 24 hours of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SPM.
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin 2xULN
Obtain complete blood count with differential to assess eosinophilia
Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report form
Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form.
Record alcohol use on the liver event alcohol intake case report form
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct) but are optional for other abnormal liver chemistries:
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.
Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution to liver injury, detectable by HPLC assay more than 1 week following acetaminophen use) (James, 2009).
Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody.
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.
6.2.7. Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.
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6.2.7.1. Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Note: An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition
New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study
Signs, symptoms, or the clinical sequelae of a suspected interaction
Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concomitant medication (overdose per se will not be reported as an AE/SAE).
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events that do not meet the definition of an AE include:
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE
Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital)
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen
The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition
6.2.7.2. Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
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NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development ofdrug dependency or drug abuse.
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.
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6.2.8. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs.
6.2.9. Pregnancy
Subjects who become pregnant during the study must discontinue Investigational Product immediately. The Investigator should counsel the subject regarding the possible effects of prior Investigational Product exposure on the foetus (See SmPC and USPI) and the need to inform the study site of the outcome of the pregnancy. Subjects should be instructed to notify the Investigator if they become pregnant at any time during the study, or if they become pregnant within 30 days of last Investigational Product dose.
Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to Sponsor within 24 hours of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the investigational product, must be promptly reported to Sponsor.
In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information must be reported to GSK as described above.
6.2.10. Time Period and Frequency of Detecting AEs and SAEs
AEs will be collected from the Entry Visit and until subjects leave the study. If subject is taking Ambrisentan and this is stopped then AEs will be required to be collected up until 30 days post the last dose of Investigational product.
All deaths, regardless of cause or relationship, must be reported for subjects on study and for all deaths occurring within 30 days of last investigational product dose or within 30 days of last study evaluation, whichever is longer.
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a
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Sponsor concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to Sponsor within 24 hours, as indicated in Section 6.2.11.
6.2.11. Prompt Reporting of Serious Adverse Events and Other Events to Sponsor
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to Sponsor as described in the following table once the investigator determines that the event meets the protocol definition for that event.
Initial Reports Follow-up Information on a Previous Report
Type of Event Time Frame Documents Time Frame DocumentsAll SAEs 24 hours “SAE” data
collection tool24 hours Updated “SAE”
data collection tool Pregnancy 24 hours Pregnancy
Notification Form24 hours Pregnancy Follow
up FormLiver chemistry abnormalities
ALT3xULN andBilirubin2xULN (>35% direct) (or ALT3xULN andINR>1.5, if INR measured)***
24 hours* SAE data collection tool.**Liver Event
Case Report Form (CRF) and liver imaging and/or biopsy CRFs if
*Sponsor to be notified at onset of liver chemistry elevations to discuss subject safety.** Liver event documents should be completed as soon as possible*** INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving
anticoagulants.
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to Sponsor are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.
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6.2.11.1. Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. The sponsor will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and the sponsor policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from the sponsor will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.3. Efficacy assessments
6.3.1. 6 minute walking distance (6MWD) test
The 6MWD will be assessed every three months during the first 18 months, and at thetime the subject exits the study.
6.3.2. Clinical worsening of CTEPH
Clinical worsening of CTEPH is defined as the first occurrence of:
Death (all cause) Lung transplantation Hospitalization for CTEPH deterioration Atrial septostomy Addition of parenteral prostanoids Appearance of two or more CTEPH worsening events*
*Worsening events to consider:
1. A decrease from baseline of at least 20 percent in the distance walked during the six-minute walk test;
2. An increase of one or more WHO Functional Class; 3. Worsening right ventricular failure (e.g., as indicated by increased
jugular venous pressure, new/worsening hepatomegaly, ascites, or peripheral edema);
4. Rapidly progressing cardiogenic, hepatic, or renal failure; 5. Refractory systolic hypotension (systolic blood pressure less than
85 mmHg).
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Time to clinical worsening is defined as the time from randomization in AMB115811 to the first occurrence of any of the events above. It will be assessed for the first 18 months of the study.
6.3.3. Addition of Other Targeted PAH Therapeutic Agents
Addition of another targeted PAH therapeutics agents is defined as addition of other PAH agents due to • Deterioration of clinical condition;• Lack of beneficial effect with previous therapy (not reaching set treatment goals).
6.3.4. Change in Dose of Ambrisentan
Change in dose of Ambrisentan or other targeted PAH therapeutic agents(prostanoids, PDE-5 inhibitors) is defined as a dose change due to deterioration of clinical condition.
6.3.5. Subject Global Assessment (SF-36 short form)
Subject Global assessments (SF-36 short form) will be performed every three months for the first 18 months, and at the time the subject exits the study. For information can be found in Section 6.4.1 below.
