ResCu - Paul Ehrlich Institute

Non-interventional study ResCu Study code IFX9502 Remsima® (Infliximab)

Integrated report: Version 1.0, 19th of January 2018

Integrated Report

ResCu

Non-interventional study to monitor effectiveness, tolerability, and quality of life in real world patients in Crohn’s disease or ulcerative

colitis treated with Remsima®

Type of study: Non-interventional study according to § 4 (23) 3 German Medicinal

Products Act (AMG)

Study code: IFX9502

Indication: Crohn’s disease and ulcerative colitis

Study drug: Remsima® 100 mg powder for concentrate for solution for infusion

Active substance: Infliximab

Survey data: First Examination: 11th of June 2015

Last Examination: 31st of March 2017

Responsible

person for

medical affairs:

Mundipharma GmbH

Mundipharmastraße 2

65549 Limburg (Lahn)

Responsible

person for

statistics:

ANFOMED Gesellschaft für angewandte Forschung in der Medizin mbH

Röttenbacher Straße 17

91096 Möhrendorf


Integrated report: Version 1.0, 19th of January 2018 I

Synopsis

Title Non-interventional study to monitor effectiveness, tolerability, and quality of life in real world patients in Crohn’s disease or ulcerative colitis treated with Remsima®.

Country Germany

Type of study Non-interventional study according to § 4 (23) 3 German Medicinal Products Act (AMG);

Multicenter, prospective and observational study

Clinical phase Post Marketing Authorisation, non-interventional

Indication Crohn’s disease and ulcerative colitis

Study drug Remsima® 100 mg powder for solution for infusion

Active substance Infliximab

Area of application Treatment of moderate to severe, active Crohn‘s disease, treatment of fistulising, active Crohn‘s disease and moderate to severe active ulcerative colitis in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment or who are intolerant to or have medical contraindications for such therapies.

Study objectives The aim of the non-interventional study was to document the efficacy and safety of Remsima® in patients with inflammatory bowel disease under real life conditions. The influence on quality of life, fatigue, depression, and abdominal pain should be documented.

End point of study Primary end points of study

The activity of Crohn‘s disease and ulcerative colitis were determined with Harvey-Bradshaw-Index (HBI) and Mayo-Score.

Secondary end points of study

The influence on quality of life was documented by the Inflammatory Bowel Disease Questionnaire (IBDQ-D), fatigue by the Brief Fatigue Inventory (BFI), depression by the General Depression Scale (long version, ADS-L), and abdominal pain by the Short-form McGill (SF-McGill) questionnaire.

Study sites 70 specialists for gastroenterology planned

70 specialists for gastroenterology involved

Sample size 400 patients planned

381 patients enrolled and statistically analysed

Study duration 28th of September 2015 until 15th of May 2017 (after extension)

First Patient First Visit 11th of June 2015 (included retrospectively)

Last Patient Last Visit 31st of March 2017

Observation period An observational period per patient of about 14 weeks was intended.

Administration According to the usual therapeutic procedure of the attending physician and in accordance with the authorized indications and summary of product characteristics (SmPC).


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Dosage According to SmPC

Procedure of the study

Patients were included in the study when physicians decided in advance to start treatment with Remsima® according to the local SmPC. The physician had to obtain patient‘s written consent. Data were documented in following survey periods:

• Baseline of data collection (Visit 0): before start of treatment

• Follow-up data collection (Visit 1): about 2 weeks after start of treatment

• Follow-up data collection (Visit 2): about 6 weeks after start of treatment

• Final survey of data collection (Visit 3): about 14 weeks after start of treatment

Patient questionnaire forms were handed out at baseline, at follow-up examinations and at final examination to be filled out by the patient. These forms had to be returned to the attending physician at the same examination.

Survey data • Date of visits

• Demographic data

• Medical history of CIBD (chronic inflammatory bowel disease)

• Assessment of severity of acute episode (HBI, Mayo-Score)

• Localisaton and description of acute episode

• Imaging diagnostics (if available)

• Laboratory parameters (if available in the routine clinical practice)

• (Pre-) treatment of CIBD

• Treatment with Remsima®

• Concomitant diseases and medication

• Questionnaires for evaluation of quality of life (IBDQ-D)

• Questionnaires for evaluation of influence on fatigue (BFI)

• Questionnaires for documentation of depression (ADS-L)

• Questionnaires for evaluation of abdominal pain (SF-McGill)

• Adverse events and adverse drug reactions

• Assessment of Remsima® therapy by the attending physician and the patient

Statistical Methods Data processing and statistical analysis were performed with the SAS™ program system. Taking into account the non-interventional character of the study, the statistical analysis was performed in a descriptive and explorative way. Collected variables were illustrated using graphical diagrams and frequency or parameter tables. If reasonable, lists of individual patient data were prepared. Adverse events/adverse drug reactions were coded according to MedDRA. All cases were listed in frequency tables based on preferred terms and system organ classes. A line listing of all events was prepared.

Adverse Drug Reactions

Any adverse drug reaction (serious or non-serious) during the non-interventional study, in which relation to Remsima® therapy could not be excluded, had to be, independet of severity, carefully documented in the „ADR report section“ of the eCRF within 24 hours. This ADR report was then automatically forwarded to the drug safety department of ANFOMED GmbH and after processing to Mundipharma GmbH. Additionally, all adverse events (AE), in which relation to Remsima® therapy could be excluded, had to be documented in the eCRF.


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Principal investigator

Scientific Advisor

Summary of results

Disposition Patients n=381

Study sites n=70

Patients per study site n=5.44

Duration of observation per patient (months, mean±SD)

3.36±1.54

Patient characteristics

Sex (gender, n=381)

Male n=180 47.24%

Female n=201 52.76%

Age (years, n=380)

Mean±SD 41.10±14.62

Minimum 18.00

Maximum 91.00

BMI (kg/m², n=376)

Mean±SD 25.01±5.29

Minimum 15.21

Maximum 47.18

Form of IBD (n=381)

Crohn’s disease n=223 58.53%

Ulcerative colitis n=158 41.47%

Diagnosis of IBD (months, n=351)

Mean±SD 106.64 ±108.32

Median 76.03

Minimum 0.52 (15.6 days)

Maximum 479.34 (39.94 years)

Number of episodes since diagnosis (n=114)


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Mean±SD 4.73±6.18

Minimum 1.00

Maximum 30.00

Intestinal resection due to CIBD (n=378)

Yes n=61 16.14%

No n=317 83.86%

Number of intestinal resections (n=378)

Mean±SD 0.20±0.51

Minimum 0.00

Maximum 3.00

Duration of acute episode (months, n=374)

Mean±SD 14.34±43.72

Median 2.93

Minimum 0.00

Maximum 380.20 (31.68 years)

Hospitalization due to acute episode (n=375)

Yes n=82 21.87%

No n=293 78.13%

Duration of hospitalization (weeks, n=82)

Mean±SD 2.51±3.50

Median 1.43

Minimum 0.14

Maximum 20.00

Pre-treatment of acute episode (n=381)

Without pre-treatment n=127 33.33%

With pre-treatment n=254 66.67%

Continued pre-treatment of acute episode (n=381)

Without treatment n=240 62.99%

With treatment n=141 37.01%

Imaging procedures (n=381)

Without imaging procedures n=123 32.28%

With imaging procedures n=258 67.72%

- Endoscopy n=223 58.53%

- Sonography n=110 28.87%

- Magnetic resonance imaging n=25 6.56%


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…

Laboratory parameters

Erythrocytes (Mio/µl) n=327 4.52 (±0.56)

Leukocytes (Tsd/µl) n=335 9.24 (±3.80)

Thrombocytes (Tsd/µl) n=334 344.77 (±129.40)

Hemoglobin (mmol/l) n=350 8.30 (±1.51)

Hematocrit (%) n=301 39.33 (±5.42)

Serum iron (µmol/l) n=130 12.96 (±6.88)

Ferritin (µg/l) n=140 98.27 (±108.72)

Transferrin (mg/dl) n=71 268.62 (±56.15)

Transferrin saturation (%) n=74 21.29 (±15.87)

Urea (mg/dl) n=94 18.10 (±14.22)

Creatinine (mg/dl) n=242 0.85 (±0.22)

C-reactive protein (mg/l) n=345 37.69 (±80.59)

Erythrocyte sedimentation rate (mm)

n=72 25.21 (±19.70)

Calprotectin (µg/g) n=147 747.20 (±831.44)

Pre-treatment of underlying IBD (n=381)

Without pre-treatment n=55 14.44%

With pre-treatment n=326 85.56%

- Immunosuppressive agents n=193 50.66%

- Antidiarrheals, intestinal anti-inflammatory/antiinfective agents

n=184 48.29%

- Corticosteroids for systemic use n=89 23.36%

...

Concomitant disease (n=381, MedDRA preferred term)

Without concomitant disease n=281 73.75%

With concomitant disease n=100 26.25%

- Hypertension n=18 4.72%

- Depression n=8 2.10%

- Hypothyroidism n=8 2.10%

...

Treatment of concomitant disease (n=381, ATC anatomical main group)


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- Agents acting on the renin-angiotensin system

n=14 3.67%


- Drugs for acid related disorders n=8 2.10%

...

Reason for the prescription of Remsima® (n=381)

No reason specified n=4 1.05%

Reason specified n=377 98.95%

- Low effectiveness of the previous medication

n=240 62.99%

- Due to contraindication or intolerance to conventional therapy

n=92 24.15%

- Due to low tolerability of the previous medication

n=37 9.71%

...

Treatment with Remsima®

Remsima® Dose (mg/kg, patients with infusion only)

Mean±SD Minimum Maximum

Visit 0 (n=376) 5.09(±0.62) 3.00 10.00

Visit 1 (n=244) 5.07(±0.47) 3.00 7.81

Visit 2 (n=252) 5.13(±0.53) 3.00 9.57

Visit 3 (n=238) 5.22(±0.93) 2.90 10.00

<5mg/kg <5mg/kg <5mg/kg

Visit 0 (n=376) 4.52% 84.04% 11.44%

Visit 1 (n=244) 5.33% 78.69% 15.98%

Visit 2 (n=252) 3.57% 79.76% 16.67%

Visit 3 (n=238) 5.04% 77.31% 17.65%

Premature end of Remsima® treatment (n=381)

Without premature end of therapy n=336 88.19%

Premature end of therapy n=45 11.81%

- Adverse drug reaction n=31 8.14%

- Lack of efficiency n=7 1.84%

- At patient’s request n=7 1.84%

...

Treatment of underlying IBD during the study (n=381)


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- Antidiarrheals, intestinal antiinflammatory/antiinfective agents

n=128 33.60%


- Immunosuppressive agents n=66 17.32%

...

Hospitalization during the study because of an acute episode (n=364)

With hospitalization n=13 3.57%

Without hospitalization n=351 96.43%

Duration of hospitalization during the study (weeks, n=12)

Mean±SD 1.48±0.93

Minimum 0.29 (2 days)

Maximum 4.00

Imaging procedures during the study (n=366)

No n=321 87.70%

Yes n=45 12.30%

- Sonography n=26 7.10%

- Endoscopy n=23 6.28%

...

Surgical measures of acute episode during the study (n=366)

Without surgical measure n=362 98.91%

With surgical measure n=4 1.09%

- Fistula drainage n=2 0.55%

- Abscess drainage n=1 0.27%

- Hemicolectomy n=1 0.27%

Results in effectiveness

Inflammatory bowel disease questionnaire (IBDQ)

Data of 311 patients were available for analysis of life quality. The mean value of IBDQ total score (1 = poorest quality of life, 7 = best quality of life) increased from 4.37 (±1.25, median 4.47) points at admission to 5.21 (±1.13, median 5.44) at the end of the NIS indicating a significant better quality of life under treatment with Remsima® (p<0.0001). The mean difference from the first to the last documentation was 0.84 (±1.14, median 0.64).

Brief fatigue inventory (BFI)

A total of 318 patients were included in the analysis of fatigue. The mean value of BFI (0 = no impairment, 10 = complete impairment) decreased from 4.55 (±2.31, median 4.67) points at baseline to 3.62 (±2.30, median 3.28) points at the final examination. The mean reduction of BFI points from the


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initial to the last documentation was statistically significant (p<0.0001). BFI was reduced by 0.94 (±2.16, median 0.77) points.

General depression scale – long version (ADS-L)

ADS-L values of 277 patients were analyzed. A significant decrease of the ADS-L mean value was determined from admission (20.69±11.84, median 20.00) to final examination (15.91±11.70, median 14.00) with a difference of 4.79 (±11.09, median -4.00; p<0.0001). Nevertheless, mean values of ADS-L suggested an absence of clinically relevant depressive symptoms prior to Remsima® therapy and during the observation period.

Short-form McGill Pain questionnaire (SF-McGill)

VAS-values (0 = no pain, 100 = worst imaginable pain) of 282 patients were available for evaluation. A significant decrease of mean value was determined from the baseline (27.23±25.39, median 23.00) to the last documentation (18.22±22.16, median 7.00) showing a difference of 9.00 (±25.90, median 4.00; p<0.0001).

Disease activity of Crohn’s disease

Disease activity of Crohn’s disease was reduced during the treatment with Remsima®. The mean Harvey-Bradshaw-Index (HBI) of 6.91 (±4.14, median 7.00) points at baseline significantly decreased to 3.06 (±3.25, median 2.00) at the last documentation (p<0.0001), indicating a positive impact on disease activity from mild disease to remission state.

Disease activity of ulcerative colitis

Disease activity of ulcerative colitis was determined by Mayo score at baseline, at the follow-up examinations and at the final documentation. The mean score significantly decreased from 7.27 (±2.66, median 8.00) points to 2.81 (±2.59, median 2.00) points (p<0.0001) indicating a substantial improvement of disease activity from moderate-severe to mild disease.

Global assessment of efficacy

Efficacy of Remsima® was assessed once by the physicians and once by the patients themselves at the end of the NIS.

The attending physicians evaluated the effectiveness of Remsima® treatment as very good for 30.33% (101 patients) of the patients at the final documentation. The efficacy was documented to be good in 54.95% (183 patients) of the cases, moderate in 13.81% (46 patients) and poor in 0.90% (3 patients) of enrolled patients.

Concerning the result of patient’s assessment, the percentage distribution was comparable to the documentation of the physicians. Efficacy of Remsima® treatment was rated as very good by 28.40% (94 patients) of the patients at last assessment. The percentage of patients who assessed effectiveness as good was 53.47% (177 patients) whereas 16.92% (56 patients) of the patients assessed the efficacy as moderate and 1.21% (4 patients) as poor.

Laboratory parameters

Concerning erythrocytes, the number slightly increased from 4.52 Mio/µl (±0.55, median 4.57) at baseline to 4.61 Mio/µl (±0.49, median 4.60) at the final documentation with a mean difference of 0.09. The mean increase was statistically significant (p=0.0013). Compared to visit 1, more patients showed


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values within the reference range at the last examination (204 patients, 78.76% versus 192 patients, 74.13%).

Mean value regarding leukocytes was reported to be 7.85 (±3.10, median 7.20) Tsd/µl at admission (versus 9.26 Tsd/µl at visit 1). Mean reduction of 1.41 was statistically significant (p<0.0001). At both visits (baseline and last examination), mean numbers of leukocytes were within the normal area. However, the percentage of patients with normal levels was higher at the end of the NIS (76.73% versus 65.09% at baseline).

Number of thrombocytes significantly decreased by 46.24 (±92.64) from 345.63 (±124.06, median 317.50) Tsd/µl at baseline to 299.39 (±97.03, median 281.50) Tsd/µl at the final documentation (p<0.0001). 55.11% of the patients had normal thrombocyte levels at the end of the NIS (versus 41.61% at start of Remsima® therapy).

Haemoglobin concentration was documented to be 8.28 (±1.52, median 8.20) mmol/l at admission and 8.57 (±1.91, median 8.32) mmol/l at the final documentation, respectively. The mean value significantly increased by 0.30 (±2.05, p<0.0001). Compared to the start of the NIS, more patients showed values within the reference area: 149 patients (51.38%) at visit 1 and 170 patients (58.62%) at last visit, respectively.

Hematocrit proportion was comparable between admission and final examination. Mean value was reported to be 39.04 (±4.59, median 39.90) % at visit 1. At the end of the study, the mean value was 39.68 (±5.16, median 40.00) % displaying an increase of 0.64 percentage points under treatment with Remsima®. At baseline, 48.05% of the patients had a hematocrit proportion within the normal range. At the last visit, a higher percentage of patients showed normal values (59.74%).

Regarding serum ion, a mean concentration of 12.74 (±7.05, median 11.47) µmol/l was recorded at baseline. The mean value slightly increased by 1.42 (±8.83) during the course of the NIS and was found to be 14.17 (±7.61, median 13.15) µmol/l at the end of the study. Number of patients with values within the reference area increased from admission to the last visit with percentages of 61.63% compared to 66.28%.

Ferritin levels decreased under therapy with Remsima®. Mean concentration was reported to be 108.32 (±128.74, median 69.50) µg/l at baseline and 89.18 (±106.42, median 65.00) µg/l at the end of the study (mean difference of 19.14 µg/l, ±113.56). Compared to baseline, the number of patients with reference values had increased during the NIS (73.17% versus 78.05% at the last visit).

Concerning transferrin concentration at baseline and final visit, a mean difference of 2.60 mg/dl (±52.89) was documented. Mean values slightly increased from 273.06 (±52.74, median 270.00) mg/dl up to 275.66 (57.26, median 280.00). 92.00% of the patients had normal transferrin levels at the end of the study (versus 88.00% at admission). Furthermore, transferrin saturation increased from 21.91 (±17.38, median 18.00) % at baseline to 20.65 (±12.18, median 18.00) % at last visit and the percentage of patients with normal levels between 18.0 and 45.0% simultaneously rose from 45.61% to 49.12%.

Mean urea level somewhat increased during the NIS and was reported as follows: 16.00 (±15.02, median 6.45) mg/dl at baseline and 16.20 (±13.54, median 8.05) mg/dl at the end of the study. The number of patients with a normal urea concentration was equal at visit 1 and final examination (26.47%


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each). Mean creatinine concentration did not change under the treatment with Remsima®. Mean value was reported to be 0.83 mg/dl at both visits (V1 and V3). However, number of patients with normal values increased during the observational time from 92.74% (baseline) to 96.09% (final documentation).

The amount of C-reactive protein was 34.97 (±75.42, median 10.70) mg/l at admission and decreased down to 21.11 (±38.65, median 5.62) mg/l at last visit. Mean reduction of 13.86 (±70.12) was statistically significant (p<0.0001). In contrast to a percentage of 48.56% at baseline, 63.67% of the patients had normal values at the end of the NIS.

Concerning the sedimentation rate of erythrocytes, mean values were higher at admission (24.85±21.78 mm, median 22.00 versus 16.96±15.93, median 11.50). Mean difference was 7.89 (±17.39). Number of patients with normal values rose from 37.50% to 62.50% during the observation.

