An Open Label, Single Group Assignment Design Study to Correlate Soluble ST2 With Clinical, Endoscopic and Histological Activity in Moderate to Severe Ulcerative Colitis Patients Under Golimumab.
Phase: PHASE4
Conditions: Colitis, Ulcerative
Sponsor: Merck Sharp & Dohme LLC

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: An open label, single group assignment design study to correlate 
soluble ST2 with clinical, endoscopic and histological activity in 
moderate to severe Ulcerative Colitis patients under golimumab 
NCT number: 
NCT02318667 
Document Date: 
13-Mar-2017 

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AMENDMENT NO. 3, 13Mar2017 
 
 
 
 
Protocol Template 26 NOV 2013 Maintained by CSO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AMENDMENT NO. 3, 13MAR2017 
 
 
 
Investigator Signature Page 
Abbreviated Title 
EVOLUTION study 
Title 
An open label, single group assignment design study to 
correlate 
soluble 
ST2 
with 
clinical, 
endoscopic 
and 
histological activity in moderate to severe Ulcerative Colitis 
patients under golimumab  
(Phase 4; Protocol No. MK-8259-022-03) 
Sponsor 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
Trial Physician 
 
 
Date of Finalization of This Current 
Version of the Protocol 
Amendment No 3, 13Mar2017 
Previous Version(s) of the Protocol 
Amendment No 2, 20Jan2016 
Amendment No 1, 17Jun2015 
Initial Protocol, 06Aug2014_v1.6 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR PRODUCT IS 
PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG OR PRODUCT 
AND IS SUBJECT TO RECALL AT ANY TIME.  THE INFORMATION IN THIS DOCUMENT MAY 
NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS REQUIRED BY APPLICABLE LAWS OR 
REGULATIONS.  SUBJECT TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED 
ONLY TO THOSE PERSONS INVOLVED IN THE TRIAL WHO HAVE A NEED TO KNOW, WITH 
THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION.  THESE 
RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL OR 
WRITTEN INFORMATION, SUPPLIED TO YOU BY THE SPONSOR OR ITS AFFILIATES OR 
REPRESENTATIVES THAT IS DESIGNATED AS "PRIVILEGED" OR "CONFIDENTIAL". 
 
 
 
 
 
dd MMM yyyy 
Medical Director 
 
I have read Protocol No. MK 8259-022-03 dated 13 March 2017, including all 
appendices, and agree to conduct the trial in accordance with the protocol.  The 
amendment to the protocol and trial documents must also be approved by the 
IRBs/IECs and regulatory authorities as appropriate, before implementation at the 
site.  I agree to implement the amendment to the protocol and trial documents only 
after all necessary approvals have been obtained and the sponsor has confirmed 
that it is acceptable to do so. 
 
 
 
 
 
 
Name, Degree, full mailing address of Investigator 
Site Number 
dd MMM yyyy 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
1.0 TITLE PAGE 
Abbreviated Title 
EVOLUTION study 
Title 
An open label, single group assignment design study to 
correlate soluble ST2 with clinical, endoscopic and 
histological activity in moderate to severe Ulcerative 
Colitis patients under Golimumab  
MK 8259-022-03 
Sponsor 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
Sponsor’s Address 
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ 08889-0100, U.S.A. 
IND No. 
Not Applicable 
EudraCT No. 
2014–003262–25 
Trial Physician 
 
 
Phase 
4 
Date of Finalization of This Current 
Version of the Protocol 
Amendment No 3, 13Mar2017 
Previous Version(s) of the Protocol 
Initial Protocol, 06Aug2014_v1.6 
Amendment No 1, 17Jun2015 
Amendment No 2, 20Jan2016 
Protocol Template Approval Date 
26 Nov 2013 
 
C O N F I D E N T I A L 
TRIAL PROTOCOL 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR 
PRODUCT IS PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF 
THIS DRUG OR PRODUCT AND IS SUBJECT TO RECALL AT ANY TIME.  THE 
INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH 
DISCLOSURE IS REQUIRED BY APPLICABLE LAW OR REGULATIONS.  
SUBJECT TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED 
ONLY TO THOSE PERSONS INVOLVED IN THE TRIAL WHO HAVE A NEED TO 
KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS 
INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL APPLY 
EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION SUPPLIED TO 
YOU BY THE SPONSOR OR ITS AFFILIATES OR REPRESENTATIVES THAT IS 
DESIGNATED AS “PRIVILEGED” OR “CONFIDENTIAL”. 
 