6.3.6. WHO functional class
WHO functional class will be determined every three months for the first 18 months, and at the time the subject exits the study.
6.3.7. N-terminal pro-B type natriuretic peptide (NT-Pro BNP)
Blood samples for determination of N-Terminal pro-B-type Natriuretic Peptide plasmaconcentrations will be collected every three months for the first 18 months or early withdrawal. A central lab (Quest Diagnostics) will analyze all samples.
6.3.8. Cardiopulmonary hemodynamic assessments
Cardiopulmonary hemodynamic assessments data will be collected in subjects in whomhemodynamic data is considered part of the standard of care (see Appendix 1).
6.3.9. Borg CR10 Scale (BCR10S)
See Section 11.4 Appendix 4
The Borg CR10 Scale should be performed straight after every 6MWD test for the first 18 months.
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6.4. Health Outcomes
6.4.1. SF-36 Health Survey
The SF-36 Health Survey [Ware, 2000] is provided (the US Version) in.Appendix 6. The SF-36v2 Health Survey will be used.
The SF-36 Health Survey asks 36 questions to measure functional health and well-being from the patient's point of view. It’s called a generic health survey because it can be used across age (18 and older), disease, and treatment group, as opposed to a disease-specific health survey which focuses on a particular condition or disease.
Whilst not specifically validated in CTEPH, it has been used in a number of PH trials.
The SF-36 Health Survey consists of 8 health domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health) as well as 2 summary measures (Physical Health and Mental Health).
Further details of the SF-36 will be detailed in the RAP and the scoring will follow the algorithm of Ware, Kosinski and Gandek (2000).
7. DATA MANAGEMENT
For this study, subject data will be entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK, and combined with data provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and an internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy. In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.
8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1. Hypotheses
The primary objective of this study is to assess long term safety, efficacy and long term treatment success (absence of clinical worsening) of Ambrisentan in patients with CTEPH. No formal hypothesis testing is planned for the study
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8.2. Study Design Considerations
8.2.1. Sample Size Assumptions
Sample size is based on number of subjects entering the AMB115811 study and no more than 160 will be enrolled in the study.
8.2.2. Sample Size Sensitivity
No sample size sensitivity calculations were performed.
8.2.3. Sample Size Re-estimation
No more than 33 subjects will be included in AMBER 2, given the decision to stop study AMB115811.
8.3. Data Analysis Considerations
8.3.1. Analysis Populations
The safety population is defined as all enrolled subjects who received at least 1 dose of study drug. Subjects will be considered as belonging to the treatment group according to dose received. The safety population will be used in all safety summaries.
8.3.2. Analysis Data Sets
Analysis datasets will consist of all data collected in the study and evaluated according tothe population described in Section 8.3.1. Baseline will be defined for all endpoints as the time of the initiation of study active study drug. Therefore, baseline in AMB115811 will define baseline for patients who were randomized to Ambrisentan in AMB115811. Entry into the study visit will define baseline for patients who were randomized to placebo in AMB115811.
8.3.3. Treatment Comparisons
8.3.3.1. Primary Comparisons of Interest
There are no formal comparisons planned for this study. Descriptive displays will be provided based on available data by and across dose levels for:
oedema, ascites and signs of deep vein thrombosis); Vital Signs (including body mass index at the entry visit only); The time to change in dose of Ambrisentan or other targeted PAH therapeutic
agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events).
The time to clinical worsening of CTEPH
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The time to occurrence of each of the components of clinical worsening of CTEPH.
8.3.3.2. Other Comparisons of Interest
The following data will also be presented descriptively and graphically by and across dose levels:
The change from Study AMB115811 baseline and week 16 visits in the 6 minute walking distance (6MWD) test evaluated every three months;
The change from Study AMB115811 baseline and week 16 visits in Subject Global Assessment every three months using the SF-36 health survey;
The change from Study AMB115811 baseline and week 16 visits in WHO functional class every three months;
Change from Study AMB115811 and week 16 visits baseline in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration every three months;
Change from Study AMB115811 baseline and week 16 visits in cardiopulmonary hemodynamic assessments data in subjects in whom hemodynamic data is considered part of the standard of care (see Appendix 1).
8.3.4. Interim Analysis
No interim analysis is planned for this study.
8.3.5. Key Elements of Analysis Plan
The analyses planned in this protocol will be expanded in the RAP. Any deviations from the analyses described in this protocol will be described in the RAP and the final study report(s) as appropriate.
8.3.5.1. Safety Analyses
All subjects who received at least one dose of Ambrisentan (safety population) will be assessed for clinical safety and tolerability. No formal statistical analysis is planned for safety parameters. All data will be presented descriptively (e.g. mean, standard deviation, minimum, median, maximum, etc) and where available, it will be summarized by visit.