Mean calprotectin concentration was reported to be 865.63 (±818.77, median 578.00) µg/g at baseline. Mean value decreased by 298.23 (±1158.06) down to 567.40 (±831.14, median 310.00) µg/g at last visit. A reference value ≤50.0 µg/g was achieved by 19.67% of the patients (versus 6.56% at baseline).

Results in safety

Global assessment of tolerability

Evaluation of tolerability of Remsima® was performed once by the physicians and once by the patients at the end of the NIS.

The attending physicians evaluated tolerability of Remsima® treatment at the last visit as very good for 40.72% (136 patients) and as good for 54.79% (183 patients) of the patients. The number of patients for whom tolerability was recorded to be moderate (3.59%, 12 patients) or poor (0.90%, 3 patients) was low.

Concerning the result of patient’s assessment, 116 patients (34.73%) rated tolerability as very good at last assessment. The number of patients who evaluated tolerability as good was 194 (58.08%). Only 19 (5.69%) and 5 patients (1.50%) assessed tolerability as moderate and poor, respectively, at last visit.

Adverse drug reactions

In this study, 136 adverse events (AE) were reported in 80 patients (21.00% of all patients) and 65 adverse drug reactions (ADR) occurred in 48 patients (12.60%) during the observation period of approximately 14 weeks. For the majority of the patients with ADRs one type of reaction was reported (37 patients, 9.71%). Most frequently reported ADRs were assigned to the MedDRA preferred term (PT) hypersensitivity (8 patients, 2.10% of all patients), followed by erythema (6 patients, 1.57%), ineffective drug (5 patients, 1.31%), anaphylactic reaction (4 patients, 1.05%), dizziness, alopecia, fatigue, pruritus, and rash (2 patients each, 0.52%). All further ADRs were reported at a frequency of one patient (0.26%).

The ADRs documented in this NIS were most often associated with the following MedDRA system organ classes (SOC): skin and subcutaneous tissue dirsorders (14 patients, 3.67% of all patients), immune system disorders (13 patients, 3.41%), general disorders and administration site conditions (8 patients, 2.10%), nervous system disorders (4 patients, 1.05%), gastrointenstinal disorders (3 patients, 0.79%), infections and infestations (3 patients, 0.79%), vascular disorders, musculoskeletal and connective tissue


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disorders, and respiratory, thoracic and mediastinal disorders (2 patients each, 0.52%).

From all documented ADRs, 23 events in 18 patients (4.72% of all patients) were recorded to be serious. Hypersensitivity and anaphylactic reaction were the most frequently reported serious ADRs (4 events in 4 patients each, 1.05%). All other serious events occurred at a frequency of one and were reported for one patient in each case.

Seven events that occurred in four patients (1.05% of all patients) were classified as suspected unexpected serious adverse reactions (SUSARs, 10.77% of reported ADRs): anaemia, anaphylactic shock, carotid artery dissection, cerebral infarction, deep vein thrombosis, hypertensive crisis, and thrombophlebitis.

From 65 reported ADRs, the outcome was stated to be ongoing for two events (3.08% of all reported ADRs, 1 patient, 0.26%), recovering for eight events (12.31%, 7 patients, 1.84%) and recovered for the majority of ADRs (47 events, 72.31%, 35 patients, 9.19%). Status was reported to be not recovered for five events (7.69%, 3 patients, 0.79%). The outcome of one ADR was still unknown (1.54%, 1 patient, 0.26%). Data on one event each were missing and were not applicable, respectively (1.54%, 1 patient, 0.26% each).

Conclusion In conclusion, results of the non-interventional study presented here strongly support the effectiveness of Remsima® in the treatment of patients with Crohn’s disease and ulcerative colitis, respectively. Patient cohort analysed was considered to be representative. Safety analysis indicated general tolerability of Remsima® under routine medical practice conditions. Furthermore, effectiveness and tolerability of Remsima® were predominantly evaluated within the global assessment by physicians and patients as very good or good.

Date of report 19th of January 2018


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Signatures

CRO

ANFOMED GmbH

_____________________ Date

______________________ Signature

Biometrics

ANFOMED GmbH

_____________________ Date

______________________ Signature

Head of Medical Affairs

Mundipharma GmbH

_____________________ Date

______________________ Signature


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Table of contents

I. STUDY ADMINISTRATIVE STRUCTURE .................................................................................................. 1

I.1. Sponsor ......................................................................................................................................... 1

I.2. Contract Research Organization (CRO) ......................................................................................... 1

I.3. Data management......................................................................................................................... 1

I.4. Statistics ........................................................................................................................................ 1

I.5. Medical writing ............................................................................................................................. 1

II. INTRODUCTION ................................................................................................................................... 2

III. GENERAL REGULATIONS ..................................................................................................................... 3

IV. STUDY OBJECTIVES ............................................................................................................................. 4

IV.1. Primary endpoints of the study .................................................................................................. 4

IV.2. Secondary endpoints of the study .............................................................................................. 4

V. STUDY DESIGN AND SAMPLE SIZE CALCULATION ............................................................................... 4

V.1. Study design ................................................................................................................................. 4

V.2. Sample size calculation ................................................................................................................ 5

VI. STUDY PLAN AND PROCEDURES ........................................................................................................ 5

VI.1. Study plan ................................................................................................................................... 5

VI.2. Participating sites and patient selection ..................................................................................... 6

VI.3. Treatment ................................................................................................................................... 6

VI.4. Observational period and total duration of the non-interventional study ................................ 7

VI.5. Conducting the study .................................................................................................................. 7

VI.6. Documentation ........................................................................................................................... 7

VI.6.1. Documentary components .................................................................................................. 8

VI.6.2. Data ..................................................................................................................................... 8

VI.6.2.1. Demographics and anamnesis ......................................................................................8

VI.6.2.2. Efficacy measurements .................................................................................................9

VI.6.2.3. Safety measurements ...................................................................................................9

VI.6.2.4. Data from patient questionnaires .................................................................................9

VI.6.3. Definition and reporting of adverse events (AE)/Adverse drug reactions (ADR) .............. 10

VI.7. Data management, quality control and statistical analysis ...................................................... 10

VI.7.1. Data management ............................................................................................................. 10

VI.7.2. Quality control ................................................................................................................... 11

VI.7.3. Statistical analysis .............................................................................................................. 11

VI.7.3.1. Missing values and last observation carried forward method .................................. 11


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VI.7.3.2. Significance tests and weighted kappa coefficient .................................................... 12

VI.7.3.3. Limitations .................................................................................................................. 12

VI.7.3.4. Software ..................................................................................................................... 12

VI.7.3.5. Dictionaries and coding systems used ....................................................................... 12

VI.7.3.6. Conventions used in this report ................................................................................. 13

VII. DISPOSITION .................................................................................................................................... 13

VIII. STUDY SUBJECTS ............................................................................................................................ 14

VIII.1. Patient characteristics ............................................................................................................ 14

VIII.1.1. Age ................................................................................................................................... 14

VIII.1.2. Sex ................................................................................................................................... 15

VIII.1.3. Height and Weight ........................................................................................................... 15

VIII.1.4. Body Mass Index .............................................................................................................. 15

VIII.2. Anamnesis ............................................................................................................................... 16

VIII.2.1. Type of inflammatory bowel disease .............................................................................. 16

VIII.2.2. Duration of CIBD .............................................................................................................. 16

VIII.2.3. Intestinal resection due to CIBD ...................................................................................... 17

VIII.2.4. Description of acute episode (Visit 0) ............................................................................. 17

VIII.2.4.1. Duration of acute episode........................................................................................ 17

VIII.2.4.2. Hospitalization ......................................................................................................... 17

VIII.2.4.3. Pre-treatment .......................................................................................................... 18

VIII.2.4.4. Ongoing pre-treatment ............................................................................................ 19

VIII.2.4.5. Surgical measures for pre-treatment of acute episode ........................................... 19

VIII.2.5. Disease activity ................................................................................................................ 19

VIII.2.5.1. Activity of Crohn’s disease ....................................................................................... 19

VIII.2.5.2. Activity of ulcerative colitis ...................................................................................... 21

VIII.2.6. Imaging diagnostics ......................................................................................................... 22

VIII.2.7. Laboratory parameters .................................................................................................... 22

VIII.2.8. Pre-treatment of underlying inflammatory bowel disease (IBD) .................................... 24

VIII.2.9. Concomitant disease ....................................................................................................... 24

VIII.2.10. Treatment of concomitant disease ............................................................................... 25

VIII.3. Treatment with Remsima® ..................................................................................................... 26

VIII.3.1. Switch to Remsima® ........................................................................................................ 26

VIII.3.2. Administered dose of Remsima® .................................................................................... 26

VIII.3.3. Premature end of therapy with Remsima® ..................................................................... 28

VIII.3.4. Treatment of underlying inflammatory bowel disease (IBD) during the study .............. 28


Integrated report: Version 1.0, 19th of January 2018 XV

VIII.3.5. Acute episode .................................................................................................................. 30

VIII.3.5.1. Hospitalization ......................................................................................................... 30

VIII.3.5.2. Imaging procedures ................................................................................................. 31

VIII.3.5.3. Surgical measures .................................................................................................... 32

VIII.3.6. Antibodies before and during the study ......................................................................... 32

IX. EFFICACY RESULTS ............................................................................................................................ 32

IX.1. Inflammatory bowel disease questionnaire (IBDQ) .................................................................. 32

IX.2. Brief fatigue inventory (BFI) ...................................................................................................... 34

IX.3. General depression scale – long version (ADS-L) ...................................................................... 35

IX.4. Short-form McGill Pain questionnaire (SF-McGill) .................................................................... 36

IX.5. Assessment of disease activity .................................................................................................. 37

IX.5.1. Crohn’s disease assessed by Harvey Bradshaw index ....................................................... 37

IX.5.2. Ulcerative colitis assessed by Mayo-score ........................................................................ 38

IX.6. Global assessment of efficacy ................................................................................................... 38

IX.7. Laboratory parameters ............................................................................................................. 39

X. SAFETY RESULTS ................................................................................................................................ 42

X.1. Global assessment of tolerability ............................................................................................... 42

X.2. Adverse events and adverse drug reactions .............................................................................. 43

X.2.1. Categories ........................................................................................................................... 43

X.2.1. Adverse drug reactions ....................................................................................................... 43

X.2.2. Adverse events ................................................................................................................... 48

X.3. Pregnancies ................................................................................................................................ 49

XI. DISCUSSION AND CONCLUSION ....................................................................................................... 50

XI.1. Discussion .................................................................................................................................. 50

XI.1.1. Discussion of demographic and baseline characteristics .................................................. 50

XI.1.2. Discussion of therapy with Remsima®............................................................................... 52

XI.1.3. Discussion of results in effectiveness ................................................................................ 53

XI.1.4. Discussion of results in safety ............................................................................................ 55

XI.2. Limitations on collected data .................................................................................................... 57

XI.3. Clinical relevance and overall conclusions ................................................................................ 58

XII. REFERENCES .................................................................................................................................... 59


Integrated report: Version 1.0, 19th of January 2018 XVI

List of abbreviation and definitions of terms

Abbreviation Explanation

ADR Adverse drug reaction

ADS-L General depression scale – long version (Allgemeine Depressionsskala – Langform)

AE Adverse event

AMG German medicinal product act (Arzneimittelgesetz)

AS Ankylosing spondylitis

ATC Anatomic therapeutic classification

BfArM Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte)

BFI Brief Fatigue Inventory

BMI Body Mass Index

CIBD Chronic inflammatory bowel disease

CHMP Committee for Medicinal Products for Human Use

CL Confidence limit

CRF Case report form

CRO Contract research organization

GEP Good Epidemiological Practice

HBI Harvey-Bradshaw-Index

IBD Inflammatory bowel disease

IBDQ Inflammatory bowel disease questionnaire

kg Kilogram

kg/m2 Kilogram per square metre

LOCF Last observed carried forward

mAb Monoclonal antibody

MedDRA Medical Dictionary for Regulatory Activities

mg Milligram

n Number of patients

NIS Non-interventional Study

p Probability

PEI Paul-Ehrlich-Institute

PF Preferred Term

PK Pharmacokinetic(s)

RA Rheumatoid arthritis

SAP Statistical Analysis Plan

SAS Statistical Analysis System

SD Standard deviation

SF-McGill Short-form McGill questionnaire

SmPC Summary of product characteristics

SOC System Organ Class

SUSAR Suspected unexpected serious adverse reactions

TNF Tumor necrosis factor alpha

WHO World Health Organization


Integrated report: Version 1.0, 19th of January 2018 XVII

Tables

Table 1: Study plan .................................................................................................................................. 5

Table 2: Coding systems used in this report ......................................................................................... 13

Table 3: Number of patients and performed visits (n=381) .................................................................. 14

Table 4: Laboratory parameters ............................................................................................................ 23

Table 5: Laboratory parameters at final examination (LOCF) ............................................................... 42

Table 6: Category and frequency of ADRs occurred and number of patients affected (n=381) ........... 43

Table 7: Adverse drug reactions listed according to the preferred term (n=381) ................................ 44

Table 8: ADRs listed according to the system organ class by MedDRA 20.0 (n=381) ........................... 45

Table 9: Serious adverse drug reactions ............................................................................................... 47

Table 10: Suspected unexpected serious adverse reactions................................................................. 47

Table 11: Serious adverse events .......................................................................................................... 48

Figures

Figure 1: Distribution of patients’ age (n=380). .................................................................................... 15

Figure 2: Distribution of patients’ sex (n=381). ..................................................................................... 15

Figure 3: Distribution of patients’ BMI (n=376). ................................................................................... 16

Figure 4: Frequency of Crohn’s disease and ulcerative colitis (n=381). ................................................ 16

Figure 5: Duration of IBD since diagnosis (n=351). ............................................................................... 17

Figure 6: Pre-treatment of acute episode according to ATC anatomical main group (n=381). ............ 18

Figure 7: Assessment of Crohn’s disease according to the HBI (n=221). .............................................. 19

Figure 8: Intestinal localization of Crohn’s disease according to the Montreal-classification

(n=220). ............................................................................................................................................ 20

Figure 9: Extraintestinal localization of Crohn’s disease (n=54 patients with extraintestinal

manifestation). ................................................................................................................................. 20

Figure 10: Assessment of ulcerative colitis according to the Mayo-score (n=154). ............................. 21

Figure 11: Intestinal localization of ulcerative colitis according to the Montreal-classification

(n=158). ............................................................................................................................................ 21

Figure 12: Extraintestinal localization of ulcerative colitis (n=158). ..................................................... 22

Figure 13: Pre-treatment of underlying IBD according to ATC anatomical main group (n=381). ......... 24

Figure 14: Reasons to start a therapy with Remsima® (n=377). ........................................................... 26

Figure 15: Remsima dose (mg/kg body weight, patients with infusion only) at admission (V0,

n=376), V1 (n=244), V2 (n=252), and V3 (n=238; x = mean, – = median, [] = interquartile, - =

minimum and maximum). ................................................................................................................ 27

Figure 16: Distribution of Remsima® dose (mg/kg BW) during the course of the NIS. ......................... 27


Integrated report: Version 1.0, 19th of January 2018 XVIII

Figure 17: Frequency of patients with discontinuation of treatment with Remsima® (n=381). .......... 28

Figure 18: Reasons for premature discontinuation of therapy with Remsima® (n=381). .................... 28

Figure 19: Treatment of underlying IBD during the study, classified according to ATC anatomical

main group (n=381). ......................................................................................................................... 29

Figure 20: Treatment of underlying IBD during the study, classified according to ATC chemical

substances (n=381). ......................................................................................................................... 30

Figure 21: Hospitalization due to an acute episode during the NIS (n=364). ....................................... 30

Figure 22: Imaging procedures during the study (n=366). .................................................................... 31

Figure 23: Finding of imaging diagnostics during the NIS. .................................................................... 31

Figure 24: IBDQ at admission (V0), at control examinations V1 and V2 and at the final examination

(n=311, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum). .................. 33

Figure 25: Mean IBDQ-values (LOCF) for patients with Crohn’s disease and ulcerative colitis. ........... 33

Figure 26: Mean IBDQ-values (LOCF) for patients with Crohn’s disease and ulcerative colitis. ........... 34

Figure 27: BFI at admission (V0), at control visits (V1, V2) and at the end of the NIS (V3; n=318,

LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum). ................................ 34

Figure 28: Mean BFI-values (LOCF) of patients with Crohn’s disease and ulcerative colitis. ................ 35

Figure 29: ADS-L values at admission (V0), at control examinations (V1 and V2) and at the end of

the study (V3; n=277, LOCF; x = mean, - = median, [] = interquartile, - = minimum and

maximum). ....................................................................................................................................... 35

Figure 30: Mean ADS-L values (LOCF) for patients with Crohn’s disease and ulcerative colitis. .......... 36

Figure 31: VAS values of SF-McGill at admission (V0), at control examinations (V1, V2) and at the

final documentation (n=282, LOCF; x = mean, – = median, [] = interquartile, - = minimum and

maximum). ....................................................................................................................................... 36

Figure 32: Mean VAS values (LOCF) of SF-McGill for patients with Crohn’s disease and ulcerative

colitis. ............................................................................................................................................... 37

Figure 33: Activity of Crohn’s disease assessed with HBI at admission (V0), at control examinations

V1 and V2, and at the last visit (V3; n=213, LOCF; x = mean, – = median, [] = interquartile, - =

minimum and maximum). ................................................................................................................ 37

Figure 34: Activity of ulcerative colitis assessed with Mayo-score at admission (V0), at follow-up

visits (V1 and V2) and at the last documentation (V3; n=143, LOCF; x = mean, – = median, [] =

interquartile, - = minimum and maximum). ..................................................................................... 38

Figure 35: Global assessment of efficacy by physician and patient. ..................................................... 39

Figure 36: Assessment of tolerability of Remsima®. ............................................................................. 43


Integrated report: Version 1.0, 19th of January 2018 XIX

List of appendices

Appendix A: Statistical analysis

A – Total sample

Subgroup analysis:

B – Crohn’s disease

C – Ulcerative colitis

D – Patients with and without antibody pre-treatment

E - Patients with antibody pre-treatment: switch ≤ 56 days, > 56 days

Appendix B: Study documents (observational study plan, CRF, SmPC)


Integrated report: Version 1.0, 19th of January 2018 XX

INDEX OF TABLES IN APPENDIX

Page A – Total sample

1-2 Number of centers and patients

3 Visits present

4 Duration of observation

5 Demographic data - Age

6 Demographic data - sex

7-8 Demographic data - height, weight, BMI

9-13 Anamnesis

14-23 Description of acute episode (Visit 1)

24-25 Imaging procedures

26-27 Laboratory parameters / Visit 1

28-29 Pre-treatment of underlying inflammatory bowel disease / ATC - anatomical main group