 
 
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2.0 SYNOPSIS 
TITLE OF TRIAL: An open label, single group assignment design study to correlate soluble 
ST2 with clinical, endoscopic and histological activity in moderate to severe Ulcerative 
Colitis patients under Golimumab  
(Phase 4; Protocol No. MK 8259-022-03) 
ABBREVIATED TITLE: Evolution study 
OBJECTIVES:  Evaluate soluble ST2 as a surrogate marker of clinical, endoscopic and histological 
activity in moderate to severe ulcerative colitis patients under treatment with golimumab sc. 
Primary Trial Objectives:  
• 
To evaluate the correlation of serum soluble ST2 levels with endoscopic activity 
(endoscopic Mayo score) at week 6 in moderate to severe UC subjects under golimumab 
treatment.  
• 
To evaluate the correlation of serum soluble ST2 with histological activity (Geboes index) at 
week 6 in moderate to severe UC subjects under golimumab treatment. 
Secondary Trial Objectives:   
• 
To evaluate the correlation of serum soluble ST2 levels with endoscopic activity 
(endoscopic Mayo score) at week 16 in moderate to severe UC subjects under golimumab 
treatment. 
• 
To evaluate the correlation of serum soluble ST2 levels with histological activity (Geboes 
index) at week 16 in moderate to severe UC subjects under golimumab treatment. 
• 
To correlate serum soluble ST2 levels with fecal calprotectin, at week 6 and week 16 in 
moderate to severe UC subjects under golimumab treatment. 
• 
To correlate serum soluble ST2 with clinical activity (total Mayo score) at week 6 and week 
16 in moderate to severe UC subjects under golimumab treatment. 
• 
To evaluate the potential of serum soluble ST2 as a predictor of endoscopic response 
(endoscopic Mayo score) to golimumab in moderate to severe UC subjects. 
• 
To evaluate the correlation between serum soluble ST2 levels with maintenance of 
endoscopic response (endoscopic Mayo score) to golimumab.  
• 
To correlate Mayo endoscopic score with UCEIS overall score at week 6 and week 16 in 
moderate to severe UC subjects under golimumab treatment. 
Exploratory Objectives: 
To evaluate the relationships of serum levels of golimumab and the presence of anti-golimumab 
antibodies with clinical, endoscopic, and histological activities and with biomarker levels in subjects 
with moderate to severe UC 
Trial Design 
Overview: This is an exploratory, multi-site, nonrandomized, open label, prospective, interventional, 
single-arm, study to evaluate the correlation of serum soluble ST2 levels with clinical, endoscopic 
and histological activity in subjects with moderate to severe active UC who received golimumab. 
After signing the informed consent, subjects will enter a screening period of up to 42 days. After 
confirmation of eligibility criteria, subjects will initiate treatment with golimumab according to SmPC 
(Baseline – V2). Subjects will be followed for a period of 16 weeks for clinical assessments and data 
collection. Biomarker samples (ST2 and fecal calprotectin) will be collected at baseline and at all 
subsequent visits. All subjects will be evaluated for endoscopic (fibrosigmoidoscopy) and histologic 
activity at screening, week 6 and week 16.  
Number of Trial Centers:  Approximately 10 
Duration of Participation:  Each subject will participate in the trial for approximately 22 weeks from 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
TITLE OF TRIAL: An open label, single group assignment design study to correlate soluble 
ST2 with clinical, endoscopic and histological activity in moderate to severe Ulcerative 
Colitis patients under Golimumab  
(Phase 4; Protocol No. MK 8259-022-03) 
ABBREVIATED TITLE: Evolution study 
the time the subject signs the Informed Consent Form (ICF) until the final contact. After a screening 
period of up to 6 weeks, each subject will initiate golimumab according to the Summary of Product 
Characteristics and will be followed for a period of 16 weeks.  
Duration of Trial: The trial will require approximately 2 years from the beginning to the end of the 
overall trial (first subject signing informed consent to last contact with last subject). 
Key Inclusion/Exclusion Criteria:  Subjects with a diagnosis of moderate to severe ulcerative colitis 
will be selected to participate in the trial. 
Inclusion criteria: Age 18 years or older at time of enrollment; diagnosis of moderate to severe 
ulcerative colitis at inclusion (defined as a clinical Mayo score ≥6) including endoscopy that shows 
inflammation as judged by a Mayo endoscopy score ≥2; subject is eligible to receive golimumab as 
per product monograph; signed the informed consent 
Exclusion criteria: as per golimumab’s product monograph; history of asthma, autoimmune 