The number and percentage of subjects with Adverse events and Serious Adverse events will be summarized descriptively, The number and percentage of subjects with AE that led to dose interruption, drug withdrawal or study withdrawal will be summarized separately.
Clinical laboratory parameters and vital signs will be summarized descriptively (e.g. mean, standard deviation, minimum, median, maximum, etc.) by visit. In addition, for each laboratory test and vital sign, the number and percentage of subjects with values above the reference range will be displayed.
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Descriptive statistics (e.g. mean, standard deviation, minimum, median, maximum, etc.) will be presented for the physical examination results, as well as the number and percentage of subjects in pre-specified subgroups (e.g. age, BMI, etc.).
The time to change in dosing of Ambrisentan or other PAH therapeutic agent due to tolerability issue will be summarized descriptively (e.g. mean, median standard deviation, minimum, maximum, etc.), as well as the number and percentage of subjects who experience change in dosing in pre-specified time intervals and will be presented graphically by Kaplan Meier Curve.
8.3.5.2. Efficacy Analyses
All subjects who receive one dose of Ambrisentan will be included in the analysis of efficacy data.
Given the small sample size, all efficacy data will be summarized descriptively
(including 95% CI) and graphically. Data will be summarized by dose and overall treatment group at the time of each visit.
Time to Clinical Worsening (and each component) will be displayed graphically as a Kaplan Meier Curve. The frequency of each event will be separately tabulated.
Specific details of the statistical analysis will be presented in the Reporting and Analysis Plan (RAP).
8.3.5.3. Health Outcomes Analyses
The mean change from Study AMB115811 baseline in SF-36 scores will be calculated every three months.
8.3.5.4. Pharmacodynamic Analyses
Not planned
8.3.5.5. Pharmacokinetic/Pharmacodynamic Analyses
Not planned
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9. STUDY CONDUCT CONSIDERATIONS
9.1. Posting of Information on Publicly Available Clinical Trial Registers
Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.
9.2. Regulatory and Ethical Considerations, Including the Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments.
Subject informed consent.
Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the study.
9.3. Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.
GSK will monitor the study to ensure that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.
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The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.
9.4. Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.
9.5. Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe non-compliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6. Records Retention
Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that
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an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.
9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.
GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.
GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis.
GSK aims to post a results summary to the GSK Clinical Study Register and other publicly available registers no later than 8 months after the last subject’s last visit (LSLV) [this applies to each data analysis phase for studies with multiple phases, e.g., primary analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-reviewed journal for publication within 18 months of LSLV. GSK also aims to publish the full study protocol on the GSK Clinical Study Register at the time the results of the study are published as a manuscript in the scientific literature.
When manuscript publication in a peer-reviewed journal is not feasible, further study information will be posted to the GSK Clinical Study Register to supplement the results summary.
A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.
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9.8. Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.
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10. REFERENCES
Ambrisentan EU Summary of Product Characteristics 2011
Ambrisentan Investigator Brochure Eleventh Edition 08 September 2011
Becattini C, Manina G, Busti C, Gennarini S, Agnelli G. Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. Thromb Res. 2010 Jul;126(1):e51-6.
Bresser P, Fedullo PF, Auger WR, Channick RN, Robbins IM, Kerr KM, Jamieson SW, Rubin LJ. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur Respir J. 2004 Apr;23(4):595-600.
Condliffe R, Kiely DG, Gibbs JS, Corris PA, Peacock AJ, Jenkins DP, Hodgkins D, Goldsmith K, Hughes RJ, Sheares K, Tsui SS, Armstrong IJ, Torpy C, Crackett R, Carlin CM, Das C, Coghlan JG, Pepke-Zaba J. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2008 May 15;177(10):1122-7.
Condliffe R, Kiely DG, Gibbs JS, Corris PA, Peacock AJ, Jenkins DP, Goldsmith K, Coghlan JG, Pepke-Zaba J. Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension. Eur Respir J. 2009 Feb;33(2):332-8.
Doyle RL, McCrory D, Channick RN, et al. Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126 (1 Suppl): 63S-71S.
Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46(3):529-535.
Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009b; 34(6):1219-63.
Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the Ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117:3010-19.
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Hughes RJ, Jais X, Bonderman D, Suntharalingam J, Humbert M, Lang I, Simonneau G, Pepke-Zaba J. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J. 2006 Jul;28(1):138-43.
Jaïs X, D'Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, Hoeper MM, Lang IM, Mayer E, Pepke-Zaba J, Perchenet L, Morganti A, Simonneau G, Rubin LJ; Bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension study group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan effects in inoperable forms of chronic thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008 Dec 16;52(25):2127-34.