30-31 Pre-treatment of underlying inflammatory bowel disease / ATC - chemical substances

32 Pre-treatment of underlying inflammatory bowel disease / antibody pre-treatment

33-36 Concomitant disease / MedDRA 20.0 - preferred code

37-38 Concomitant disease / MedDRA 20.0 - Primary system organ classes

39-40 Treatment of concomitant diseases / ATC - anatomical main group

41-43 Treatment of concomitant diseases / ATC - chemical substances

44-49 Treatment with Remsima

50 Treatment of underlying inflammatory bowel disease during study / ATC - anatomical main group

51-52 Treatment of underlying inflammatory bowel disease during study / ATC - chemical substances

53-57 Description of acute episode

58-64 Antibodies before and during study

65-74 IBDQ-D score / Inflammatory bowel disease questionnaire

75-76 BFI / Brief Fatigue Inventory (0-10 points)

77-78 ADS-L / Allgemeine Depressionsskala (0-60 points)

79-86 SF-McGill / Short-form McGill Pain Questionnaire

87-90 Global assessment of effectiveness


Integrated report: Version 1.0, 19th of January 2018 XXI

91-132 Laboratory parameter

133-134 Global assessment of tolerability

135-136 Adverse drug reactions / MedDRA 20.0 - preferred terms

137 Adverse drug reactions / MedDRA 20.0 - Primary system organ class

138-144 Adverse drug reactions / MedDRA 20.0 - Hierarchy

145-146 Adverse drug reactions / MedDRA 20.0 - preferred terms / Seriousness

147-148 Adverse drug reactions / MedDRA 20.0 - preferred terms / SUSAR

149-152 Adverse drug reactions / MedDRA 20.0 - preferred terms / Outcome

153-156 Adverse events / MedDRA 20.0 - preferred terms

157-158 Adverse events / MedDRA 20.0 - Primary system organ class

159-162 Adverse events / MedDRA 20.0 - preferred terms / Seriousness

163-166 Adverse events / MedDRA 20.0 - preferred terms / Relation

167-174 Adverse events / MedDRA 20.0 - preferred terms / Outcome

175-194 Adverse events / individual patient data listing

Page B – Crohn’s disease






8-11 Anamnesis


15 Assessment of disease activity of Crohn's disease (Harvey-Bradshaw Index)

16-24 Localization of the acute episode (Montreal-classification)






36-37 Concomitant disease / MedDRA 20.0 - Primary system organ classes




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48 Treatment of underlying inflammatory bowel disease during study / ATC - chemical substances


54-57 Assessment of disease activity of Crohn's disease (Harvey-Bradshaw Index, patients with Crohn's disease only)








127 Adverse drug reactions / MedDRA 20.0 - preferred terms



134 Adverse drug reactions / MedDRA 20.0 - preferred terms / Seriousness

135 Adverse drug reactions / MedDRA 20.0 - preferred terms / SUSAR



140 Adverse events / MedDRA 20.0 - Primary system organ class




Page C – Ulcerative colitis






8-11 Anamnesis



Integrated report: Version 1.0, 19th of January 2018 XXIII

15 Assessment of disease activity of ulcerative colitis (Mayo score, patients with ulcerative colitis only)

16-23 Localization of the acute episode (Montreal-classification, patients with ulcerative colitis only)



28 Pre-treatment of underlying inflammatory bowel disease / ATC - anatomical main group




34 Concomitant disease / MedDRA 20.0 - Primary system organ classes





45-46 Treatment of underlying inflammatory bowel disease during study / ATC - chemical substances


52-55 Assessment of disease activity of ulcerative colitis (Mayo score)








125 Adverse drug reactions / MedDRA 20.0 - preferred terms



132 Adverse drug reactions / MedDRA 20.0 - preferred terms / Seriousness

133 Adverse drug reactions / MedDRA 20.0 - preferred terms / SUSAR


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138 Adverse events / MedDRA 20.0 - Primary system organ class




Page D – Patients with and without antibody pre-treatment


2-3 Anamnesis - Which form of inflammatory bowel disease (IBD) is the patient suffering from?


10-15 Assessment of disease activity of ulcerative colitis (Mayo score, patients with ulcerative colitis only)







Page E - Patients with antibody pre-treatment: switch ≤ 56 days, > 56 days


2-3 Anamnesis - Which form of inflammatory bowel disease (IBD) is the patient suffering from?


10-15 Assessment of disease activity of ulcerative colitis (Mayo score, patients with ulcerative colitis only)








Integrated report: Version 1.0, 19th of January 2018 1

I. STUDY ADMINISTRATIVE STRUCTURE

I.1. Sponsor

Mundipharma GmbH

Mundipharmastraße 2

65549 Limburg (Lahn)

I.2. Contract Research Organization (CRO)

ANFOMED GmbH


91096 Möhrendorf

I.3. Data management

ANFOMED GmbH


91096 Möhrendorf

I.4. Statistics

ANFOMED GmbH


91096 Möhrendorf

I.5. Medical writing

ANFOMED GmbH


91096 Möhrendorf



II. INTRODUCTION

Monoclonal antibodies have been established as a major product class of biotechnology-

derived medicinal products. Different mAb products share some properties, e.g. being

cytotoxic to their target, or neutralizing a cytokine, but differ in aspects like the mechanism of

action. They are structurally complex and may have several functional domains within a single

molecule, depending on the isotype (antigen-binding region, complement-binding region,

constant part interacting with Fc receptors). Each individual mAb presents a unique profile

with respect to the antigen-binding region, the Fc cytotoxic effector function, and binding to

Fc receptors. Tumor necrosis factor alpha (TNFα) inhibition is an important treatment option

for several chronic inflammatory disorders in rheumatology and gastroenterology. TNFα is a

multipotent cytokine that occurs in monomeric and trimeric soluble and transmembrane

forms. Infliximab is a chimeric human-murine monoclonal antibody that binds with high

affinity to both, soluble and transmembrane forms of TNFα. TNFα receptor activation is

prevented by infliximab through binding to TNFα, thereby neutralising the biological activity

of TNFα. This monoclonal antibody was first authorised in the European Union in August

1999 under the invented name of Remicade®. It is currently approved for the following

indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, adult and

paediatric Crohn’s disease, and adult and paediatric ulcerative colitis. In June 2013, the

European Medicines Agency’s Committee for Medicinal Products for Human Use

recommended the authorisation of Remsima® (Inflectra®, CT-P13) as a biosimilar medicinal

product containing infliximab (Committee for Medicinal Products for Human Use (CHMP)

2013). As part of the comparability exercise, it was shown that all major physicochemical

characteristics and biological activities of Remsima® were comparable to those of the

reference product Remicade®.

The clinical data demonstrating similarity between Remsima® and Remicade® consisted of two

main clinical trials: a pivotal pharmacokinetic study in patients with ankylosing spondylitis

(PLANETAS study CT-P13 1.1) (Park et al. 2016) and a pivotal efficacy and safety study in

patients with active rheumatoid arthritis (PLANETRA study CT-P13 3.1) (Yoo et al. 2013). The

pharmacokinetic trial in ankylosing spondylitis patients showed, at the dose of 5 mg/kg,

comparable profiles between Remsima® and Remicade® at steady state (after 5 doses) with

the 90% confidence intervals of the geometric means ratios (%) of both primary parameters

AUCτ and Cmax,ss within the pre-specified bioequivalence interval: AUCτ:104.10 (93.93-

115.36) and Cmax,ss: 101.47 (94.57-108.86). In addition, the results of the main secondary

pharmacokinetic parameters such as Tmax, Cmin, ss, T½, CLss, Vss between weeks 22 and 30,

as well as Cmax and Cmin after the 9 treatment doses were also comparable in the Remsima®

and Remicade® treatment arms, providing further evidence of a similar pharmacokinetic

behaviour. Additional supportive data regarding the similarity at the dose of 3 mg/kg were

provided from the second main study. The efficacy and safety trial in rheumatoid arthritis

patients achieved its primary endpoint since the 95% confidence interval for the difference in

the ACR20 response rate at week 30 was contained within the predefined equivalence margin

(±15%) in both the all-randomised (95% CI: -0.06, 0.10) and per protocol populations (95% CI:



-0.04, 0.12). At week 30, the results of the secondary endpoints (in particular ACR50 and

ACR70, decreases in DAS28, SDAI and CDAI, increases in SF-36) were all consistent with the

results of the primary endpoint. These data were further supported by comparable response

rates at week 54. Additional supportive efficacy data were provided in another indication by

the pharmacokinetic study CT-P13 1.1 conducted in ankylosing spondylitis patients. The

efficacy results were comparable between treatment arms up to week 54. The evaluation of

the safety profile of the biosimilar medicinal product was supported mainly by the results from

the two clinical studies mentioned above. The type and incidence of adverse drug reactions

observed with Remsima® and Remicade® in the respective studies were generally similar and

no new safety concern was identified. Based on the robust comparisons of the

physicochemical and in vitro and ex vivo biological analyses, Remsima® was considered

biosimilar to the reference product Remicade®. These data, in combination with clinical data

demonstrating pharmacokinetic and therapeutic equivalence in rheumatology conditions,

allow for extrapolation to all other indications of Remicade® (Committee for Medicinal

Products for Human Use 2012; Assessment report Remsima 2013).

Remsima® is now recommended and available for the clinical use in patients with Crohn’s

disease and ulcerative colitis in the European Union. To date, only few data were collected

regarding clinical outcomes achieved with Remsima® for these indications. Prior studies

showed the safety and efficacy in rheumatoid arthritis and ankylosing spondylitis, however,

potential similarity in the treatment of IBD was not documented so far and is therefore

addressed in the following presentation of the prospective, multicenter, non-interventional

ResCu study.

III. GENERAL REGULATIONS

The general notification requirement according to § 67 (6) German Medicines Law (AMG)

stipulated that the National Association of Statutory Health Insurance Physicians (KBV), the

National Association of Statutory Health Insurance Funds (Spitzenverband Bund der

Krankenkassen) and the Fund for Private Health Insurances (Verband der privaten

Krankenversicherung e.V.) had to be notified (Gesetz über den Verkehr mit Arzneimitteln

2013). The names and lifetime number of all attending physicians involved had to be reported

to the KBV and the National Association of Statutory Health Insurance Funds as well as the

kind and level of quarterly achieved remuneration.

Recognized principles for conducting non-interventional studies had been observed

(Arbeitsgruppe Epidemiologische Methoden der Deutschen Arbeitsgemeinschaft für

Epidemiologie 2004; Victor et al. 1997; La Haye 2000; Sickmüller 2009; Elm et al. 2008).

Documentation was conducted according to non-interventional principles under the sole

therapeutic and medical responsibility of the attending physician. Each physician involved

assured by signing the contract that the collected data were documented according to the

observational plan.



Participating physicians were remunerated for completion of eCRF forms. Remuneration was

calculated on basis of the German physician fee scale (GOÄ). Terms of payment were settled

in the contract of participation.

An ethics committee was consulted before start of survey.

IV. STUDY OBJECTIVES

IV.1. Primary endpoints of the study

The aim of the non-interventional observational (NIS) study was to document efficacy and

safety of Remsima® in the treatment of Crohn‘s disease and ulcerative colitis under real life

conditions. The activity of Crohn‘s disease and ulcerative colitis were determined by Harvey-

Bradshaw-Index (HBI) (Harvey und Bradshaw 1980) and Mayo-Score (Lewis et al. 2008).

IV.2. Secondary endpoints of the study

The influence on quality of life, fatigue, depression and abdominal pain was documented by

validated patient questionnaire forms. The German version of the Inflammatory Bowel

Disease Questionnaire (IBDQ-D) recorded the quality of life of patients (Janke et al. 2005).

Furthermore, by using the Brief fatigue inventory (BFI), the influence of treatment with

Remsima® on fatigue was recorded (Radbruch et al. 2003). The ADS-L was used to document

depression (Hautzinger und Bailer 1993) and the SF-McGill Questionnaire to evaluate

abdominal pain (Melzack 1987).

V. STUDY DESIGN AND SAMPLE SIZE CALCULATION

V.1. Study design

The current study was a non-interventional observational trial according to the definition of

§ 4, (23), sentence 3 of the German Medicinal Products Act (AMG): ”(…) this is a study within

the scope of findings resulting from persons’ treated with medicinal products that are

analyzed using epidemiological methods pursuant to the specification for use, contained in

the marketing authorization; the treatment, including the diagnosis and monitoring, shall not

follow a predetermined trial protocol but shall result exclusively from current medical

practice.”

A prospective, multicenter, non-interventional, observational study was suited best to seek

information in order to clarify all listed issues and to investigate an adequate number of

patients. Additionally, it was the only means available to gain information on therapeutic

behaviour of physicians in routine medical practice without accompanying conditions or other

influences. Enrolment of patients into the non-interventional observational study is based

solely on the physicians’ assessment on medical usefulness and necessity.

Planning, conduction and evaluation of the study was based on the relevant combined

recommendation of BfArM (The Federal Institute for Drugs and Medical Devices) and Paul-

Ehrlich Institute (PEI).



V.2. Sample size calculation

Enrolment of about 400 patients was planned. A total number of 400 patients was intended

considering the feasibility of this non-interventional study in the routine medical practice for

obtaining a representative number of patients in the named indication.

Based on 400 documented cases:

in case of dichotomous variables for the underlying binominal probability, a 95%-

confidence interval of in maximum 10.02 percentage points in length are reached,

95%-confidence intervals on the underlying means of quantitative variables have a

length of 0.197 standard deviations,

rare events with an incidence down to 0.007 (1:134) are included at least once in

the sample with a probability of 95%.

VI. STUDY PLAN AND PROCEDURES

VI.1. Study plan

Data were documented in an electronic case report from (eCRF) or by patient questionnaire

forms. Four survey dates were planned:

Baseline of data collection (Visit 0): before start of treatment

Follow-up data collection (Visit 1): about 2 weeks after start of treatment

Follow-up data collection (Visit 2): about 6 weeks after start of treatment

Final survey of data collection (Visit 3): about 14 weeks after start of treatment

The exact examination dates were to be determined by the attending physician.

Details on each visit are listed in Table 1.

Table 1: Study plan

Baseline

(Visit 0)

Follow-up after about 2 weeks

(Visit 1)

Follow-up after about 6 weeks

(Visit 2)

Final survey after about

14 weeks (Visit 3)

Date of visit X X X X

Demographic data X

Medical history of CIBD X

Assessment of severity of acute episode

X X X X

Localization and description of acute episode

X

Imaging diagnostic X X X X

Laboratory parameter X X X X

Pre-treatment of CIBD X

Treatment with Remsima® X X X X



Concomitant diseases and medication

X X X X

IBDQ-D X X X X

BFI X X X X

ADS-L X X X X

SF-McGill X X X X

Harvey-Bradshaw Index (patients with Crohn's disease only)

X X X X

Mayo score (patients with ulcerative colitis only

X X X X

Global assessment of Remsima® therapy by physician and patient

X X

Adverse drug reactions and adverse events

X X X

VI.2. Participating sites and patient selection

A total number of 70 participating physicians specialized in gastroenterology was intended.

The distribution of the physicians extended throughout Germany.

It was estimated that one physician should enrol a maximum of 6 patients. But in the

discretion of time schedule and medical practice during the non-interventional trial,

enrolment of more than 6 patients per site was accepted.

A patient was included in the study when the physician decided in advance to start treatment

with Remsima® according to the local SmPC (Mundipharma 2015). The prescription of

Remsima® was independent of enrolment in the non-interventional study and not determined

by the observational plan in advance.

A signed patient consent form was required for participation in the study. Only patients of full

age who were capable of understanding the nature, significance and implications of the study

and to form a rational intention in the light of the facts, were enrolled in the study.

VI.3. Treatment

Remsima® is indicated for symptomatic treatment of moderate to severe, active Crohn‘s

disease, treatment of fistulising, active Crohn‘s disease and moderate to severe active

ulcerative colitis in adult patients who have not responded despite a full and adequate course

of therapy with conventional treatment or who are intolerant to or have medical

contraindications for such therapies.

According to the summary of product characteristics (SmPC) the recommended dose is

5 mg/kg as an intravenous infusion (Mundipharma 2015). Application of Remsima® was

according to usual therapeutic procedure of the attending physician and in accordance with

the authorized indications and SmPC (Mundipharma 2015).



VI.4. Observational period and total duration of the non-interventional study

Observational period per patient was about 14 weeks. The non-interventional study started

on 28th of September 2015. Last patient was enrolled on 31st of December 2016. End of the

non-interventional study was 31st of April 2017. Data entry into eCRF was possible until 15th

of May 2017 (after extension).

VI.5. Conducting the study

Sales representatives of Mundipharma GmbH were responsible for distributing study

documents and were at hand to answer administrative questions related to survey

conduction. Distribution of documents was executed according to the FSA codex (Kodex zur

freiwilligen Selbstkontrolle 2013) and were not linked to any pharmaceutical advertising

actions. Central coordination of the study was conducted by the assigned clinical research

organization ANFOMED GmbH.

To obtain individual user name and password for log in on the study website, physician had to

forward the filled out and signed contract to ANFOMED GmbH. Physicians received the access

data in written form.

The physician selected suitable patients who met all the required criteria for data collection

within the scope of the non-interventional study and obtained their written consent. It should

be particularly noted that selection of patients, who were included in the study, was based

solely on the assessment of medical sense and necessity by the attending physician. Patients

were considered for enrollment, after treatment with Remsima® had been decided on.

The physician investigated selected patients at scheduled dates and documented the data in

the eCRF. Study website was subdivided into different visits leading the physician through the

documentation of the examination.

The patient questionnaire forms were handed out at baseline, at follow-up examinations and

at final examination to be filled out by the patient. These forms had to be returned to the

attending physician at the same examination. The physician forwarded the completed patient

questionnaires directly after each visit to ANFOMED GmbH for data entry, validation and

evaluation.

VI.6. Documentation

The documentation occurred online on a password-protected website. The online

documented data were proofed for completeness and plausibility according to defined and

validated rules. Following conditions were required for online documentation in the eCRF:

internet access

working browser (e.g. Microsoft Internet Explorer etc.)

The attending physician had to log in on the internet website (https://www.NIS-

Remsima.com) with individual user name and password for the documentation.



Patient data were pseudonymized. Each attending physician had only access to the data of his

supervised patients.

The eCRF was structured in several pages. When changing to a next page, entered data were

proofed for completeness, consistency and formatting. Sections of the eCRF with erroneous

input were highlighted and an error message appeared.

For security reasons, the whole data transfer between client and web server followed Secure

Socket Layer protocol (SSL) with 128-bit encoding. The study database was copied to a second

hard disc each hour and to tape once a day.

Patient questionnaire forms were available on paper. After completion by the patient they

were forwarded to ANFOMED GmbH for electronic registration.