diseases, hypertension. 
INVESTIGATIONAL PRODUCT, DOSE, MODE OF ADMINISTRATION 
Investigational Product: Golimumab (SIMPONI) sc as per product monograph  
Reference Product: Not applicable 
STATISTICAL METHODS:  All quantitative variables will be summarized through descriptive statistics 
namely mean, median, standard deviation and range (minimum and maximum) and qualitative 
variables through absolute (n) and relative frequencies (%) and 95% confidence intervals (if 
applicable). The statistical analysis will be performed through frequency tables for qualitative 
variables and tables with descriptive statistics for quantitative variables. 
The association between two quantitative variables will be performed through Pearson correlation 
coefficient or Spearman correlation coefficient, in case the normality assumption was not verified. 
The association of two categorical variables will be tested through the Chi-Square test or Fisher 
Exact test (if applicable). Cohen's kappa coefficient will be performed. 
The comparison of two independent samples in respect to quantitative variables will be performed 
through t-test for independent samples or the Mann-Whitney non-parametric test, according to the 
assumption validations of the statistical test. 
ROC curve analysis will be performed as well as sensitivity, specificity, and positive and negative 
predictive values. 
Data Set(s) to be Analyzed:  The primary analysis is to be performed on the Full Analysis Set, 
defined as all subjects who had received study medication and had at least one valid post baseline 
assessment 
for 
the 
primary 
endpoint 
that 
correlates 
ST2 
with 
endoscopic 
activity. 
In addition, a Per Protocol Set is defined as subjects receiving treatment, who meet key eligibility 
and evaluability criteria. Sensitivity analyses will be based on this Per Protocol Set. 
All safety analyses will be performed on the All Treated Set, comprising all subjects who received at 
least one dose of study medication. 
Sample Size:  Based on the recruitment capacity of sites it is expected to include a total of 37 
subjects for analysis. With this sample size there is a probability of 80% that the lower limit of a one-
sided 95% confidence interval is higher than 0.50, if the observed correlation coefficient is at least 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
TITLE OF TRIAL: An open label, single group assignment design study to correlate soluble 
ST2 with clinical, endoscopic and histological activity in moderate to severe Ulcerative 
Colitis patients under Golimumab  
(Phase 4; Protocol No. MK 8259-022-03) 
ABBREVIATED TITLE: Evolution study 
0.75. 
Study Analysis:  
The primary analysis is to investigate the correlation between serum soluble ST2 and: 
• 
endoscopic activity of disease (measured by endoscopy Mayo subscore) at 6 weeks in UC 
subjects receiving golimumab;  
• 
histological activity (measured by Geboes index score) at 6 weeks in UC subjects receiving 
golimumab.  
For both analyses the Spearman correlation coefficient will be used. 
For the key secondary endpoints the following analysis will be performed: 
• 
The correlation between serum soluble ST2 with endoscopic activity of disease (measured 
by endoscopy Mayo subscore) at 16 weeks in UC subjects receiving golimumab, through 
the Spearman correlation coefficient;  
• 
The correlation between serum soluble ST2 histological activity (measured by Geboes 
index score) at 16 weeks in UC subjects receiving golimumab, through the Spearman 
correlation coefficient. 
• 
Serum soluble ST2 levels at baseline, Week 6 and Week 16 will be correlated with fecal 
calprotectin levels at baseline, week 6 and week 16 through Pearson correlation coefficient 
or Spearman correlation coefficient in case the normality assumption is not verified. The 
two biomarkers will be categorized by the cut-offs and Cohen's kappa coefficient will be 
obtained.  
• 
Serum soluble ST2 levels at baseline, week 6 and week 16 will be correlated with clinical 
activity (total Mayo score), through Spearman correlation coefficient. 
• 
Comparative analyses of means (active disease versus inactive disease at week 6) with 
serum ST2 at baseline and change between baseline and week 6. 
• 
Comparative analyses of subjects who achieved response at week 6 and maintained 
through week 16 versus subjects who did not maintain response, regarding serum soluble 
ST2 at baseline, week 6 and change between baseline and week 6. ROC curve analysis of 
the serum soluble ST2 at week 6 regarding maintenance of response between week 6 and 
16 will be performed. This exploratory analysis will detect the cut-off levels of the serum 
soluble ST2 at week 6 associated with maintenance of response. 
 