James LP. Drug Metab Disp 2009; 37:1779–1784
Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, Channick RN, Fedullo PF, Auger WR. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg. 2003 Nov;76(5):1457-62; discussion 1462-4.
Kirchengast M, Munter K. Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. Proc Soc Exp Biol Med 1999; 221(4):312-325.
Lang IM. Managing chronic thromboembolic pulmonary hypertension: pharmacological treatment options. Eur Respir Rev. 2009 Mar 1;18(111):24-8.
Leuchte HH, Holzapfel M, Baumgartner RA, Neurohr C, Vogeser M, Behr J. Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension. Chest. 2005 Oct;128(4):2368-74.
Lewczuk J, Piszko P, Jagas J, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001; 119: 818-23.
Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103:685-92.
Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M,Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000 Aug 22;102(8):865-70.
Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, et al. ARIES Study Group. Long-term Ambrisentan therapy for the treatment of pulmonary arterial hypertension. JACC 2009; 54:1971-81.
Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun 1995; 209(2):483-489.
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Park MH, Scott RL, Uber PA, Ventura HO, Mehra MR. Usefulness of B-type natriuretic peptide as a predictor of treatment outcome in pulmonary arterial hypertension. Congest Heart Fail. 2004 Sep-Oct;10(5):221-5
Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011 Jan 27;364(4):351-60.
Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81: 151-8.
Saouti N, de Man F, Westerhof N, Boonstra A, Twisk J, Postmus PE, Vonk Noordegraaf A. Predictors of mortality in inoperable chronic thromboembolic pulmonary hypertension. Respir Med. 2009 Jul;103(7):1013-9.
Suntharalingam J, Treacy CM, Doughty NJ, Goldsmith K, Soon E, Toshner MR, Sheares KK, Hughes R, Morrell NW, Pepke-Zaba J. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest. 2008 Aug;134(2):229-36.
Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998; 97(8):752-756.
Ware, JE; Kosinski, M; Gandek, B. SF-36 Health Survey: Manual and Interpretation Guide, Lincoln, RI: QualityMetric Inc, 2000.
Hemodynamic assessments are neither scheduled nor required as a part of this study; however, any time that hemodynamic data are being collected as a part of the standard of care for a subject enrolled in this study, the following data may be transcribed to the eCRF:
Hemodynamic assessments will include:
heart rate; mean blood pressure (systolic, diastolic); mean pulmonary arterial pressure (PA; systolic, diastolic); mean right atrial (RA) pressure; left ventricular end diastolic pressure (LEVDP); or pulmonary capillary wedge pressure (PCWP); cardiac output; cardiac index (calculated value); arterial and mixed venous oxygen saturation (Record method used to calculate
cardiac output measurement, if Fick’s principle was used it must be stated if oxygen consumptions is measured or assumed).
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11.2. Appendix 2: List of Highly Effective Methods for Avoidance of Pregnancy in Women of Childbearing Potential
The following is a list of the highly effective methods for avoiding pregnancy (i.e., have a failure rate of less than 1% per year).
Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label [Hatcher, 2004]
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject [Hatcher, 2004]. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.
Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) [Trussell, 2003].
Nonoxynol-9 is the critical component in most spermicides, and is regarded as an acceptable spermicidal agent. Concern has been raised that nonoxynol-9 damages the epithelial lining of the vagina, and exposure may facilitate transmission of viruses, particularly human immunodeficiency virus (HIV). The World Health Organization (WHO) conducted a technical consultation in October 2001 and concluded that the increased risk for such transmission was low to minimal [Trussell, 2003].
References
Hatcher RA, Trussell J, Stewart F, Nelson AL, Cates W, Guest F, Kowal DD, editors. Contraceptive Technology. New York: Ardent Media, 2004: 226. Table 9-2, “% of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States”, column entitled, “% of Women Experiencing an Unintended Pregnancy Within the First Year of Use. Perfect Use”.
Trussell J. Personal communication WHO/CONRAD Technical consultation on nonoxynol-9. WHO, Geneva, 9-10 October 2001. Summary Report. World Health Organization, 2003
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11.3. Appendix 3: 6 Minute Walk Distance Test
The 6-minute walk test will be conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. Please refer to the following guidelines for conducting the 6-minute walk test.
The Test Location
Select a quiet, enclosed corridor, free of distractions and drafts.
Depending on your site’s standard operating procedures, please mark out a 30 m or 100 ft course.
The start and end of the course must be visibly marked by placing tape on the floor, using chairs etc.
The course should be sub-divided into 3m or 10ft sections using a method unnoticeable to the subject.
The Day Before the Test
Tell the subject the time their test will take place.
Give the subject the following instructions:
- Take a light meal 3 to 4 hours before the test.