Patient data and physician data were subject to data protection requirements according to

legal regulation of protecting against abuse of personal data in data processing (federal data

protection act).

VI.6.1. Documentary components

At the beginning of the non-interventional study the attending physician received a

documentary folder containing all required documents for 6 patients, including:

• two contracts of participation (one original and one copy for physician)

• a short summary of the survey

• patient overview

• the observational plan

• the SmPC of Remsima®

• ethics committee vote

• patient information and consent forms (one copy for patient and one for physician)

• patient questionnaire forms

• manual for eCRF

• return envelopes to send the contract of participation and patient questionnaire

forms

VI.6.2. Data

The following data were documented within the NIS:

VI.6.2.1. Demographics and anamnesis

Patient data (year of birth, sex, height, weight)

Anamnesis (date of diagnosis and type of IBD, information on relapses and intestinal

resections)

Data on acute episode (hospitalization, assessment of activity, localization, imaging

diagnostics, laboratory parameters)



(Pre-)Treatment of IBD and acute episode

Treatment with Remsima® (reason for adjustment, therapy start, batch-number,

dosage)

VI.6.2.2. Efficacy measurements

Dosage, therapy change, continuation of treatment with Remsima®

Data on acute episode during therapy with Remsima® (hospitalization, assessment

of activity, imaging diagnostics, laboratory parameters)

Treatment of IBD and acute episode

Concomitant medication

Physicians‘ assessment of efficacy

VI.6.2.3. Safety measurements

Adverse events/adverse drug reactions

Physicians‘ assessment of tolerability

VI.6.2.4. Data from patient questionnaires

All patients received patient questionnaire forms which were to be filled out completely.

Questionnaires had to be returned to the physician at baseline, at follow-up examinations and

at final visit.

The physician forwarded the completed patient questionnaires directly after each visit to

ANFOMED GmbH for electronic registration and further processing.

Inflammatory Bowel Disease Questionnaire

The German version of the Inflammatory Bowel Disease Questionnaire (IBDQ-D) was designed

to find out how the patient had been feeling in the last two weeks and was therefore used to

document the quality of life of patients (Janke et al. 2005).

Brief Fatigue Inventory

The Brief Fatigue Inventory (BFI) served to quickly assess the severity of fatigue as well as its

impact on patients’ capability over the previous 24 h (Radbruch et al. 2003).

General depression scale

The general depression scale (Allgemeine Depressionsskala – Langform, ADS-L) was used as a

self assessment tool to evaluate the impairment due to depressive symptoms within the last

week. Emotional, motivational, cognitive, somatic and motoric complaints were asked

(Hautzinger und Bailer 1993).

Short-Form McGill Pain Questionnaire

The German version of the Short-Form McGill Pain Questionnaire (SF-McGill) was used in this

non-interventional study to evaluate abdominal pain (Melzack 1987).



VI.6.3. Definition and reporting of adverse events (AE)/Adverse drug reactions (ADR)

Attending physicians were responsible to document carefully all serious and non-serious

adverse drug reactions (ADR) in the eCRF, independent of severity, in which relation to

Remsima® therapy was not excluded and occurred during the course of the study.

The ADR report section recorded all information such as type and duration, measures or

therapies and assessment of causality. Additionally, all adverse events (AE), in which relation

to Remsima® therapy was excluded, were to be documented in the eCRF.

Adverse drug reactions (ADR) are defined in § 4, (13) of the German Medicinal Products Act

(AMG) as ”noxious and adverse reactions to a drug, in medicines intended for use in humans”.

Serious adverse drug reactions are reactions that

result in death,

are life threatening,

require hospitalization or prolong an existing hospitalization,

result in persistent or significant disability or incapacity,

result in congenital anomaly or birth defect and

are a medically important condition.

Medically important conditions were events that threatened the patient significantly and

possibly required a medical or surgical intervention to prevent a serious adverse event.

Any adverse drug reaction (serious or non-serious) during the non-interventional study, in

which relation to Remsima® therapy could not be excluded, independent of severity, had to

be carefully documented in the “ADR report section” of the eCRF within 24 hours. This ADR

report was automatically forwarded to the drug safety department of ANFOMED GmbH and

after processing to Mundipharma GmbH.

Mundipharma was responsible for further processing of all case reports concerning adverse

drug reactions including acquisition, documentation, scientific assessment and any report

required according to AMG §63c.

VI.7. Data management, quality control and statistical analysis

VI.7.1. Data management

Data management was based on the “Guidelines and recommendations for ensuring Good

Epidemiological Practice (GEP)” (Deutsche Arbeitsgemeinschaft für Epidemiologie 2004).

This non-interventional study was based on online documentation. Entered data were

automatically transmitted to central data collection of ANFOMED GmbH for statistic analysis.

Consistency of the ADR data was ensured by comparing the project database with the drug

safety database of Mundipharma GmbH. Discrepancies were resolved by joint consultation.



VI.7.2. Quality control

In case of incomplete or incorrect entered data in the eCRF physicians directly received an

automatically generated warning message to correct entered data. Once an adverse drug

reaction was entered in the eCRF, physicians received a warning message to fill out the „ADR

report section”. Furthermore, the data in the eCRF were checked for suspicious ADRs and also

checked at regular intervals for updates in the data files of the patients with ADRs.

VI.7.3. Statistical analysis

Taking into account the non-interventional character of the study, the statistical analysis was

performed in a descriptive and explorative way. In detail, the following descriptive procedures

were used:

• Absolute, relative and adjusted relative frequencies were computed; for the latter, patients

with missing data were omitted.

• Multiple entries, e.g. drug names, were counted; the relative frequencies referred to the

number of cases so that the total of 100% could be exceeded through multiple entries per

case. In each case, the number of patients that had given multiple replies was recorded. This

included relative (related to the population) and adjusted relative frequencies (related to the

population minus the missing data).

• Cross tables:

The results tables include two types of cross tables: The first input value for the first type is a

grouping variable and the second are the various expressions or qualities of the analysed

variable. The percentage relates to the sum of the line (last column) that contains the number

of patients per group. In the second type of cross tables, the two input values are formed by

the expression of the same variable. The percentage relates to the total of the patients

represented in the table that can be read from the crossing point of the last line and the last

column. This type of illustration is used to investigate shifts between two specific time points.

• Calculations of mean, standard deviation, quartiles, 95%-confidence limits (95%-CL) and

also listing of maximum and minimum values.

AEs/ADRs were entered separately and coded according to MedDRA. All cases were listed in

frequency tables on the basis of preferred terms (PT) and system organ class (SOC). A line

listing of all events was prepared.

When reasonable, lists of individual data were prepared.

VI.7.3.1. Missing values and last observation carried forward method

For variables that had been documented once in the course of the study, missing values were

not replaced. The frequency of missing values of each parameter was listed in the tables.

For variables that had been documented several times in the course of the investigation, an

analysis according to the last observation carried forward method (LOCF) was given in addition

to the representation of all existing values and complete cases. With LOCF, missing values in



the course of the study were replaced by the last actual observation. Condition for the

application of this method was the existence of a baseline value and a value after baseline.

VI.7.3.2. Significance tests and weighted kappa coefficient

No statistical hypotheses were formulated in advance. If considered as relevant, tests of

significance were presented for important parameters, but should be interpreted in a

descriptive-exploratory way only. The p-values reported were two-tailed and an alpha level of

0.05 was used to assess statistical significance. No correction of alpha level for multiple tests

was performed.

Tests used were:

Bhapkar's test of marginal homogeneity: marginal homogeneity refers to the situation

where the marginal distributions of row and column variables of an n*k table (shift-table)

are the same.

Wilcoxon's signed-rank test: the Wilcoxon signed-rank test is a non-parametric statistical

hypothesis test used when comparing two related samples, matched samples, or repeated

measurements on a single sample to assess whether their population mean ranks differ.

The weighted kappa coefficient is a statistic that measures inter-rater agreement for

ordinal items. Values < 0 are considered as indicative for no agreement, 0–0.20 for slight,

0.21–0.40 for fair, 0.41–0.60 for moderate, 0.61–0.80 for substantial, and 0.81–1 for almost

perfect agreement (Landis 1977).

VI.7.3.3. Limitations

Due to missing reference group of patients without or with alternative therapy, the efficacy

of Remsima® treatment could not be mathematically isolated. One advantage of this study

design was the better transfer to non-selected patients in non-study situations.

VI.7.3.4. Software

The statistical analysis was done using the SASTM Version 9.4 on a personal computer with

Windows 10TM.

VI.7.3.5. Dictionaries and coding systems used

Pre-treatments, concomitant therapies and ADRs were coded according to the coding system

in Table 2.



Table 2: Coding systems used in this report

Variable Coding system used

Previous and concomitant therapies ATC (Anatomic Therapeutic Classification, 2017)

Adverse events/reactions MedDRA 20.0

Concomitant diseases MedDRA 20.0

VI.7.3.6. Conventions used in this report

Unless otherwise stated, percentages presented in this report are adjusted percentages,

meaning subjects with missing values for a particular parameter were not taken into account.

References to tables with an A- to E-prefix (i.e. Table A11) refer to tables in appendixes,

whereas references without a prefix refer to tables within this report.

VII. DISPOSITION

Data of 381 patients were available for statistical analysis. These patients were under

physicians care of 70 centres (Table A1). The number of patients per centre was on average

(±SD) 5.44 (±3.66, median 4.50) and varied from one patient up to 13 patients. Data were most

frequently documented on three, one or six patients per centre (11 centres, 15.71% of the

centers; 10 centres, 14.29%; 10 centres, 14.29%; Table A2).

The first patient was enrolled on 11th of June 2015 retrospectively. The last documentation of

the last patient was performed on 31th of March 2017.

Data of all visits (admission to final examination, V0-V3) were available for 291 patients

(76.38% of all patients) for statistical analysis. Overview about the number of patients and the

visits performed is given in Table 3 (Table A3).



Table 3: Number of patients and performed visits (n=381)

Mean duration of observation was 3.36 (±1.54, median 3.25) months with a minimum of

0.36 months and a maximum of 12.20 months. The most frequent duration was 3-4 months

(179 patients, 49.18% of all patients with data concerning duration of treatment). The sum of

the observed patient years was 101.87 years. Data of 17 patients were missing (Table A4).

VIII. STUDY SUBJECTS

VIII.1. Patient characteristics

VIII.1.1. Age

Patients’ mean age was 41.10 (±14.62, median 39.00) years with a range of 18 to 91 years.

Attending patients were predominantly between 20 to <40 years (180 patients, 47.37% of the

patients with data on age) old (Table A5).

The distribution of patients’ age is depicted in detail in Figure 1.

Admission

(V0)

Control

examination

(V1)

Control

examination

(V2)

Final

examination

(V3)

Number of patients

(n)

Percent (%)

X . . . 15 3.94

X . . X 3 0.79

X . X . 2 0.52

X . X X 14 3.67

X X . . 22 5.77

X X . X 4 1.05

X X X . 30 7.87

X X X X 291 76.38

Number of patients (n)

381 347 337 312 381 100.00

Percent (%)

100.00 91.08 88.45 81.89 . .



Figure 1: Distribution of patients’ age (n=380).

VIII.1.2. Sex

Gender was reported for 381 patients. Of

these, 180 patients (47.24%) were male

and 201 patients (52.76%) were female

(Figure 2, Table A6).

Figure 2: Distribution of patients’ sex (n=381).

VIII.1.3. Height and Weight

Mean height of 376 patients was 173.34 cm (±8.95, median 172.50) and varied between the

minimum of 152.00 cm and the maximum of 203.00 cm. Data were missing for five patients

(Table A7). Concerning weight, a mean value of 75.33 (±17.66, median 73.50) kg was

calculated from data of 376 patients. Weight information of five patients was not available

(Table A7).

VIII.1.4. Body Mass Index

The mean body mass index (BMI) of 376 patients was 25.01 (±5.29, median 24.12) kg/m2 and

varied between 15.21 and 47.18 (Table A7).

0%

1%

2%

3%

4%

5%

17 22 27 32 37 42 47 52 57 62 67 72 77 82 87

47.24%52.76%

Male

Female



Most of the patients were of standard

weight (187 patients, 49.73%) and

111 patients (29.52%) were overweight.

Minority of patients were obese

(53 patients, 14.10%) or underweight

(25 patients, 6.65%). Figure 3 shows the

distribution of the patients to the weight

classes. Values of five patients were

missing (Tables A8).

Figure 3: Distribution of patients’ BMI (n=376).

VIII.2. Anamnesis

VIII.2.1. Type of inflammatory bowel disease

The type of inflammatory bowel disease

(IBD) was documented for 381 patients.

Crohn’s disease was more frequently

diagnosed than ulcerative colitis

(223 patients, 58.53% vs. 158 patients,

41.47%; Figure 4, Table A9).

Figure 4: Frequency of Crohn’s disease and ulcerative colitis (n=381).

VIII.2.2. Duration of CIBD

Mean duration since diagnosis was 106.64 (±108.32, median 76.03) months with a range of

about a half month to more than 39 years, but frequently less than 5 years (157 patients,

44.73% of the patients with data on duration; Figure 5). Data of 30 patients were missing

(Table A10).

6.65%

49.73%29.52%

14.10%

Underweight

Standard weight

Overweight

Adiposity

58.53%

41.47%

Crohn's disease

Ulcerative colitis



Figure 5: Duration of IBD since diagnosis (n=351).

The mean number of episodes since diagnosis was reported for 114 patients with a mean of

4.73 (±6.18, median 2.00) episodes. Most patients stated occurrence of one episode since

diagnosis (35 patients, 30.70%). Data on the frequency of episodes were not available for

267 patients (Table A11).

VIII.2.3. Intestinal resection due to CIBD

An intestinal resection due to CIBD was performed in 61 patients (16.14% of patients with

data on intestinal resection) whereas 317 patients (83.86%) were without an intestinal

resection in the past. Information was missing for three patients (Table A12). Up to

three intestinal resections were reported (one resection, 47 patients, 12.43%; two resections,

12 patients, 3.17%; three resections, 2 patients, 0.53%; Table A13).

VIII.2.4. Description of acute episode (Visit 0)

VIII.2.4.1. Duration of acute episode

Data on duration of acute episodes at study start were available in 374 patients. The mean

duration of acute episodes at enrolment was 14.34 (±43.72, median 2.93) months. Most of

the patients suffered from an acute episode for less than 6 months (262 patients, 70.05%) and

in 78 patients the acute episode started >6-24 months before baseline (78 patients, 20.86%).

Further information is given in Table A14.

VIII.2.4.2. Hospitalization

Concerning hospitalization prior to study start, patients were asked if they had been

hospitalized due to the current episode. Most patients answered in the negative (293 patients,

78.13% of the patients with data on hospitalization). Information of six patients was missing

(Table A15).

Patients with hospitalization stayed on average 2.51 (±3.50, 1.43 median) weeks at the

hospital. The time varied from one day up to 20 weeks. The number of weeks in hospital was

quite diverse, but most patients stayed up to one week (32 patients, 39.02%), followed by up

9.40%

16.52%

18.80%

22.22%20.80%

12.25%

0%

5%

10%

15%

20%

25%

> 0 - 6 months > 6 - 24 months > 24 - 60 months > 5 - 10 years > 10 - 20 years > 20 years

Duration



to two weeks (25 patients, 30.49%) and up to three weeks (11 patients, 13.41%). Additional

information is given in Table A16.

VIII.2.4.3. Pre-treatment

Most patients stated a pre-treatment of acute episode (254 patients, 66.67%) while

127 patients (33.33%) were not previously treated. Almost three-quarters of pre-treated

patients stated one pre-treatment (73.23% of patients with pre-treatment), followed by two

(16.14%), three (7.48%), and four pre-treatments (2.36%). Only for one single patient five and

six pre-treatments, respectively, were documented (0.39%).

Medication was classified according to the ATC anatomical main group (Table A17). Treatment

with corticosteroids for systemic use (172 patients, 45.14% of all patients) and

antidiarrheals/intestinal antiinflammatory or antiinfective agents (80 patients, 21.00%) were

most frequently reported (Figure 6).

Figure 6: Pre-treatment of acute episode according to ATC anatomical main group (n=381).

In addition, medication was classified according to ATC chemical substances (Table A18). Most

commonly reported chemical compounds were prednisolone (137 patients, 35.96% of all

patients) and mesalazine (55 patients, 14.44%). Azathioprine (9.71%) was indicated for

37 patients and budesonide was reported for 31 patients (8.14%). All other chemical

substances were documented with a percentage below 5%. All chemical substances are listed

in Table A18-A19.

45.14%

21.00%

16.27%

2.36%

1.84%

1.84%

1.05%

0.79%

0.79%

0.79%

0.79%

0.26%

0.26%

0.26%

0.26%

0.26%

0.26%

0.26%

33.33%

0% 10% 20% 30% 40% 50%

Corticosteroids for systemic use

Antidiarrheals, intestinal antiinflammatory/…

Immunosuppressive agents

Antibacterials for systemic use

Analgesics

Stomatological preparations

Vitamins

Antianemic preparations

Corticosteroids, dermatological preparations

Cytostatics

Drugs for acid related disorders

Antiprotozoals

Antivirals for systemic views

Drugs for functional gastrointestinal…

Laxatives

Lipid modifying agents

Mineral supplements

Other dermatological preparations

Without pre-treatment



VIII.2.4.4. Ongoing pre-treatment

At enrolment, continuation of pre-treatment of acute episode was documented for 141 from

381 patients (37.01%). One continued pre-treatment was recorded for most of them

(113 patients, 80.14% of patients with ongoing pre-treatment when medication was classified

according to the anatomical main group; Table A20).

Medication was classified according to ATC anatomical main group (Table A20) and chemical

substances (Table A21-A22), respectively. With regard to the anatomical main group,

corticosteroids for systemic use were most frequently reported (93 patients, 66.67% of the

patients with continued pre-treatment), followed by antidiarrheals/intestinal

antiinflammatory or antiinfective agents (46 patients, 32.62%) and immunosuppressive agents

(18 patients, 12.77%). Concerning chemical classification, the following compounds were

specified most often: prednisolone, mesalazine, azathioprine, budesonide, and cortisone

(70 patients, 49.65%; 32 patients, 22.70%; 18 patients, 12.77%; 17 patients, 12.06%;

15 patients, 10.64%).

VIII.2.4.5. Surgical measures for pre-treatment of acute episode

From 381 patients, the majority was without any surgical measures for pre-treatment of acute

episode before start of the NIS (358 patients, 93.96%). Operative interventions were reported

for 23 patients (6.04%). 19 patients had one measure (4.99%) and two patients each had two

or three operations (0.52%). Ileocecal resection was the most frequently noted measure

(8 patients, 34.78% of the patients with operation), followed by abscess drainage (4 patients,

17.39%), fistula drainage, hemicolectomy, and small bowel resection (3 patients each,

13.04%). Additional information is given in Table A23.

VIII.2.5. Disease activity

Disease activity was assessed for patients suffering from Crohn’s disease by the Harvey-

Bradshaw-Index (HBI) and for patients with ulcerative colitis by the Mayo-score.

VIII.2.5.1. Activity of Crohn’s disease

Data on disease activity according to the

HBI was available for 221 patients and was

classified as follows: remission

(0-4 points), mild disease (5-7 points) and

moderate disease (8-16 points). The mean

value was 6.84 (±4.15, median 7.00)

points. A remission of disease was

determined for 74 patients (33.48%), a

mild disease activity for 54 patients

(24.43%) and a moderate disease activity

for 93 patients (42.08%, Figure 7). Data of

two patients were missing (Table B15). Figure 7: Assessment of Crohn’s disease according to the HBI

(n=221).

33.48%

24.43%

42.08%

Remission

Mild disease

Moderate disease



The intestinal localisation of acute episodes of Crohn’s disease according to the Montreal-

classification was available for 220 patients (98.65% of all patients with Crohn’s disease). Most

intestinal manifestations were located at the terminal ileum (91 patients, 41.36% of the

patients with data on intestinal localisation), the colon (88 patients, 40.00%), and the ileocolon

(80 patients, 36.36%). Other parts of the gastrointestinal tract were less frequently affected.

An overview of all localizations stated is given in Figure 8 and listed in Table B16.

Figure 8: Intestinal localization of Crohn’s disease according to the Montreal-classification (n=220).

Information on fistula and extraintestinal manifestations were documented for 220 patients

and 223 patients, respectively. Formation of fistulae was affirmed by 39 patients (17.73%) and

extraintestinal manifestation was confirmed by 54 patients (24.22%). Most of the patients

with extraintestinal complaints suffered from arthralgia (27 patients, 50.00% of the patients

with extraintestinal manifestation; Figure 9, Table B17).

Figure 9: Extraintestinal localization of Crohn’s disease (n=54 patients with extraintestinal manifestation).

41.36%

40.00%

36.36%

6.82%

0.91%

0.45%

0.45%

0.45%

0.45%

0.45%

0.45%

0% 5% 10% 15% 20% 25% 30% 35% 40% 45%

Terminal ileum

Colon

Ileocolon

Upper gastrointestinal tract

Duodenum

Anastomosis

Ileocecal valve

Lower gastrointestinal tract

Neoterminal ileum

Perianal area

Preterminal ileum

50.00%

24.07%

14.81%

5.56%

3.70%

3.70%

3.70%

1.85%

1.85%

1.85%

1.85%

1.85%

0% 10% 20% 30% 40% 50% 60%

Arthralgia

New fistulae

Anal fissures

Aphthous ulcerations

Abscess

Erythema nodosum

Uveitis

Fistula

Hydronephrosis

Ileocoecal resection

Myalgias

Pyoderma gangrenosum



VIII.2.5.2. Activity of ulcerative colitis

Disease activity was classified according to

the Mayo-score either as normal

(0-1 point), mild (2-5 points) or

moderate/severe (>5 points). For

154 patients, the mean value was

7.32 (±2.65, median 8.00) points. Normal

activity of disease was calculated for

6 patients (3.90%), a mild disease activity

for 23 patients (14.94%) and a moderate to

severe disease activity for 125 patients

(81.17%; Figure 10). Information of

four patients was missing (Table C15). Figure 10: Assessment of ulcerative colitis according to the

Mayo-score (n=154).

Information on the intestinal localisation of the acute episode of ulcerative colitis according

to the Montreal-classification was available for 156 patients (98.73% of all patients with

ulcerative colitis). Intestinal manifestations were mostly described as a left-hand colitis of the

descending and sigmoid colon (84 patients, 53.16% of patients with information on intestinal

manifestation) as well as a pancolitis of the colon (62 patients, 39.24%). An overview of all

types is depicted in Figure 11 and listed in Table C16.

Figure 11: Intestinal localization of ulcerative colitis according to the Montreal-classification (n=158).

Extraintestinal manifestations were noticed for 27 patients (17.09% of all patients with

ulcerative colitis). Mostly stated complaint was arthritis (14 patients, 8.86%; Figure 12, Table

C17).

53.16%

39.24%

10.13%

0.63%

0.63%

0.63%

0.63%

0% 10% 20% 30% 40% 50% 60%

Left-hand colitis

Pancolitis

Proctitis

Colon

Colon descendens

Cytomegalovirus infection

Subtotal colitis

3.90%

14.94%

81.17%

Normal

Mild

Moderate/severe



Figure 12: Extraintestinal localization of ulcerative colitis (n=158).

VIII.2.6. Imaging diagnostics

At baseline (visit 0), physicians documented whether and which imaging procedure(s) were

already carried out in order to assess the condition of the mucous membrane. In addition,

physicians were asked for global assessment of the acute episode (normal findings, mild,

moderate or severe episode). No imaging procedure was applied to 123 patients (32.28%)

whereas 258 patients (67.72%) were investigated by imaging diagnostics.

For most patients who underwent an imaging procedure, endoscopy was documented

(223 patients), followed by sonography (110 patients) and magnetic resonance imaging

(25 patients).

For 10 patients with an endoscopic examination, the acute episode was assessed by

endoscopy as unobtrusive (normal finding, 4.48%). 29 patients (13.00%) had a mild episode,

99 patients (44.39%) a moderate episode and for 85 patients (38.12%) the episode was

reported severe. Result of sonography was stated to be normal in 23 cases (20.91%).

Furthermore, the acute episode was assessed as mild in 16 patients (14.55%), moderate in

54 patients (49.09%) or severe in 17 patients (15.45%). Three patients (12.00%) with magnetic

resonance imaging had a normal finding. For four patients (16.00%) the acute episode was

mild, for 10 patients (40.00%) it was moderate and eight patients (32.00%) suffered from a

severe episode.

Other imaging procedures were reported for fewer patients. Detailed information is listed in

Table A25.

VIII.2.7. Laboratory parameters

Physicians documented at the start of the NIS whether and which laboratory parameters were

determined prior to treatment with Remsima®. A full list of reported laboratory data is given

in Tables A26-27. Mean values including standard deviations of individual parameters are

depicted in the following table (Table 4).

8.86%

3.16%

1.27%

1.27%

1.27%

0.63%

0.63%

0.63%

0.63%

0.63%

0.63%

0% 2% 4% 6% 8% 10%

Arthritis

Bechterew's disease

Erythema nodosum

Primary sclerosing…

Psoriasis

Anaemia

Glaucoma

Gonarthritis

Joint trouble

Pankreatitis

Uveitis



Table 4: Laboratory parameters

Parameter Patients Mean value (±SD)

Erythrocytes (Mio/µl) 327 4.52 (±0.56)

Leukocytes (Tsd/µl) 335 9.24 (±3.80)

Thrombocytes (Tsd/µl) 334 344.77 (±129.40)

Hemoglobin (mmol/l) 350 8.30 (±1.51)

Hematocrit (%) 301 39.33 (±5.42)

Serum iron (µmol/l) 130 12.96 (±6.88)

Ferritin (µg/l) 140 98.27 (±108.72)

Transferrin (mg/dl) 71 268.62 (±56.15)

Transferrin saturation (%) 74 21.29 (±15.87)

Urea (mg/dl) 94 18.10 (±14.22)

Creatinine (mg/dl) 242 0.85 (±0.22)

C-reactive protein (mg/l) 345 37.69 (±80.59)

Erythrocyte sedimentation rate (mm) 72 25.21 (±19.70)

Calprotectin (µg/g) 147 747.20 (±831.44)

Concerning data on erythrocytes, most of 327 patients showed values within the reference

range1 (241 patients, 73.70%; reference 4.6-5.9 Mio/µl, male; 4.0-5.2 Mio/µl, female). Values

regarding leukocytes were also for most of the 335 patients within the normal area ranging

from 4.0 to 10.0 Tsd/µl (216 patients, 64.48%). For 191 patients (57.19%), the number of

thrombocytes was higher than the reference (150.0-300.0 Tsd/µl) and 140 patients (41.92%)

had normal values.

About half of 350 patients had normal haemoglobin levels (184 patients, 52.57%) and 42.29%

of the patients had a concentration below the reference area (reference 8.7-11.2 mmol/l,

male; 7.5-9.9 mmol/l, female; 148 patients).

From 301 patients, 146 patients each (48.50%) had a hematocrit proportion within or below

the normal range of 43.0-49.0% (males) and 37.0- 45.0% (females), respectively.

For 63.85% of the patients, serum iron concentration was documented to be within the

reference area (9.0- 29.0 µmol/l, males; 9.0- 27.0 µmol/l, females; 83 patients from

130 patients with measurement) and for 33.08% values were below the normal range

(43 patients).

Applied reference area of ferritin for males was between 30.0-300.0 µg/l and for females

between 10.0-200.0 µg/l, respectively. About three quarters of a total of 140 documented

patients had levels within the normal range (75.71%).

1 Center-specific reference values were not available, therefore global values were applied. All reference values

used are depicted in Table A27.



Additional information and details about laboratory parameters at baseline are available in

the corresponding Tables A26-A27.

VIII.2.8. Pre-treatment of underlying inflammatory bowel disease (IBD)

Pre-treatment of IBD was documented for 326 patients (85.56% of all patients). For the

majority of patients one or two pre-treatments were recorded by the physicians (183 patients,

48.03%; 107 patients, 28.08%). Most commonly reported treatments were

immunosuppressive agents (193 patients, 50.66%), antidiarrheals/intestinal antiinflammatory

or antiinfective agents (184 patients, 48.29%) and corticosteroids for systemic use (89 patients,

23.36%) when classified according to ATC anatomical main group (Tables A28). An overview is

given in Figure 13.

Figure 13: Pre-treatment of underlying IBD according to ATC anatomical main group (n=381).

Concerning chemical classification, the following compounds were specified most frequently:

mesalazine, azathioprine, prednisolone, budesonide, adalimumab and infliximab

(158 patients, 41.47%; 133 patients, 34.91%; 71 patients, 18.64%; 57 patients,

14.96%; 57 patients, 14.96%; 36 patients, 9.45%). All other chemical substances were reported

with a proportional distribution below 5.00% and are fully listed in Tables A30-A31. Pre-

treatment with one or two compounds was most commonly reported (146 patients, 38.32%;

115 patients, 30.18%; Table A30).

VIII.2.9. Concomitant disease

From 381 patients, 100 patients (26.25%) suffered from concomitant disease. One or two

diseases were most frequently reported (60 patients, 15.75%; 20 patients, 5.25%; Table A33).

As classified according to the MedRA preferred code, hypertension (18 patients, 4.72%),

50.66%

48.29%

23.36%

6.30%

1.57%

0.79%

0.52%

0.52%

14.44%

0% 10% 20% 30% 40% 50% 60%


Antidiarrheals, intestinal antiinflammatory/antiinfective agents


Cytostatics

Stomatological preparations

Antiinflammatory and antirheumatic products


Drugs for acid related disorders

…

Without pretreatment



depression (8 patients, 2.10%), hypothyroidism (8 patients, 2.10%), gastrooesophageal reflux

disease (6 patients, 1.57%), and coronary artery disease (5 patients, 1.31%) were most

commonly mentioned (Table A33). Further details on all documented concomitant diseases

are listed in Tables A33-36.

The most frequent system organ classes according to MedDRA were gastrointestinal disorders

(23 patients, 6.04%), vascular disorders (22 patients, 5.77%), musculoskeletal and connective

tissue disorders (17 patients, 4.46%), metabolism and nutrition disorders (14 patients, 3.67%),

cardiac disorders (10 patients, 2.62%), and endocrine disorders (10 patients, 2.62%; Table

A37).

Further concomitant diseases specified by MedDRA system organ class were documented for

less than 10 patients and are listed in Tables A37-A38.

VIII.2.10. Treatment of concomitant disease

A medical treatment of concomitant illness was documented in 79 patients (20.73%). One or

two treatments were most frequently reported (50 patients, 13.12%; 20 patients, 5.25%;

Table A39).

Medication was classified according to ATC anatomical main group (Tables A39-A40) and

chemical substances (Table A41-A43), respectively. With regard to the anatomical main group,

agents acting on the renin-angiotensin system (14 patients, 3.67% of patients with co-

medication), corticosteroids for systemic use (11 patients, 2.89%) and drugs for acid related

disorders (8 patients, 2.10%) were most frequently reported.

Concerning chemical classification, the following compounds were specified most commonly:

prednisolone, ramipril, iron (iii) hydroxide polymaltose complex, levothyroxine sodium, and

pantoprazole (10 patients, 2.62%; 7 patients, 1.84%; 6 patients, 1.57%; 6 patients, 1.57%;

6 patients, 1.57%; Table A41-A43).



VIII.3. Treatment with Remsima®

VIII.3.1. Switch to Remsima®

At baseline (visit 0), physicians were asked why the patients were to be treated with

Remsima®. From a total of 381 patients, reasons were specified for 377 patients (98.95%). For

the majority of patients, one reason was documented (346 patients, 90.81%). Up to

three reasons were recorded by the attending physician (Table A44).

The most frequently stated reasons to start a therapy with Remsima® were switch of

treatment due to low effectiveness of the previous medication (240 patients, 63.66% of

patients with data on reasons for switch) and treatment initiated due to contraindication or

intolerance to conventional therapy (92 patients, 24.40%).

Further details and reasons for prescription of Remsima® are illustrated in the following figure

(Figure 14). An entire list of all mentioned reasons is available in Tables A44-A45.

Figure 14: Reasons to start a therapy with Remsima® (n=377).

VIII.3.2. Administered dose of Remsima®

Details on dose of Remsima® were analyzed at baseline (visit 0) for 376 patients, at visit

1 (about two weeks after start of treatment) for 244 patients, at visit 2 (about six weeks after

therapy start) for 252 patients, and at visit 3 (about 14 weeks after start of treatment) for

238 patients.

63.66%

24.40%

9.81%

2.65%

1.86%

0.80%

0.80%

0% 10% 20% 30% 40% 50% 60% 70%

Switch of treatment due to loweffectiveness of the previous medication

Treatment initiated due to contraindicationor intolerance to conventional therapy

Switch of treatment due to low tolerabilityof the previous medication

No reason specified

Recommencement of treatment after break

Cortisone/steroid dependency

Start of treatment

…



Mean dose of Remsima® was

documented by the attending

physicians at baseline, control visits

(1-2) and at the end of the study

(visit 3). Dosage was relatively stable

during the course of the NIS and

increased only slightly from

5.09 mg/kg body weight (BW) at

baseline to 5.22 mg/kg BW at the

last documentation (Figure 15, Table

A46).

Figure 15: Remsima dose (mg/kg body weight, patients with infusion only) at admission (V0, n=376), V1 (n=244), V2 (n=252), and V3 (n=238; x = mean, – = median, [] = interquartile, - = minimum and maximum).

According to SmPC, Remsima® dose should be 5 mg/kg body weight (BW). The majority of

patients received the recommended dosage during the course of the NIS (316 from a total of

376 patients at V0; 192 from a total of 244 patients at V1; 201 from a total of 252 patients at

V2; 184 from a total of 238 patients at V3; Table 47). A moderate increase of patients who

received >5 mg/kg BW was recorded from baseline to visit 3 (11.44% versus 17.65%) whereas

the number of patients treated with 5 mg/kg BW was slightly reduced (84.04% versus 77.31%).

An overview of the distribution of dose is given in Figure 16.

Figure 16: Distribution of Remsima® dose (mg/kg BW) during the course of the NIS.

5.09 5.07 5.13 5.22

0

2

4

6

8

10

12

V0 V1 V2 V3

4.52% 5.33% 3 57% 5.04%

84.04% 78.69% 79.76% 77.31%

11.44% 15.98% 16.67% 17.65%

0%

20%

40%

60%

80%

100%

Visit 0 (n=376) Visit 1 (n=244) Visit 2 (n=252) Visit 3 (n=238)

>5 mg/kg BW

5 mg/kg BW

<5 mg/kg BW



VIII.3.3. Premature end of therapy with Remsima®

Most of the patients did not abort

Remsima®-treatment during the course

of the NIS (336 patients, 88.19%; Figure

17). Patients who discontinued the study

prematurely (45 patients, 1.81%) stated

in most cases one reason for termination

(36 patients, 80.00% of patients with

premature end). Two causes were

mentioned by nine patients (20.00%,

Table A49).

Figure 17: Frequency of patients with discontinuation of Reasons for a premature termination of treatment with Remsima® are depicted in the

following figure (Figure 18). Adverse drug reaction, lack off efficacy and due to patients’

request were the most frequent causes for dropout (31 mentions, 8.14%; 7 mentions, 1.84%;

7 mentions, 1.84%). Further details are given in Table A49.

Figure 18: Reasons for premature discontinuation of therapy with Remsima® (n=381).

VIII.3.4. Treatment of underlying inflammatory bowel disease (IBD) during the study

Treatment of underlying IBD during the study was documented for 208 patients (54.59%). For

the majority of patients one or two treatments were recorded by the physicians (140 patients,

67.31% of patients with concomitant treatment; 54 patients, 25.96%). Most commonly

reported treatments were antidiarrheals/intestinal antiinflammatory or antiinfective agents

(128 patients, 61.54% of patients with treatment of IBD), corticosteroids for systemic use

(75 patients, 36.06%), and immunosuppressive agents (66 patients, 31.73%) when classified

according to ATC anatomical main group (Tables A50). An overview of most frequently

documented treatments is given in Figure 19 (percentage distribution of all patients).

8.14%

1.84%

1.84%

1.05%

0.52%

0.52%

0.26%

0% 2% 4% 6% 8% 10%

Adverse drug reaction

Lack of efficiency

At patient's request

Adverse event

On request of health insurance

Other biosimilar

Patient stayed away

88.19%

11.81% Withoutpremature end oftherapy

Premature end oftherapy



Figure 19: Treatment of underlying IBD during the study, classified according to ATC anatomical main group (n=381).

Concerning chemical classification of concomitant IBD treatment, the following compounds

were specified most frequently: mesalazine, azathioprine, prednisolone, budesonide,

cortisone and prednisone (109 patients, 52.40% of patients with concomitant treatment

during the NIS; 64 patients, 30.77%; 60 patients, 28.85%; 24 patients, 11.54%; 10 patients,

4.81%; 7 patients, 3.37%). Treatment with one or two compounds was most commonly

reported (127 patients, 61.06%; 59 patients, 28.37%; Table A51). Figure 20 shows the most

often recorded chemical substances (percentage distribution of all patients). All other

chemical substances are listed in Tables A51-A52.

33.60%

19.69%

17.32%

1.05%

1.05%

45.41%

0% 10% 20% 30% 40% 50%

Antidiarrheals, intestinal antiinflammatory/antiinfective agents




Cytostatics

…

Without treatment



Figure 20: Treatment of underlying IBD during the study, classified according to ATC chemical substances (n=381).