- Take nothing by mouth (po) except clear liquids for 1 hour before the test.
- Do not take heart medication within 2 hours of the test, including short-acting nitrates.
- Do not smoke for at least 2 hours before the test.
- Prior to all clinic visits, withhold the daily dose of Investigational Product such that the last dose of Investigational Product is administered more than 16 hours prior to the 6MWD and BCR10S assessments
Immediately Before the Test
The test should be performed on the subject’s "usual" oxygen. If the subject usually breathes room air, they should perform the test on room air. If the subject normally requires supplemental oxygen with ambulation, they should perform the test with supplemental oxygen.
Subjects who require supplemental oxygen should receive the same oxygen flow rate as baseline during all subsequent 6-minute walk tests. Subjects who add supplemental oxygen after initiation of therapy should walk without oxygen whenever possible so data is comparable to baseline conditions.
If the oxygen flow rate must be increased during subsequent visits due to worsening gas exchange, the 6-minute walk test may be conducted at the increased oxygen flow rate and this should be noted in the CRF.
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If the subject reduces or discontinues supplemental oxygen use during the study, they should still perform the 6-minute walk test with the same flow rate of oxygen that was used during previous tests.
Ask the subject to sit quietly for 10 minutes.
Read the following instructions verbatim to the subject:
“The object of this test is to walk as far as possible for 6 minutes. You will walk back and forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will probably get out of breath or become exhausted. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able. Are you ready to do that?”
Repeat the entire set of instructions if the subject does not seem to understand.
Repeat the sentence:
“Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog.”
Instruct the subject to start by saying:
“Start now, or whenever you are ready.”
During the Test:
Do not influence the walking pace of the subject.
Use an even tone of voice when using the standard phrases of encouragement.
Encourage the subject every 60 seconds (1 minute) during the test but do not convey information about their performance.
Examples of appropriate encouragement are, “You are doing well.” or “Keep up the good work.”
Only speak to the subject at the 60-second points.
If the subject is slowing down or expresses that he/she wants to stop say:
“You can lean against the wall if you would like; then continue walking whenever you feel able.”
Note the number of laps of the corridor walked by the subject but do not convey this information to the subject.
At 6 minutes, tell the subject to stop and not to move until the distance walked has been measured.
After the Test
If the subject walked for less than 6 minutes (i.e., stops prior to 6 minutes and DOES NOT start again), record the time walked as well as the distance.
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When the distance has been measured tell the subject to sit down and observe him/her for at least 10 minutes.
The distance covered during any walking test must not be revealed to the subject at any time during the study.
Parameters to be recorded:
Distance walked, to the nearest meter or foot
Time walked, to the nearest second (if subject walked for less than 6 minutes)
Comments if subject was unable to walk for 6 minutes
The BCR10 scale immediately following completion of the 6-minute walk test (Appendix 4)
For all the 6 Minute Walk Distance Tests of a subject the same track will be used throughout the study. A track needs to be 30m (5m)
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11.4. Appendix 4: Borg CR10 ScaleCCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws and therefore have been excluded.
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11.5. Appendix 5: SF-36 Quality of Life QuestionnaireCCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws and therefore have been excluded.
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11.6. Appendix 6: Liver Chemistry Stopping and Followup Criteria
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11.7. Appendix 7: Country Specific Requirements
NONE
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11.8. Appendix 8: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment is applicable to all countries and sites
Summary of Amendment Changes with Rationale
Update to maximum study sample size following changes to the Double-Blind study (AMB115811). Section 4.1
Correction to the IP storage conditions to change from 15-30ºC to up to 30C (86 F). Section 5.1
Revision of pregnancy follow-up information to include partners of male subjects in the study and is consistent with the AMB115811 study. Section 6.2.9.
Correct to the description of several efficacy assessments and timepoints to remove the requirement to perform efficacy tests 30 days after discontinuation of IP (concomitant medication and safety only are required for this follow-up). This makes the section consistent with the Time and Events Schedule. Section 6.2.5.1, Section 6.3.1. Section 6.3.5 and Section 6.3.6.
Section 4.1: Number of Subjects
As this study is only open to subjects who have participated in AMB115811, no more than 275 160 subjects will be enrolled into this extension study.
Section 5.1: Investigational Product and Other Study Treatment
Study medication will be stored in secure (locked) areas at a temperature between 15and to up to 30 C (86 F) and dispensed according to the protocol under the supervision of the Investigator or his/her designee. Investigational product must be dispensed or
Section 6.2.9: Pregnancy
In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information must be reported to GSK as described above.
Section 6.2.5.1: Safety Tests
The following tests are required at the time the subject exits the study, at follow-up after discontinuing and at intervals listed below.