VIII.3.5. Acute episode

VIII.3.5.1. Hospitalization

Regarding hospitalization during the

study, physicians were asked if patients

had to be treated in the clinic due to an

acute episode. Almost all patients were

not hospitalized during the whole study

period (351 patients, 96.43% of the

patients with data on hospitalization

versus 13 patients, 3.57%). Information

of one patient was missing (Table A53).

Figure 21: Hospitalization due to an acute episode during the NIS (n=364).

Patients with hospitalization stayed on average 1.48 (±0.93, 1.29 median) weeks at the

hospital. The time varied from 0.29 (minimum) up to 4.00 weeks (maximum). 66.67% of the

patients who had been hospitalized stayed more than one to two weeks in the clinic

(8 patients), followed by up to one week (3 patients, 25.00%) and more than tree to four weeks

(1 patient, 8.33%). Information was missing for one patient. Corresponding data are given in

Table A54.

28.61%

16.80%

15.75%

6.30%

2.62%

1.84%

45.41%

0% 10% 20% 30% 40% 50%

Mesalazine

Azathioprine

Prednisolone

Budesonide

Cortisone

Prednisone

…

Without treatment

3.57%

96.43%

Withhospitalization

Withouthospitalization



VIII.3.5.2. Imaging procedures

Physicians documented at each visit throughout the NIS whether and which imaging

procedures were performed in order to assess the condition of the mucous membrane (Figure

22).

As a result, 321 patients (87.70%) had not

been examined by imaging procedures

whereas a total of 45 patients (12.30%)

had been investigated by imaging

diagnostics during the NIS (Figure 22,

Table A55).

Figure 22: Imaging procedures during the study (n=366).

In addition, physicians were asked for global assessment of the acute episode (categorized

into normal findings, mild, moderate or severe episode). Details are depicted below in Figure

23 and refer to data in Table A56.

Figure 23: Finding of imaging diagnostics during the NIS.

For most patients who underwent an imaging procedure, sonography was documented

(26 patients), followed by endoscopic examination (23 patients), magnetic resonance imaging

(3 patients), and examination by CAT scanner (2 patients).

50.00

33.33

26.09

61.54

34.78

23.08

50.00

66.67

17.39

7.69

21.74

7.69

0% 20% 40% 60% 80% 100%

CAT scanner (n=2)

Magnetic resonanceimaging (n=3)

Endoscopy (n=23)

Sonography (n=26)

Normal findings Mild episode Moderate episode Severe episode

12.30%

87.70%

Yes No



For 26 patients with sonographic examination, the acute episode was assessed as unobtrusive

(normal finding, 61.54%). Six patients had a mild episode (23.08%), two patients a moderate

episode (7.69%) and for two patients the episode was reported severe (7.69%). Result of

patients with an endoscopy was stated to be normal in six cases (26.09%). Furthermore, the

acute episode was assessed as a mild (8 patients, 34.78%), moderate (4 patients, 17.39%) or

severe episode (5 patients, 21.74%). One patient (33.33%) showed a normal finding and for

two patients (66.33%) a severe episode was documented when examined by magnetic

resonance imaging. Two patients were examined by CAT scanner, which resulted in a normal

condition and moderate episode, respectively (50% each; Table A56).

VIII.3.5.3. Surgical measures

From a total of 365 patients, almost all patients were without any surgical measures for

treatment of acute episode during the NIS (377 patients, 98.95%). Operative interventions

were reported for four patients (1.05%). Two of them had a fistula drainage (50.00% of

patients with an operation) and for one patient each an abscess drainage and hemicolectomy,

respectively, was documented during the study (25.00% each, Table A57).

VIII.3.6. Antibodies before and during the study

Physicians should report data on antibody detection (if applicable) for patients under

infliximab treatment at each visit. Data were provided for 35 patients and are listed in Tables

A58-64.

IX. EFFICACY RESULTS

Investigation of the patient’s questionnaires was performed for the total sample as well as for

the subgroups (patients with Crohn’s disease and patients with ulcerative colitis). Analysis was

carried out once for cases with any values, for the complete cases only, and according to the

LOCF-method. The following results refer to LOCF-values.

IX.1. Inflammatory bowel disease questionnaire (IBDQ)

The IBDQ is an international validated disease specific instrument to assess the health-related

quality of life and consists of 34 questions, which are divided in 4 topics: subjective

experienced bowel symptoms, emotions, systemic symptoms, and social functions (Janke et

al. 2005). A value of one point indicates the worst quality of life whereas the best quality of

life corresponds to seven points.



Data of 311 patients were available

for statistical analysis. The mean

value of IBDQ increased from

4.37 (±1.25, median 4.47) points at

admission to 5.21 (±1.13, median

5.44) at the final visit indicating a

significant better quality of life

under treatment with Remsima®

(p<0.0001; Figure 24, Tables A65-

A66). The mean difference from the

initial to the last documentation was

0.84 (±1.14, median 0.64).

Figure 24: IBDQ at admission (V0), at control examinations V1 and V2 and at the final examination (n=311, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum).

Stratification of the sample in patients suffering from Crohn’s disease or ulcerative colitis

implied a general improvement of quality of life according to the IBDQ. In general, patients

with Crohn’s disease showed higher values at baseline and at each of the following

examinations compared to patients with ulcerative colitis, however, the difference of the

IBDQ-values was statistically significant for both subgroups (p<0.0001 each; Figure 25, Tables

B56-B57 and C53-A54).

Figure 25: Mean IBDQ-values (LOCF) for patients with Crohn’s disease and ulcerative colitis.

4.37

4.96 5.18 5.21

1

2

3

4

5

6

7

V0 V1 V2 V3

1

2

3

4

5

6

7

V0 V1 V2 V3

Crohn's disease (n=185) Colitis ulcerosa (n=126)



Figure 26 depicts the subscores of the IBDQ. The figure shows that an improvement was

achieved in all areas.

Figure 26: Mean IBDQ-values (LOCF) for patients with Crohn’s disease and ulcerative colitis.

IX.2. Brief fatigue inventory (BFI)

The BFI score was originally developed to measure severity of fatigue in cancer patients. It

includes the following 6 items: activity, mood, walking ability, work, relations to other people,

and enjoyment of life (Radbruch et al. 2003). Rating of 0 means no fatigue and rating of

10 corresponds to fatigue as bad as one can imagine. Scores are categorized into mild

(1-3 points), moderate (4-6 points) or severe (7-10 points).

A total of 318 patients were included

in the analysis of fatigue. Mean BFI

value decreased from 4.55 (±2.31,

median 4.67) points at baseline to

3.62 (±2.30, median 3.28) points at

the final examination. The mean

reduction of BFI points from the

initial to the last documentation was

statistically significant. BFI was

reduced by 0.94 (±2.16,

median 0.77) points (p<0.0001;

Figure 27, Tables A75-A76).

Figure 27: BFI at admission (V0), at control visits (V1, V2) and at the end of the NIS (V3; n=318, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum).

1

2

3

4

5

6

7Bowel symptoms

Emotional function

Systemic symptoms

Social function

1=worst quality of life , ..., 7=best quality of life

V0

Last measurement

4.553.82 3.73 3.62

0

2

4

6

8

10

12

V0 V1 V2 V3



BFI-values significantly decreased in patients with Crohn’s disease and in patients with

ulcerative colitis (p<0.0001). Patients with ulcerative colitis had lower values at baseline and

at each examination compared to patients with ulcerative colitis (Figure 28, Tables B68-

B69 and C66-C67).

Figure 28: Mean BFI-values (LOCF) of patients with Crohn’s disease and ulcerative colitis.

IX.3. General depression scale – long version (ADS-L)

The ADS-L served as a self assessment tool to evaluate the impairment due to depressive

symptoms. It contains 20 items on emotional, motivational, cognitive, somatic, and motoric

complaints. The sum score may range between 0 and 60 points whereas values >23 points

indicate serious depressive disorders (Hautzinger und Bailer 1993).

ADS-L values of 277 patients were

analyzed. A significant decrease of

the ADS-L mean value was

determined from the admission to

the last value of the final

examination with a difference of

4.78 (±11.09, median 4.00;

p<0.0001). Nevertheless, mean

values of ADS-L suggested an

absence of clinically relevant

depressive symptoms prior to

Remsima® therapy and during the

observation period (Figure 29).

Corresponding data are shown in

Tables A77-A78.

Figure 29: ADS-L values at admission (V0), at control examinations (V1 and V2) and at the end of the study (V3; n=277, LOCF; x = mean, - = median, [] = interquartile, - = minimum and maximum).

1

2

3

4

5

6

7

V0 V1 V2 V3


20.6917.18 15.74 15.91

0

10

20

30

40

50

60

V0 V1 V2 V3



ADS-L values were significantly reduced for both, patients with Crohn’s disease and ulcerative

colitis (p<0.0001). Patients with ulcerative colitis showed slightly lower values during the

whole study compared to patients with Crohn’s disease. However, neither the change of

values during the study nor the difference between the two groups of patients might be

medically significant (Figure 30, Tables B70-71 and C68-A69).

Figure 30: Mean ADS-L values (LOCF) for patients with Crohn’s disease and ulcerative colitis.

IX.4. Short-form McGill Pain questionnaire (SF-McGill)

The SF-McGill was used to evaluate abdominal pain. It consists of 15 items (11 sensory and

4 affective) rated on an intensity scale from 0 (=no pain) to 3 (=severe pain). Additionally, the

present pain intensity (PPI) and a visual analogue scale (VAS) ranging from 0 (=no pain) to

100 (=worst imaginable pain) were included to provide overall pain intensity scores (Melzack

1987). The following results refer to analyses of the VAS-values of the SF-McGill questionnaire.

VAS-values of 282 patients were

analyzed. A significant decrease of

mean value was determined from

the baseline (27.32±25.39; median

23.00) to the last documentation

(18.22±22.16, median 7.00) showing

a difference of 9.00 (±25.90, median

4.00; p<0.0001; Figure 31). Further

details are presented in Tables A85-

A86.

Figure 31: VAS values of SF-McGill at admission (V0), at control examinations (V1, V2) and at the final documentation (n=282, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum).

Subgroup analysis revealed that patients suffering from ulcerative colitis showed slightly

higher VAS-values at baseline compared to patients with Crohn’s disease (27.71 versus 26.91).

0

10

20

30

40

50

60

V0 V1 V2 V3


27.2320.90 17.70 18.22

0

10

20

30

40

50

60

70

80

90

100

V0 V1 V2 V3



The decrease from admission to the last documentation was statistically significant for both

subgroups (p<0.0001; Figure 32), but reduction of mean values was more pronounced in

patients with ulcerative colitis than in patients suffering from Crohn’s disease (10.51 versus

8.01; Tables B78-B79 and C76-C77).

Figure 32: Mean VAS values (LOCF) of SF-McGill for patients with Crohn’s disease and ulcerative colitis.

IX.5. Assessment of disease activity

IX.5.1. Crohn’s disease assessed by Harvey Bradshaw index

The Harvey Bradshaw index (HBI) was used to assess disease activity of Crohn’s disease and

consists of the following clinical parameters: general well-being, abdominal pain, number of

liquid stools per day, abdominal mass, and complications (Harvey und Bradshaw 1980). A

score less than 5 points indicated a remission state and patients with higher scores were

considered to have a mild (5-7 points), moderate (8-16 points) or severe (>16 points) disease.

Activity of Crohn’s disease was

reduced during the treatment with

Remsima® (Figure 33). The mean

HBI-value of 6.91 (±4.14, median

7.00) points at baseline significantly

decreased to 3.06 (±3.25, median

2.00) at the last documentation

(p<0.0001; Tables B54-B55).

Figure 33: Activity of Crohn’s disease assessed with HBI at admission (V0), at control examinations V1 and V2, and at the last visit (V3; n=213, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum).

0

10

20

30

40

V0 V1 V2 V3


6.91

3.943.22 3.06

0

2

4

6

8

10

12

14

16

V0 V1 V2 V3



IX.5.2. Ulcerative colitis assessed by Mayo-score

The Mayo-score includes clinical and endoscopic characteristics to evaluate the disease

activity of ulcerative colitis: stool frequency, rectal bleeding, mucosal appearance, and

physician rating of disease activity (Lewis et al. 2008). Values between 2-5 correlate to a mild

disease and values of 6-12 indicate a moderate to severe finding.

Disease activity of ulcerative colitis

was determined at baseline, at the

follow-up visits and at the last

examination. The mean score

significantly decreased from

7.27 (±2.66, median 8.00) points to

2.81 (±2.59, median 2.00) points

(p<0.0001, Tables C52-C53).

Development of disease activity

during Remsima®-treatment is

illustrated in Figure 34.

Figure 34: Activity of ulcerative colitis assessed with Mayo-score at admission (V0), at follow-up visits (V1 and V2) and at the last documentation (V3; n=143, LOCF; x = mean, – = median, [] = interquartile, - = minimum and maximum).

IX.6. Global assessment of efficacy

Efficacy of Remsima® was assessed once by the physicians and once by the patients.

At the final assessment, the attending physicians evaluated the effectiveness of Remsima®

treatment as very good for 30.33% (101 patients). The efficacy was documented to be good

in 54.95% of the cases (183 patients), moderate in 13.81% (46 patients) and poor in 0.90%

(3 patients, Table A87).

Concerning the result of patient’s assessment, the percentage distribution was comparable to

the documentation of the physicians. Efficacy of Remsima® treatment was rated as very good

by 28.40% of the patients (94 patients) at the last assessment. The percentage of patients who

rated effectiveness as good was 53.47% (177 patients) whereas 16.92% of the patients

(56 patients) assessed the efficacy as moderate and 1.21% (4 patients) as poor, respectively

(Table A88).

7.27

3.97

2.98 2.81

0

2

4

6

8

10

12

V0 V1 V2 V3



Figure 35 shows that the assessments of

the doctors and patients were in good

agreement. A more detailed comparison is

depicted in Table A89. The weighted Kappa

coefficient for the aggreement between

the assessments was 0.65, meaning a

substantial agreement according to Landis

(1977, Table A89 and A90).

Figure 35: Global assessment of efficacy by physician and patient.

IX.7. Laboratory parameters

Physicians were asked to document laboratory values (if applicable) during the course of the

NIS. Data on the following parameters were recorded: erythrocytes, leukocytes,

thrombocytes, haemoglobin, hematocrit, serum iron, ferritin, transferrin, transferrin

saturation, urea, creatinine, C-reactive protein, erythrocyte sedimentation rate, and

calprotectin (Table A91-A132). Reticulocytes were recorded only in one patient at baseline

and one follow up visit. Therefore, the values of this parameter are not displayed here.

Analysis was carried out once for cases with any values, for the complete cases only, and

according to the LOCF-method. The following results refer to LOCF-values.

Concerning erythrocytes (n=259), the number slightly increased from 4.52 Mio/µl (±0.55,

median 4.57) at baseline to 4.61 (±0.49, median 4.60) Mio/µl at the final documentation with

a mean difference of 0.09. The mean increase was statistically significant (p=0.0013; Tables

A91-A92). Compared to baseline, more patients showed values within the reference range at

the last examination (204 patients, 78.76% versus 192 patients, 74.13%; reference area: 4.6-

5.9 Mio/µl, male; 4.0-5.2 Mio/µl, female). Further information about the progress of the

number of erythrocytes is provided in Table A93.

Mean value regarding leukocytes (n=275) was reported to be 7.85 (±3.10, median 7.20) Tsd/µl

at last measurement (versus 9.26±3.82 Tsd/µl, median 8.50, at visit 0). Mean reduction of

1.41 was statistically significant (p<0.0001, Tables A94-A95). At both visits (baseline and last

examination), mean numbers of leukocytes were within the normal area ranging from 4.0 to

10.0 Tsd/µl. However, the percentage of patients with normal levels was higher at the end of

the NIS (76.73% versus 65.09 at baseline). Corresponding data are available in Table A96.

30.33% 28.40%

54.95%53.47%

13.81% 16.92%

0.90% 1.21%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Physician Patient

poor

moderate

good

very good



Number of thrombocytes (n=274) significantly decreased by 46.24 (±92.64, median 34.00)

from 345.63 (±124.06, median 317.50) Tsd/µl at baseline to 299.39 (±97.03, median 281.50)

Tsd/µl at the final documentation (p<0.0001, Tables A97-A98). 55.11% of the patients had

normal thrombocyte levels within the reference of 150.0-300.0 Tsd/µl at the end of the NIS

(versus 41.61% at start of Remsima® therapy; Table A99).

Haemoglobin concentration (n=290) was documented to be 8.28 (±1.52, median 8.20) mmol/l

at admission and 8.57 (±1.91, median 8.32) mmol/l at the final documentation, respectively.

The mean value significantly increased by 0.30 (±2.05, median 0.19, p<0.0001, Tables A100-

A101). Compared to the start of the NIS, more patients showed values within the reference

area (8.7-11.2 mmol/l, male; 7.5-9.9 mmol/l, female): 149 patients (51.38%) at visit 0 and

170 patients (58.62%) at last measurement, respectively (Table A102).

Haematocrit proportion (n=231) was comparable between admission and final examination.

Mean value was reported to be 39.04 (±4.59, median 39.90) % at visit 0. At the end of the

study, the mean value was 39.68 (±5.16, median 40.00) % displaying an increase of 0.64 (±5.17,

0.20) percent points under treatment with Remsima® (Table A103-A104). At baseline, 48.05%

of the patients had a haematocrit proportion within the normal range of 43.0-49.0% (males)

and 37.0- 45.0% (females), respectively. At the last visit, a higher percentage of patients

showed normal values (59.74%, Table A105).

Regarding serum ion (n=86), a mean concentration of 12.74 (±7.05, median 11.47) µmol/l was

recorded at baseline. The mean value slightly increased by 1.42 (±8.83, median 1.09) during

the course of the NIS and was found to be 14.17 (±7.61, median 13.15) µmol/l at the end of

the study (Tables A106-A107). As shown in Table A108, number of patients with values within

the reference area (9.0- 29.0 µmol/l, males; 9.0- 27.0 µmol/l, females) increased from

admission to the last visit with percentages of 61.63% compared to 66.28%.

Ferritin levels (n=82) decreased under therapy with Remsima®. Mean concentration was

reported to be 108.32 (±128.74, median 69.50) µg/l at baseline and 89.18 (±106.42, median

65.00) µg/l at the end of the study (Tables A109-A110; mean difference was 19.14 µg/l±13.56,

median 5.95). Reference area of ferritin for males is between 30.0-300.0 µg/l and for females

between 10.0-200.0 µg/l, respectively. Compared to baseline, the number of patients with

reference values had increased during the NIS (73.17% versus 78.05% at the last visit). Further

information is given in Table A111.