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Section 6.3.1: 6 minute walking distance (6MWD) test
The 6MWD will be assessed every three months during the first 18 months, and at thetime the subject exits the study, and 4 to 6 weeks after discontinuing Ambrisentan for those subjects who do not remain on Ambrisentan.
Section 6.3.5: Subject Global Assessment (SF-36 short form)
Subject Global assessments (SF-36 short form) will be performed every three months for the first 18 months, and at the time the subject exits the study, and 4 to 6 weeks after discontinuing Ambrisentan for those subjects who do not remain on Ambrisentan. For information can be found in Section 6.4.1 below.
Section 6.3.6: WHO functional class
WHO functional class will be determined every three months for the first 18 months, and at the time the subject exits the study, and 4 to 6 weeks after discontinuingAmbrisentan for those subjects who do not remain on Ambrisentan.
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AMENDMENT 2
Where the Amendment Applies
This amendment is applicable to all countries and sites
Summary of Amendment Changes with Rationale
-This is an open label, long term extension to Study AMB115811. All subjects mayremain in the extension study for a minimum of 18 months. Beyond the 18-monthperiod, subjects may continue in the extension study . Investigational plan; study design (Section 3).
-In case of prematurely withdrawal from study AMB115811 for whatever reason, the investigator will decide whether or not the subject will receive the IP.
-Add of some general inclusion criteria on reliable methods of contraception, non participation to another study and signature of the approved consent form. Inclusion criteria (Section 4.2)
-Corrections and clarification on the treatment given after the end of the study. (Section 5.7)
-Change on the month 1 and monthly visits timings which will be done 7 days (Section 6)
-Vital signs, clarification on blood pressure measurements (Section 6)
-Clarification of the investigational product temperature storage conditions.
Section 3: investigational plan
- Study design
This is an open label, long term extension to Study AMB115811. All subjects mayremain in the extension study for a minimum of 18 months. Beyond the 18-month period, subjects may continue in the extension study until one of the following conditions is met:The product is approved locally and made commercially available for use in inoperable CTEPH patients;
Section 4.2: inclusion criteria
- Subject prematurely withdrew from AMB115811 for whatever reason: the investigator will decide whether or not the subject will receive the IP.
- General considerations:Subject is able and willing to give written informed consent.
1) Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least
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30 days following the last dose of Investigational Product (reliable methods of contraception are described in Appendix 2).
2) Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.
3) Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures.
Section 5.1: Investigational Product and Other Study TreatmentStudy medication will be stored in secure (locked) areas at a temperature between 15 C and 30 C (59-86 F)
Section 5.7: treatment after the end of the study
The product is approved locally and reimbursed for use in inoperable CTEPH patients;
GSK will continue to provide post-study medication only to subjects in territories where the medication is not available through normal distribution channels. The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition. whether or not GSK is providing specific post study treatment.
Section 6: study assessments and procedures, time and event table:
Month 1 and monthly visits can be done 7 days
Section 6.2.3: Vital Signs, Body Weight
Vital signs (including heart rate and blood pressure) will be collected at each clinic visit. One measurement of blood pressure and heart rate after the subject has been sitting quietly for at least 5 minutes should be taken. This same procedure should be followed throughout the study.
Section 9.8: Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.
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AMENDMENT 3
Where the Amendment Applies
This amendment is applicable to the UK
Summary of Amendment Changes with Rationale
-This is an open label, long term extension to Study AMB115811. All subjects may remain in the extension study for a minimum of 18 months. Beyond the 18-month period, subjects may continue in the extension study until the product is approved locally for use in inoperable CTEPH patients, ie until May 2016. (protocol summary and Section 3.1)
-a subject will discontinue from the investigational product or from the study for pregnancy (Section 4.4).
-a subject can remain in the study until May 2016 (Section 5.7).
Protocol summary and section 3.1 study design
This is an open label, long term extension to Study AMB115811. All subjects may remain in the extension study for a minimum of 18 months. Then risk-benefit will be reviewed and if necessary an amendment will be requested allowing subjects to continue in the extension study until one of the following:
The product is approved locally for use in inoperable CTEPH patients, ie until May 2016.
Section 4.4: Withdrawal Criteria
A subject will also be discontinued from Investigational Product, or from the study, for the following reasons:
• Liver chemistry values exceeding the threshold criteria (as outlined in Section 6.2.7);
• Adverse event which in the opinion of the investigator requires withdrawal;
• Pregnancy;
Section 5.7: Treatment after the End of the Study
Subjects can remain in this study until one of the following conditions is met:
The product is approved locally for use in inoperable CTEPH patients, ie until May 2016
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COMPLEMENT TO AMENDMENT 3
Where the Amendment Applies
This amendment is applicable to the UK
Summary of Amendment Changes with Rationale
The subjects can continue in the extension study until 1st May 2016. This treatmentperiod in the current study is appropriate due to the nature of CTEPH and the need forchronic therapy whilst also taking into account current knowledge of the risk-to-benefitprofile of Ambrisentan. Once further data are available and the risk-to-benefit profile canbe re-evaluated, the study duration may be amended (protocol summary, section 3.1,section 5.7).