Concerning transferrin concentration (n=50) at baseline and final visit, a mean difference of

2.60 (±52.89, median 8.99) mg/dl was documented. Mean values slightly increased from

273.06 (±52.74, median 270.00)mg/dl up to 275.66 (±57.26, median 280.00; Table A112 and

A113). 92.00% of the patients had normal transferrin levels at the end of the study (versus

88.00% at admission). Reference range of transferrin is between 170.0-330 mg/dl (male) and

160.0-350.0 mg/dl (female), respectively (Table A114).

Furthermore, transferrin saturation (n=57) increased from 21.91 (±17.38, median 18.00) % at

baseline to 20.65 (±12.18, median 18.00) % at last measurement and the percentage of



patients with normal levels between 18.0% and 45.0% simultaneously rose from 45.61% to

49.12% (Tables A115-A117).

Mean urea level (n=68) somewhat increased during the NIS and was reported as follows:

16.00 (±15.02, median 6.45) mg/dl at baseline and 16.20 (±13.54, median 8.05) mg/dl at the

end of the study (Tables A117-A118). The number of patients with a normal urea

concentration was similar at visit 0 and final examination (26.47% each; reference ranges from

6.0-26.0 mg/dl). Additional information is available in the corresponding Table A120.

Creatinine concentration (n=179) did not change under the treatment with Remsima®. Mean

value was reported to be 0.83 mg/dl at baseline (±0.22, median 0.80) and last measurement

(±0.17, median 0.82; Tables A121-A122). However, number of patients with normal values

(male: 0.6-1.2 mg/dl; female: 0.5-1.0 mg/dl) increased during the observational time from

92.74% (baseline) to 96.09% (final documentation, Table A123).

The amount of C-reactive protein (n=278) was 34.97 (±75.42, median 10.70) mg/l at admission

and decreased down to 21.11 (±38.65, median 5.62) mg/l at last measurement (Tables A124-

A125). Mean reduction of 13.86 (±70.12, median 1.80) was statistically significant (p<0.0001).

In contrast to a percentage of 48.56% at baseline, 63.67% of the patients had normal values

at the end of the NIS (reference range ≤ 10.0 mg/l). Further information is shown in Table

A126.

Concerning the sedimentation rate of erythrocytes (n=46), mean values were higher at

admission (24.85±21.78 mm, median 22.00 versus 16.96±15.93, median 11.50). Mean

difference was 7.89 (Tables A127-A128). Number of patients with normal values rose from

56.52% to 78.26% during the NIS (reference range of male: ≤20.0 mm; reference range of

female: ≤30.0 mm). Corresponding data are listed in Table A129.

Mean calprotectin concentration (n=61) was reported to be 865.63 (±818.77, median 578.00)

µg/g at baseline. Mean value decreased by 298.23 (±1158.06, median 232.00) down to

567.40 (±831.14, median 310.00) µg/g at last measurement (Tables A130-A121). A reference

value ≤50.0 µg/g was achieved by 19.67% of the patients at last measurement (versus 6.56%

at baseline, Table A132).



Table 5: Laboratory parameters at final examination (LOCF)

Parameter Patients Mean value (±SD)

Erythrocytes (Mio/µl) 259 4.61 (±0.49)

Leukocytes (Tsd/µl) 275 7.85 (±3.10)

Thrombocytes (Tsd/µl) 274 299.39 (±97.03)

Haemoglobin (mmol/l) 290 8.57 (±1.91)

Haematocrit (%) 231 39.68 (±5.16)

Serum iron (µmol/l) 86 14.17 (±7.61)

Ferritin (µg/l) 82 89.18 (±106.42)

Transferrin (mg/dl) 50 275.66 (±57.26)

Transferrin saturation (%) 57 20.65 (±12.18)

Urea (mg/dl) 68 16.20 (±13.54)

Creatinine (mg/dl) 179 0.83 (±0.17)

C-reactive protein (mg/l) 278 21.11 (±38.65)

Erythrocyte sedimentation rate (mm)

46 16.96 (±15.93)

Calprotectin (µg/g) 61 567.40 (±831.14)

X. SAFETY RESULTS

X.1. Global assessment of tolerability

Evaluation of tolerability of Remsima® was performed once by the physicians and once by the

patients (Figure 36).



At the final assessment, the attending physicians evaluated tolerability of Remsima® as very good for 40.72% (136 patients) of the patients. The tolerability was documented to be good in 54.79% of the cases (183 patients), moderate in 3.59% (12 patients) and poor in 0.90% of patients (3 patients, Table A133).

Tolerability of Remsima® treatment was rated as very good by 34.73% (116 patients) of the patients at last assessment. The percentage of patients who rated the tolerability as good was 58.08% (194 patients) whereas 5.69% of the patients (19 patients) assessed the tolerablity as moderate and 1.50% (5 patients) as poor, respectively (Figure 36, Table A134).

Figure 36: Assessment of tolerability of Remsima®.

X.2. Adverse events and adverse drug reactions

All adverse events (AE) and adverse drug reactions (ADR, serious and non-serious) that

occurred during this non-interventional study had to be reported by the attending physician.

The documented events were analysed according to their preferred term and their system

organ class by MedDRA. Low-level terms were not considered in statistical analysis.

X.2.1. Categories

An overview of the categories of events that occurred during the study is given in Table 6.

Table 6: Category and frequency of ADRs occurred and number of patients affected (n=381)

Category Frequency events Frequency patients

n %

Adverse drug reaction (ADR) 65 48 12.60%

− Non-serious ADRs 42 30 7.87%

− Serious ADRs 23 18 4.72%

− Suspected unexpected serious adverse reactions

(SUSAR) 7 4 1.05%

Adverse events (AE) 136 80 21.00%

X.2.1. Adverse drug reactions

The majority of patients were without any adverse drug reaction during the course of the

study (333 from 381 patients, 87.40%). 65 ADRs occurred in 48 patients (12.60%).

40.72%34.73%

54.79%58.08%

3.59% 5.69%

0.90% 1.50%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Physician Patient

poor

moderate

good

very good



For most of the patients with ADRs one type of reaction was reported (37 patients, 77.08% of

the patients with ADRs). Two types were documented for seven patients (14.58%) and four

types of reactions were recorded for four patients (8.33%). In one patient each, the reaction

hypersensitivity and the reaction dizziness, respectively, were recorded twice (Tables A135-

A136).

Most frequently reported ADRs were assigned to the preferred term hypersensitivity (9 events

in 8 patients, 2.10% of all patients), followed by erythema (6 events in 6 patients, 1.57%),

ineffective drug (5 events in 5 patients, 1.31%), and anaphylactic reaction (4 events in

4 patients, 1.05%). The event dizziness was documented for two patients (0.52%, in one

patient twice and in the other one once). Alopecia, fatigue, pruritus, and rash were recorded

as 2 events each in two patients (0.52%). All further ADRs were reported at a frequency of one

event in one patient (0.26%) and are fully listed in the following table according to their

preferred term by MedDRA 20.0.

Table 7: Adverse drug reactions listed according to the preferred term (n=381)

MedDRA 20.0 / Preferred term Events Patients Percent

Hypersensitivity 9 8 2.10%

Erythema 6 6 1.57%

Drug ineffective 5 5 1.31%

Anaphylactic reaction 4 4 1.05%

Dizziness 3 2 0.52%

Alopecia 2 2 0.52%

Fatigue 2 2 0.52%

Pruritus 2 2 0.52%

Rash 2 2 0.52%

Abdominal abscess 1 1 0.26%

Abdominal pain upper 1 1 0.26%

Anaemia 1 1 0.26%

Anaphylactic shock 1 1 0.26%

Arthralgia 1 1 0.26%

Asthenia 1 1 0.26%

Carotid artery dissection 1 1 0.26%

Cerebral infarction 1 1 0.26%

Colitis 1 1 0.26%

Crohn’s disease 1 1 0.26%

Deep vein thrombosis 1 1 0.26%

Drug specific antibody present 1 1 0.26%

Eczema 1 1 0.26%




Headache 1 1 0.26%

Hepatitis 1 1 0.26%

Hyperhidrosis 1 1 0.26%

Hypertensive crisis 1 1 0.26%

Libido disorder 1 1 0.26%

Musculoskeletal discomfort 1 1 0.26%

Pleural effusion 1 1 0.26%

Pruritus allergic 1 1 0.26%

Psoriasis 1 1 0.26%

Pulmonary tuberculosis 1 1 0.26%

Pustular psoriasis 1 1 0.26%

Rash macular 1 1 0.26%

Stridor 1 1 0.26%

Swelling face 1 1 0.26%

Thrombophlebitis 1 1 0.26%

Upper respiratory tract infection 1 1 0.26%

Urticaria 1 1 0.26%

Uveitis 1 1 0.26%

The ADRs were most frequently associated with the following MedDRA system organ classes

(SOC): skin and subcutaneous tissue dirsorders (14 patients, 3.67%), immune system disorders

(13 patients, 3.41%), general disorders and administration site conditions (8 events, 2.10%),

nervous system disorders (4 patients, 1.05%), gastrointenstinal disorders (3 patients, 0.79%),

infections and infestations (3 patients, 0.79%), vascular disorders, musculoskeletal and

connective tissue disorders, and Respiratory, thoracic and mediastinal disorders (2 patients

each, 0.52%). All further SOCs were affected at a frequency of one (0.26%). Table 8 presents

all affected system organ classes (Table A137).

Table 8: ADRs listed according to the system organ class by MedDRA 20.0 (n=381)

MedDRA 20.0 / System organ class Patients Percent

Skin and subcutaneous tissue disorders 14 3.67%

Immune system disorders 13 3.41%

General disorders and administration site conditions 8 2.10%

Nervous system disorders 4 1.05%

Gastrointestinal disorders 3 0.79%

Infections and infestations 3 0.79%

Vascular disorders 2 0.52%

Musculoskeletal and connective tissue disorders 2 0.52%



MedDRA 20.0 / System organ class Patients Percent

Respiratory, thoracic and mediastinal disorders 2 0.52%

Blood and lymphatic system disorders 1 0.26%

Eye disorders 1 0.26%

Hepatobiliary disorders 1 0.26%

Investigations 1 0.26%

Psychiatric disorders 1 0.26%

Information on structural hierarchy according to MedDRA of the 64 ADRs (48 patients) is given

in Tables A138-A144.

From all documented ADRs, 23 events were recorded to be serious (18 patients, 4.72% of all

patients). The following table shows a list of all serious events (Table 9). Corresponding data

are available in Tables A145-A146. Hypersensitivity and anaphylactic reaction were the most

frequently reported serious ADRs (4 events in 4 patients each, 1.05%). All other serious events

occurred once.



Table 9: Serious adverse drug reactions





Anaemia 1 1 0.26%




Colitis 1 1 0.26%




Hepatitis 1 1 0.26%






From all reported adverse drug reactions, seven events that occurred in four patients (1.05%

of all patients) were classified as suspected unexpected serious adverse reactions (SUSARs).

SUSARs were analysed according to PT and are listed in Tables A147-A148. An overview is

given in the following table (Table 10).

Table 10: Suspected unexpected serious adverse reactions


Anaemia 1 1 0.26%







Current clinical status of documented ADRs and affected patients, respectively, is shown in

Tables A149-A152. The outcome was stated to be ongoing for two events in one patient

(0.26%), recovering for eight events in seven patients (1.84%), and recovered for the majority

of 47 events in 35 patients (9.19%). Status was reported to be not recovered for five events in



three patients (0.79%). The outcome of one ADR in one patient (0.26%) was unknown. Data

on one ADR in one patient (0.26%) each was missing or was not applicable.

X.2.2. Adverse events

A total of 136 adverse events occurred during the course of the study in 80 patients (21.00%).

For most of the patients with AEs one type of event was reported (48 patients, 12.60%). Two

types of events were documented for 17 patients (4.46%) and three types of events were

noticed in 11 patients (2.89%). Four types of events were documented in two patients (0.52%).

Five or six events were noticed in one patient each (0.26%, Tables A153-A156).

Most frequently reported AEs were assigned to the preferred term hypersensitivity (9 events

in eight patients, 2.10% of all patients), followed by erythema (seven events in seven patients

each, 1.84%), headache (six events in six patients, 1.57%), ineffective drug (five events in five

patients, 1.31%), anaphylactic reaction, colitis ulcerative, musculoskeletal discomfort, pruritis

(four events in four patients each, 1.05%), arthralgia, fatigue (three events in three patients

each, 0.79%), dizziness (three events in two patients, 0.52%), alopecia, Crohn’s disease,

eczema, gastrointestinal infection, hepatitis, hyperhidrosis, influenzy like illness, and rash

(two events in two patients each, 0.52% of patients). All further AEs were reported at a

frequency of one event in one patient (0.26%) and are fully listed in Tables A153-A156.

From all documented AEs, 30 events in 22 patients (5.77%) were recorded to be serious.

Table 11: Serious adverse events




Colitis ulcerative 2 2 0.52%

Hepatitis 2 2 0.52%


Anaemia 1 1 0.26%




Colitis 1 1 0.26%

Crohn's disease 1 1 0.26%




Fall 1 1 0.26%




Fistula 1 1 0.26%






Urinary tract infection bacterial 1 1 0.26%

Outcome of documented AEs and affected patients is indicated in Tables A167-A174. The

outcome was stated to be ongoing for 28 events in 20 patients (5.25%), recovering for

17 events in 14 patients (3.67%) and recovered for 76 AEs in 50 patients (13.12%). Status was

reported to be not recovered for five events in three patients (0.79%) and information about

one event in one patient (0.26%) was missing. Furthermore, the outcome was unknown for six

events in three patients (0.79%) and fatal for one event in one patient (0.26%). Data on two

events in two patients (0.52%) were not applicable.

X.3. Pregnancies

One patient got pregnant during the study.



XI. DISCUSSION AND CONCLUSION

Biosimilars generally represent worthwhile alternatives to their originator biological drugs and

may lead to considerable cost savings for the health community and possibly more patients

globally will gain access to therapy when indicated. Biosimilar infliximab, known by its brand

name Remsima®, is the world’s first biosimilar monoclonal antibody to be approved by the US

Food and Drug Administration and the European Medicines Agency. Remsima® is a medicinal

product biologically similar to the original reference product Remicade®. Although both

products share an identical amino acid sequence and are produced in the similar cell line,

murine hybridoma cells, it is not excluded that differences in the production process may

influence functional properties. Up until now, clinical trials demonstrated no significant

differences with Remicade® in treatment of rheumatoid arthritis and the related condition

ankylosing spondylitis. Remsima® is likely as effective and safe for other indications, including

psoriasis and inflammatory bowel conditions like Crohn's disease and ulcerative colitis,

however, it was not tested against those conditions in detail and reliable data are needed to

finally evaluate effectiveness and safety.

The aim of this non-interventional study was to document the efficacy, safety, and tolerability

of Remsima® in the treatment of Crohn’s disease and ulcerative colitis under real life

conditions. The disease activity was assessed by HBI and Mayo-score. Furthermore, the

influence on quality of life, fatigue, depression, and abdominal pain were documented with

the patient’s questionnaire forms IBDQ, BFI, ADS-L, and SF-McGill.

XI.1. Discussion

XI.1.1. Discussion of demographic and baseline characteristics

Data of 381 patients investigated at 70 study sites were statistically analysed. Slightly more

female than male patients were included (52.76% versus 47.24%). Female predominance in

inflammatory bowel disease is not a general feature and when present, it is subject to the

geographical location (Zelinkova 2014). In Europe and North-America female:male ratio can

vary from 2.5:1 to equal distribution in different study populations (Bernstein et al. 2001;

Freeman 2004; Kyle 1992; Shivananda et al. 1996; Sincic et al. 2006). In contrast, the

population of Asia is rather characterized by male predominance (Yang et al. 2001; Ishige et

al. 2010; Yang et al. 2008). Reasons for these geographical differences are still unclear.

Differential cultural habits and gender-specific exposure of women and men to certain IBD risk

factors might contribute to these results.

In the western industrial nations, the incidence rates of Crohn’s disease and ulcerative colitis

increased in both genders in recent decades, with a high prevalence of both diseases

(Jacobsen et al. 2006). For ulcerative colitis, incidence rates in women increased from 8.3 in

1978-1982 to 17.0 per 100,000 person-years in 1998-2002. The corresponding values for men

were 7.7 and 16.7 per 100,000 person-years. For Crohn's disease, the incidence rates in

women increased from 4.1 in 1978-1982 to 10.7 per 100,000 person-years in 1998-2002 and

for men from 3.2 to 8.5 per 100,000 person-years. The prevalence of ulcerative colitis and

Crohn's disease was 294 and 151 per 100,000 inhabitants, respectively (Jacobsen et al. 2006).



Crohn's disease and ulcerative colitis are usually diagnosed in the second or third decade of

life; however, studies from Europe and New York showed a second incidence peak occurring

later in life (Quezada et al. 2013; Loftus et al. 2007; Sonnenberg 2010; Quezada und Cross

2012). Lapidus et al. reported that the mean age of Chron’s disease diagnosis increased from

25 years in 1955 to 32 years of age in 1989. A bimodal peak in incidence rates by age group

was noted, with the first peak occurring between the ages of 15–29 years and a second peak

occurring between the ages of 55–59 years (Lapidus et al. 1997). Also for ulcerative colitis,

recent studies have shown that 11% of newly diagnosed cases are greater than 60 years old

(Piront et al. 2002). Diagnosis of ulcerative colitis beyond age 40 years was found to be

associated with decreased disease extent compared to younger age groups (Quezada und

Cross 2012).

In this study, mean age of patients was 41.10 years with a range of 18 to 91 years whereby

about half of the patients was between 20 to <40 years (47.37%) old. Concerning the type of

IBD, patients with Crohn’s disease were more frequently included than ulcerative colitis

(58.53% versus 41.47%).

The mean BMI of patients included in this NIS was 25.01 kg/m2. This value is comparable to

the mean value of 25.7 that is reported for the adult population in Germany (Statistisches

Bundesamt 2009).

The mean duration of IBD since diagnosis was about nine years. The median number of

episodes was 2.00 but most patients stated occurrence of one episode since diagnosis. An

intestinal resection due to IBD was performed in 16.14% of patients. In more than 70% of the

patients the acute episode lasted up to 6 months at enrolment and most of the patients were

not hospitalized in the past due to the current episode.

Crohn’s disease activity according to the HBI was available for 221 patients. The mean value

was 6.84±4.15 (median 7.00) points. A remission of disease was determined for 74 patients

(33.48%), a mild disease activity for 54 patients (24.43%) and a moderate disease activity for

93 patients (42.08%).

Disease activity of ulcerative colitis was classified according to the Mayo score. For

154 patients, the mean value was 7.32±2.65 (median 8.00) points. Normal activity of disease

was calculated for six patients (3.90%), a mild disease activity for 23 patients (14.94%) and a

moderate to severe disease activity for 125 patients (81.17%).