Protocol Summary
Study Design
This is an open label, long term extension to Study AMB115811. All subjects mayremain in the extension study for a minimum of 18 months. Then risk-benefit will bereviewed and if necessary an amendment will be requested allowing the subjects to cancontinue in the extension study until one of the following:
The product is approved locally for use in inoperable CTEPH patients; ie until 1st
May 2016. This treatment period in the current study is appropriate due to the nature of CTEPH and the need for chronic therapy whilst also taking into account current knowledge of the risk-to-benefit profile of Ambrisentan.
Once further data are available and the risk-to-benefit profile can be reevaluated, the study duration may be amended.
Development for use in the CTEPH population is discontinued or product is notapproved by the local regulatory authorities.
The investigator decides to discontinue the subject or subject decides todiscontinue from the study.
Section 3.1 Study Design
This is an open label, long term extension to Study AMB115811. All subjects mayremain in the extension study for a minimum of 18 months. Then risk-benefit will bereviewed before and if necessary an amendment will be requested allowing the subjectsto can continue in the extension study until one of the following:
The product is approved locally for use in inoperable CTEPH patients, ie until 1st
May 2016.This treatment period in the current study is appropriate due to thenature of CTEPH and the need for chronic therapy whilst also taking into account current knowledge of the risk-to-benefit profile of Ambrisentan.
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Once further data are available and the risk-to-benefit profile can be reevaluated, the study duration may be amended.
Development for use in the CTEPH population is discontinued or product is notapproved by the local regulatory authority
The investigator decides to discontinue the subject or subject decides todiscontinue from the study.
Section 5.7: Treatment after the End of the Study
Subjects can remain in this study until one of the following conditions is met:
The product is approved locally for use in inoperable CTEPH patients, ie Until 1st
May 2016. This treatment period in the current study is appropriate due to the nature of CTEPH and the need for chronic therapy whilst also taking into account current knowledge of the risk-to-benefit profile of Ambrisentan.
Once further data are available and the risk-to-benefit profile can be reevaluated, the study duration may be amended
Development for use in the CTEPH population is discontinued or product is notapproved by the local regulatory authority
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AMENDMENT 4
Where the Amendment Applies
This amendment is applicable to Italy
Summary of Amendment Changes with Rationale
This is an open label, long term extension to Study AMB115811. All subjects shouldhave been randomized to the protocol for AMB115811 and have completed the Week 16visit in AMB115811.
OBJECTIVE(S)
The primary objective of this study is to evaluate the long term safety and tolerability ofAmbrisentan in subjects with inoperable CTEPH who have completed participatedAMB115811. The secondary objective is to obtain supportive efficacy data on the use ofAmbrisentan in CTEPH.
4.1 Number of Subjects
As this study is only open to subjects who have participated in completed AMB115811, no more than 160 subjects will be enrolled into this extension study.
4.2 Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
a) Have been randomized to the protocol for AMB115811.
b) Have completed the Week 16 visit in AMB115811.
b) Or prematurely withdrew from AMB115811 for whatever reason*
*where IP has been stopped due to safety or efficacy reasons, the subject may still enterinto the open label study regardless of what treatment they are receiving (other treatmentswill not be supplied by the sponsor). The investigator will decide whether or not thesubject will receive the IP.
4.2 Exclusion Criteria
4.2.1 Exclusion from IP
Subjects meeting any of the following criteria must not receive Ambrisentan, howevermay still be followed-up as part of the study and be treated according to best clinicalpractice as decided by the investigator:
1. Subject prematurely withdrew from AMB115811where IP has been stopped due to safety, efficacy or any other reason at the opinion of the investigator
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6.1 Critical Baseline Assessments
The subject’s week 16 final visit in study AMB115811 will be utilised upon entry intothis study (Study AMB116457). The following assessments will be performed, and theinformation will be automatically entered into the study CRF:
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AMENDMENT 5
This amendment is applicable only to China
Summary of Amendment Changes with Rationale
Inhibin B analysis is unable to be performed in China; therefore samples will be exportedto Quest Diagnostics in the United States for testing.