For most patients pre-treatment of IBD was documented (85.56%) commonly with

immunosuppressive agents (50.66% of all patients), antidiarrheals/intestinal

antiinflammatory or antiinfective agents (48.29%) and corticosteroids for systemic use

(23.36%).



Patients with or without concomitant disease(s) were enrolled into this study. 26.25% of the

patients suffered from concomitant disease. For patients with an accompanying illness,

hypertension (4.72%), depression (2.10%), and hypothyroidism (2.10%) were most commonly

mentioned.

In general, this study design represents an important tool to collect real life data concerning

treatment with Remsima® of patients with multiple comorbidities, comedications, and risk

factors. These patients are usually excluded from controlled clinical trials. Based on the

demographic and baseline characteristics, the study cohort analysed here seems to be a

representative population of the routine medical practice and can be considered

characteristic for patients with IBD.

XI.1.2. Discussion of therapy with Remsima®

The most frequently stated reasons to start a therapy with Remsima® were due to low

effectiveness of the previous medication (62.99% of all patients) and due to contraindication

or intolerance to conventional therapy (24.15%).

Mean dose of Remsima® was relatively stable during the course of the NIS and increased only

slightly from 5.09 mg/kg body weight (BW) at baseline up to 5.22 mg/kg BW at visit 3.

According to SmPC, administered Remsima® dose should be 5mg/kg BW (Mundipharma

2015). The majority of patients received the recommended dosage during the course of the

NIS. A moderate increase of patients receiving > 5mg/kg BW was recorded from baseline to

visit 3 (11.44% versus 17.65%) whereas the number of patients treated with 5mg/kg BW was

slightly reduced (84.04% versus 77.31%).

Most of the patients did not prematurely end Remsima®-treatment during the course of the

NIS (88.19%). In patients who discontinued the study prematurely, most frequently a dropout

due to adverse drug reactions, lack of efficiency, and at patients request was documented.

Adherence in IBD patients, especially to maintenance medication regimens, has traditionally

been poor, although regularly scheduled infusions of infliximab are necessary to maintain drug

levels and thus, to prevent the development of anti-infliximab antibodies. While infliximab has

demonstrated effectiveness in randomized controlled trials, its efficacy may be hampered by

poor compliance in real life settings. A systematic review of data from 4322 IBD patients

revealed widely varying rates of nonadherence to maintenance medication regimens,

including some studies showed nonadherence rates as high as 72%, but most studies reported

that 30-45% of patients were non-adherent (Jackson et al. 2010).

In this regard, a Canadian retrospective cohort study was conducted evaluating patients with

Crohn’s disease or ulcerative colitis on an induction or maintenance regimen of regularly

scheduled infliximab from 2008 to 2010. In this study, including a total of 215 patients,

nonadherence was defined by a discrepancy of >72 h between the scheduled date of infusion

and the actual date of administration. Patients were defined as nonadherent if they received

<80% of their infliximab infusions per schedule. As a result, three-quarters of patients were



adherent to infliximab induction therapy while fewer than one-third of the patients remained

adherent to their scheduled maintenance infliximab regimen (Ma et al. 2015).

Concomitant treatment of IBD during the study was documented for 54.59%. Most common

reported treatments were antidiarrheals/intestinal antiinflammatory or antiinfective agents

(33.60% of all patients), corticosteroids for systemic use (19.69%) and immunosuppressive

agents (17.32%).

Only 13 patients (3.57%) were hospitalized during the whole study period. Patients with

hospitalization stayed on average 1.48 weeks at hospital.

For four patients, operative interventions for treatment of acute episode during the NIS were

reported (1.05%). Two of them had a fistula drainage and for one patient each an abscess

drainage and hemicolectomy, respectively, was documented.

XI.1.3. Discussion of results in effectiveness

Our study data show positive clinical outcomes following administration of Remsima® in

patients suffering from IBD. Activity of Crohn’s disease and ulcerative colitis was reduced

during this non-interventional study. The mean HBI value of 6.91 points at baseline

significantly decreased to 3.06 at the last documentation. Disease activity of ulcerative colitis

also developed positively as illustrated by the Mayo score that fell from 7.27 to 2.81. The

effectiveness of infliximab Remicade® in patients suffering from IBD has been demonstrated

in many studies. In general, a clinical response in patients with Crohn’s disease is reported in

two-thirds of the treated patients and even remission in one-third of the patients under

infliximab treatment (D'haens et al. 1999; Targan et al. 1997; Present et al. 1999). In this study,

remission of Chron’s disease was reached in 155 patients (72.77%), however, disease activity

had already been in remission in 70 patients (32.86%) at baseline. A study evaluating the

clinical response in patients with ulcerative colitis reported remission rates of 64.5% for

patients treated with 5 mg/kg infliximab (versus 29.3% for patients in the placebo group)

(Rutgeerts et al. 2005). These results are in line with a Korean study of a total of 110 patients

with IBD that reported clinical remission rates of 77.3% in patients with Crohn’s disease and

of 47.8% patients with ulcerative colitis by Remsima® treatment in infliximab naive patients

at week 30 (Jung et al. 2015). Moreover, reports from several other observational studies in

patients with IBD support the use of Remsima® for this indication (Keil et al. 2016; Kang et al.

2015, 2015; Sieczkowska et al. 2016a; Sieczkowska et al. 2016b; Farkas et al. 2016; Gecse et

al. 2016). Results are in line with data from our study showing that the activity of Crohn’s

disease and ulcerative colitis were significantly reduced during the treatment with Remsima®.

Mean activity of Crohn’s disease was improved from mild disease classification to remission

state and of ulcerative colitis from moderate-severe to mild disease classification at week 14.

Fatigue is a well-known and often reported symptom in patients with IBD, even when the

disease is in remission, with severe consequences for quality of life. Fatigue was reported in

40% of IBD patients with quiescent disease and an even higher prevalence and level of fatigue

is associated with disease activity (Minderhoud et al. 2003; Minderhoud et al. 2007). Patients

frequently experience a rapid reduction of fatigue after treatment with infliximab, as shown



by a previous, placebo-controlled study, which was based on a health related quality of life

questionnaire (Lichtenstein et al. 2002). In our study, nearly all patients had received a pre-

treatment of IBD prior to treatment with Remsima® and the initial BFI values at baseline

examination already showed a moderate level of fatigue in patients with Crohn’s disease and

ulcerative colitis. Fatigue symptoms slightly decreased during treatment with Remsima®, but

were still classified as moderate for patients with Crohn’s disease whereas patients suffering

from ulcerative colitis displayed a mild to moderate level of fatigue at the end of the study.

Moreover, the quality of life significantly improved during Remsima® treatment. This is in line

with previous studies, including a randomised, placebo-controlled study where patients with

active Crohn’s disease received a single intravenous infusion of either placebo or infliximab (5,

10 or 20 mg/kg). Changes from baseline in overall IBDQ-D score and individual dimensions at

4 weeks post-infusion were compared and showed significantly larger improvement in overall

IBDQ-D score and in all IBDQ dimensions than those treated with placebo at 4 weeks

(Lichtenstein et al. 2002). We also demonstrated a beneficial effect of Remsima® on

depression, the most common psychiatric diagnosis in Crohn’s disease and a putative risk

factor for failure to achieve remission with infliximab (Persoons et al. 2005). TNF-alpha has

been reliably shown to be elevated in depressed patients (Dowlati et al. 2010), however, only

limited data are available from studies investigating the potential of the antidepressant effect

of infliximab. Findings have included improvements of depression in patients with ankylosing

spondylitis (Ertenli et al. 2012), which is supported by animal models (Karson et al. 2013), and

a correlation between a reduced remission rate and the presence of depression in patients

with Crohn’s disease under infliximab treatment (Persoons et al. 2005). In contrast, a recently

conducted, randomised, placebo-controlled trial by Raison et al. (2013) did not note an overall

association of infliximab with antidepressant effects, however, in the subgroup with increased

levels of baseline inflammatory biomarkers, infliximab improved the antidepressant response

(Raison et al. 2013). A limitation of the study was that, since no guidelines presently exist for

anti-inflammatory agents and depression, adjunctive medication could have been under or

overdosed. Other limitations were the follow-up period that was rather short and the number

of patients that was also small (Boufidou und Nikolaou 2016).

Furthermore, the majority of the analysed laboratory parameters improved during the study,

for instance erythrocyte, leukocyte, thrombocyte, haemoglobin level and C-reactive protein

(CRP) level. In particular, C-reactive protein serves as a reliable marker for inflammatory bowel

disease. An increased CRP (>45 mg/L) in patients with IBD predicts with a high certainty the

need for colectomy and this by reflecting severe ongoing and uncontrollable inflammation in

the gut (Vermeire et al. 2004). C-reactive protein levels correspond closely with clinical and

pathological indices of relapse, remission and response to therapy in patients with Crohn's

disease (Fagan et al. 1982). Effectiveness of therapy was evaluated by the measurement of

CRP level in this NIS. The mean amount of C-reactive protein was 34.97 mg/l at admission and

decreased down to 21.11 mg/l at last visit. Mean reduction of 13.86 was statistically significant

(p<0.0001). In contrast to a percentage of 48.56% at baseline, 63.67% of the patients had

normal values (≤ 10 mg/l) at the end of the NIS. Compared to data from the observational



study with 52 IBD patients under CT-P13 therapy, conducted by Keil et al., median CRP level

of both men and women decreased after 14 weeks of therapy to 1.0 mg/l (men, p=0.001) and

5.0 mg/l (women, p=0.011). However, compared to data presented here, baseline level were

substantially lower, namely 28.0 mg/l for men and 11.0 mg/l for women, respectively (Keil et

al. 2016).

Efficacy was globally assessed by the physicians and by the patients themselves. Overall,

efficacy was evaluated as very good or good for about 85% of the patients when physicians

were asked and about 82% when patients were asked.

XI.1.4. Discussion of results in safety

According to the summary of product characteristics (Mundipharma 2015), upper respiratory

tract infection was the most common adverse drug reaction (ADR) reported in clinical trials,

occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients.

The most serious ADRs associated with the use of TNF blockers that have been previously

reported for infliximab include HBV reactivation, CHF, serious infections (including sepsis,

opportunistic infections and TB), serum sickness (delayed hypersensitivity reactions),

haematologic reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating

disorders, hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cell carcinoma,

melanoma, paediatric malignancy, sarcoidosis/sarcoid-like reaction, intestinal or perianal

abscess (in Crohn’s disease), and serious infusion reactions.

In this study, 136 adverse events were reported in 80 patients (21.00%) and 65 adverse drug

reactions occurred in 48 patients (12.60%) during the observation period of approximately

14 weeks. For the majority of the patients with ADRs one type of reaction was reported

(37 patients, 9.71%). Most frequently reported ADRs were assigned to the preferred term

hypersensitivity (9 events in 8 patients, 2.10%), followed by erythema (6 events in 6 patients,

1.05%), ineffective drug (5 events in 5 patients, 1.31%), anaphylactic reaction (4 events in

4 patients, 1.05%), dizziness (3 events in 2 patients, 0.52%), alopecia, fatigue, pruritius, and

rash (2 events in 2 patients each, 0.52%). All further ADRs were reported at a frequency of one

event in one patient each (0.26%).

According to the special warnings and precaution section of the SmPC, infliximab has been

associated with acute infusion related reactions, including anaphylactic shock, and delayed

hypersensitivity reactions. In a recent prospective, nationwide, multicentre, observational

cohort that was designed to examine the efficacy, safety, and immunogenicity of CT-

P13 infliximab, adverse events were experienced in 17.1% of all IBD patients (n=210) until

week 30. Compared to our NIS with a total of 136 reported adverse events in 80 patients

(21.00%), the number of adverse events was lower. Infusion reactions occurred in 6.6% of all

patients (Gecse et al. 2016). Further studies also demonstrated an association of acute

infusion reaction with infliximab treatment (Dignass et al. 2012; van Assche et al. 2010).

Intensity as well as frequency of these reactions can differ. One centre showed at least one

infusion reaction in 9.7% of patients and 6.1% of infusions were accompanied by infusion

reactions (Cheifetz et al. 2003). Another study reported about the occurrence of infusion



reactions in 5.2% of patients (Park et al. 2015), which is comparable to data of the present NIS

where patients suffered from the following infusion reactions: hypersensitivity, 2.10% of all

patients; anaphylactic reaction, 1.05%; anaphylactic shock 0.26%).

Based on experience from clinical studies as well as adverse reactions reported from post-

marketing experience, anaphylactic reaction and serum sickness (delayed hypersensitivity

reaction) are known common adverse reactions (≥1/100 to <1/10). Furthermore, erythema,

which had been observed in six patients (1.57%) in this NIS, is known as a rare event

(≥1/10,000 to <1/1,000) while dizziness, alopecia and rash are categorized as common ADRs

(≥1/100 to <1/10).

The ADRs documented in this NIS were most frequently associated with the following MedDRA

primary system organ classes (SOC): skin and subcutaneous tissue disorders (14 patients,

3.67%), immune system disorders (13 patients, 3.41%), general disorders and administration

and site conditions (8 patients, 2.10%), nervous system disorders (4 patients, 1.05%),

gastrointenstinal disorders (3 patients, 0.79%), infections and infestations (3 patients, 0.79%),

vascular disorders, musculoskeletal and connective tissue disorders, and Respiratory, thoracic

and mediastinal disorders (2 patients each, 0.52%). All further reactions struck one SOC only

(0.26%).

From all documented ADRs, 23 reactions in 18 patients (4.72%) were recorded to be serious.

Hypersensitivity and anaphylactic reaction were the most frequently reported serious ADRs

(4 events in 4 patients each, 1.05%). All other serious ADRs occurred at a frequency of one and

were reported for one patient (0.26%) in each case: abdominal abscess, anaemia,

anaphylactic shock, carotid artery dissection, cerebral infarction, colitis, deep vein thrombosis,

drug ineffective, drug specific antibody present, hepatitis, hypertensive crisis, pleural effusion,

pulmonary tuberculosis, pustular psoriasis, and thrombophlebitis. Three of these

complications were classified as infectious events according to MedDRA: abdominal abscess

(primary SOC), pulmonary tuberculosis (primary SOC), and upper respiratory tract infection

(non-primary SOC). In the above mentioned infliximab study from Gecse et al., serious

infectious adverse events occurred in 5.7% of all patients (Gecse et al. 2016).

TNFα mediates inflammation and modulates cellular immune responses. Experimental data

show that TNFα is required for the clearing of intracellular infections. As described in the

special warning and precaution section of the SmPC, patients taking TNF-blockers are more

susceptible to serious infections. Tuberculosis, bacterial infections, including sepsis and

pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in

patients treated with infliximab. There have been reports of active tuberculosis in patients

receiving infliximab. It should be noted that in the majority of these reports tuberculosis was

extrapulmonary, presenting as either local or disseminated disease. If active tuberculosis is

diagnosed, Remsima therapy must not be initiated. If a latent tuberculosis is diagnosed,

treatment must be started with antituberculosis therapy before the initiation of Remsima

(Mundipharma 2015). As mentioned above, one patient suffered from tuberculosis. In this

case, a pulmonary tuberculosis was diagnosed. According to SmPC, tuberculosis is categorized

as an uncommon adverse reaction (≥1/1,000 to <1/100).



Some ADRs mentioned in the SmPC were hardly reported or not at all. This is probably based

on a limited observation period of the underlying NIS and the phenomenon of under-reporting

in non-interventional trials as physicians may tend to under-report events already mentioned

in the SmPC (Lopez-Gonzalez et al. 2009).

Not all reported ADRs were known effects of treatment with Remsima®. From all reported

adverse drug reactions during the NIS presented here, a total of seven events that occurred in

four patients (1.05% of all patients) were classified as suspected unexpected serious adverse

reactions (SUSARs, 11.86% of reported ADRs): anaemia, anaphylactic shock, carotid artery

dissection, cerebral infarction, thrombophlebitis, hypertensive crisis, and deep vein

thrombosis. In a recent CT-P13 study in 52 patients with ulcerative colitis or Crohn’s disease,

four adverse events were identified after 14 weeks of therapy (n=1 each). Similar to the

current study, one patient was affected by deep vein thrombosis, however, it could not be

confirmed whether it was treatment-related (Keil et al. 2016).

The outcome was stated to be ongoing for two adverse reactions in one patient (0.26%),

recovering for eight events in seven patients (1.84%), and recovered for the majority of

47 events in 35 patients (9.19%). Status was reported to be not recovered for five events in

three patients (0.79%). The outcome of one ADR in one patient (0.26%) was unknown. Data

on one ADR in one patient (0.26%) each was missing or assessment was not applicable.

Tolerability of Remsima® was assessed by the physicians and by the patients themselves.

Tolerability was evaluated as very good or good in most cases. At last assessment, physicians

evaluated tolerability for about 96% of the patients as very good or good and 93% of the

patients rated tolerability as very good or good.

XI.2. Limitations on collected data

In general, this study design represents an important tool to collect real life data concerning

treatment with Remsima® of patients with multiple comorbidities, comedications and risk

factors, patients usually excluded from controlled clinical trials.

The initially planned sample size of 400 patients was almost achieved in the course of the

observation period. 381 patients were included. The number was sufficient to obtain a

representative cohort of patients treated in the routine medical practice of 70 centres

throughout Germany. The study was designed as a non-interventional study including non-

randomization of the study population and the absence of a comparative placebo- or parallel-

group. Therefore, the treatment effect of Remsima® was not directly compared to placebo

and/or other drugs. Patients were not selected by specific inclusion or exclusion criteria but

indication and contraindications mentioned in the SmPC were to be considered. The

advantage of this study design was the better transfer to non-selected patients in non-study

situations. However, due to a missing reference group of patients (without or with alternative

therapy), the efficacy of Remsima® treatment could not be conclusively assessed.



XI.3. Clinical relevance and overall conclusions

The population analysed in the course of the NIS was considered characteristic for patients

with Crohn‘s disease and ulcerative colitis conditions. Therapy with Remsima® resulted in an

overall positive therapeutic effect on disease activity of patients with Crohn‘s disease and

ulcerative colitis. Furthermore, quality of life, fatigue and pain symptoms were improved

during the study. Concerning depression, a significant decrease of the ADS-L mean value was

achieved (but note that mean values of ADS-L suggested an absence of clinically relevant

depressive symptoms prior to Remsima® therapy). In addition, the majority of the analysed

laboratory parameters improved during the study, for instance erythrocyte, leukocyte,

thrombocyte, haemoglobin level and C-reactive protein level.

Effectiveness and tolerability of Remsima® were predominantly evaluated within the global

assessment by physicians and patients as very good or good. Safety analyses of the study

indicated general tolerability of the drug, but under-reporting of events by health-care

professionals in contrast to previously performed clinical trials cannot be excluded in this

practical-use study setting.

In conclusion, results of the ResCu study provide evidence for the effectiveness and tolerability

of Remsima® in the treatment of Crohn‘s disease and ulcerative colitis conditions under

routine medical practice settings.



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