Section 6. Study assessments and Procedures
All lab samples will be analysed in China except for inhibin B which will be analysed byQuest Diagnostics in the United States
Section 6.1. Critical Baseline Assessments
All lab samples will be analysed in China except for inhibin B which will be analysed byQuest Diagnostics in the United States
Section 6.2.5.1. Safety Tests
All lab samples will be analysed in China except for inhibin B which will be analysed byQuest Diagnostics in the United States
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AMENDMENT 6
This amendment is applicable only to China
Summary of Amendment Changes with Rationale
Inhibin B analysis will be performed in China;
Section 6. Study assessments and Procedures
Time and event Table: All lab samples will be analysed in China
Section 6.1. Critical Baseline Assessments
All lab samples will be analysed in China
Section 6.2.5.1. Safety Tests
All lab samples will be analysed in China
Section 6.2.6. Liver chemistry stopping and followup criteria
acetaminophen test is not required in Chinese studies as per exemption from GSKHepatotoxicity board,
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AMENDMENT 7
Where the Amendment Applies
This amendment is applicable to all sites
Summary of Amendment Changes with Rationale
The purpose of this amendement is provide clarity following GSK decision to stop the study early.
PROTOCOL SUMMARY
study design
This is an open label, long term extension to Study AMB115811 and given the decision to stop study AMB115811, this study will also be stopped.
All subjects will continue until their next scheduled study visit, at which time they will be informed and have a End of study visit and then follow up visit. Then they will be transitioned to local standard of care. Patients that have no local access to any alternative treatment and who in their physician’s opinion have responded to ambrisentan treatment may be eligible for continued treatment with ambrisentan which could be through a compassionate program according to the local regulatory environment and these subjects may continue in the study until this is secured.
1. INTRODUCTION
Current treatment options
As very similar histopathologic changes of pulmonary arterial hypertension (PAH) are seen in patients with CTEPH, the disease-modifying therapies used in other forms of pulmonary arterial hypertension have been utilised around the world. Riociguat is the first of a new class of drugs, the sGC stimulators, which has demonstrated its efficacy in CTEPH patients. It was registered in the US (in October 2013) and Europe (in March 2014) and soon in other countries.
Rationale
It is hypothesised that even after the registration of riociguat there is still an unmet medical need in CTEPH disease; therefore the study success will be an opportunity for inoperable CTEPH subjects to benefit from ambrisentan, a PAH specific treatment belonging to another pathway.
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3. INVESTIGATIONAL PLAN
Subjects currently enrolled in AMBER 2 (AMB116457) will be transitioned to local standard of care. Patients that have no local access to any alternative treatment and who in their physician’s opinion have responded to ambrisentan treatment will be eligible for continued treatment with ambrisentan which could be through a compassionate program according to the local regulatory environment or other alternatives for treatment continuation and these subjects may continue in the study until this is secured. (see paragraph 4.4).
4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Number of Subjects
At the time recruitment and randomisation activities were stopped, 18 subjects were included in AMBER 2.
Inclusion criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
Have been randomized to the protocol for AMB115811 and have met the following:
a) Completed the Week 16 visit in AMB115811;b) Or prematurely withdrew from AMB115811 for whatever reason*
*where IP has been stopped due to safety or efficacy reasons
Withdrawal Criteria
On the 11 December 2014, the Independent Data Monitoring Committee (IDMC) has made the recommendation to stop the AMBER 1 study due to futility of enrolment.
Subjects currently enrolled in AMBER 2 (AMB116457) will be transitioned to local standard of care. Patients that have no local access to any alternative treatment and who in their physician’s opinion have responded to ambrisentan treatment will be eligible for continued treatment with ambrisentan which could be through a compassionate program/alternative treatment according to the local regulatory environment.
Before their end of study visit, investigators will follow up with their local GSK study contact to secure alternative treatment for eligible AMBER 2 patients (i.e. patients with no other treatment option and who have had a good clinical response to treatment with ambrisentan) and these subjects may remain in the study until this is secured.
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5. STUDY TREATMENTS
5.7 Treatment after the End of the Study
Subjects can remain in this study until one of the following conditions is met:
The product is approved locally for use in inoperable CTEPH patients; Development for use in the CTEPH population is discontinued or product is not
approved locally; The investigator decides to discontinue the subject or subject decides to
discontinue from the study.
The Investigator should then treat the subjects according to best standard of care available to the investigator. Subjects will be followed for 30 days post their last dose of study medication. See time and event table page 28 for the follow-up visit.
Before their end of study visit, investigators will follow up with their local GSK study contact to secure alternative treatment for eligible AMBER 2 patients (i.e. patients with no other treatment option and who have had a good clinical response to treatment with ambrisentan and where this treatment is allowed under local regulations).
8 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
Sample Size Re-estimation
No sample size re-estimation is planned for the study.
No more than 33 subjects will be included in AMBER 2, given the decision to stop study AMB115811