Safety Analysis:  Adverse events and laboratory tests will be analyzed through descriptive statistics.   
Interim Analysis:  No formal interim analyses are planned  
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
2.2 
Trial Flow Chart 
Visit Title 
Screening 
Baseline 
Week 6 
Week 16 16 
Early 
Discontin. 16 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Scheduled Day 
Days -42 
thru 0 
Day 1 
Day 42 
Day 112 
Scheduling Window 
 
 
±3 days 
±3 days 
Informed Consent 
X 
 
 
 
 
Demography/Medical History 
X 
 
 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
Review of Entry Criteria 
X 
X 
 
 
 
Physical Examination (partial Mayo Score 
and Montreal Classification) 
X1 
X 
X 
X 
X 
Vital signs (SBP, DBP, heart rate, weight 
and body temperature) 
X 
X 
X 
X 
X 
Chest X-ray  
X2 
 
 
 
 
QuantiFERON-TB Gold test 3 
X 
 
 
 
 
TB evaluation 4 
X 
X 
X 
X 
X 
Fibrosigmoidoscopy (UC activity 
assessed by endoscopy Mayo subscore 
and UCEIS)  
X1,5 
 
X 
X 
X 
Histology  
X1,6 
 
X 
X 
X 
Mayo score  
 
X7 
X 
X 
X 
Serum Pregnancy Test (β-hCG) 8 
X1 
 
 
 
 
Urine pregnancy test 8 
 
 
X 
X 
X9 
Fecal calprotectin 10 
 
X 
X 
X 
X17 
Serum ST2 sampling 11 
 
X 
X 
X 
X17 
Measurement of golimumab levels  and 
anti-golimumab antibodies19  
 
 
X 
X 
X 
Plasma for Future Biomedical Research18 
 
X 
 
X 
X17 
CRP (local laboratory)  
 
X 
X 
X 
X 
Routine Laboratory 12  
X1 
 
X 
X 
X 
(Serious) Adverse Events 
X 
X 
X 
X 
X 
Stool negative for enteric pathogens 
X13 
 
 
 
 
Dispensing of Subject Identification Card 
X14 
 
 
 
 
Dispense Trial Medication15 
 
X 
X 
 
 
Trial Medication Accountability 
 
 
X 
X 
X 
Dispensing of subject diary 
 
X 
 
 
 
Review of subject diary  
 
 
X 
X 
X 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
 
All assessments must be completed prior to study product administration unless otherwise specified. 
1 
This procedure must be performed within 2 weeks prior to baseline (V2) 
2 
If historical Chest-X-ray is not available within 3 months prior to study inclusion, this exam (both posterior-
anterior and lateral views) should be performed at the Screening visit.  
3 
If historical QuantiFERON-TB Gold test result is not available within 2 months prior to study inclusion, this 
exam should be performed at the Screening Visit.  
4 
If not available within 2 months prior to study inclusion, latent TB must be evaluated at screening by 
specialized, trained, and licensed personnel, either at the participating trial site or at an external unit (e.g. Lung 
Disease Diagnostic Centers (CDPs)), as according to local guidelines. When this evaluation is performed at 
any site other than the investigator’s facility, the results must be made available in written form as source 
documentation. If TB is suspected at any time during the study, chest x-ray and QuantiFERON-TB Gold test 
should be performed and latent TB must be re-evaluated.  
5 
Fibrosigmoidoscopy must be performed within 2 weeks prior to baseline (V2). Colonoscopy will replace 
fibrosigmoidoscopy if screening for polyps or dysplasia is necessary. A screening biopsy will be performed 
even if a prior biopsy consistent with the diagnosis of UC is available. In the presence of adenomatous polyps 
these must be removed prior to visit 2 and this should be reported in subject’s Medical History if procedure 
was executed as planned or the condition did not worsen.  
6 
Histological data from screening will be used to calculate Geboes index baseline score. At all visits, samples 
will be prepared and sent to Central laboratory for histological assessment 
7 
Baseline Mayo score will be calculated using the endoscopic subscore assessed during the screening 
8 
Female subjects of childbearing age 
9 
If judged necessary by the investigator 
10 Fecal biomarkers will be collected prior to study drug administration. Sample will be sent to a certified central 
laboratory for analysis. 
11 Serum biomarkers will be collected prior to study drug administration. Sample will be sent to a certified central 
laboratory for analysis. 
12 The routine laboratory tests include: Hematology (basophils, eosinophils, hematocrit, hemoglobin, 
lymphocytes, monocytes, neutrophils, platelets, RBC, WBC); Blood chemistry (total bilirubin, ALT, AST, 
alkaline phosphatase, albumin, total protein, calcium, phosphate, sodium, potassium, chloride, urea and 
creatinine and CRP; Urinalysis (proteins, glucose, nitrates, WBC, ketone bodies, hemoglobin, urobilinogen, 
bilirubin). If historical serology results of HIV, HCV and HBV are not available within 3 months prior to study 
inclusion, these tests must be performed at the screening visit. 
13 Stool culture and Clostridium difficile assay for toxin must be performed at screening or in the case of episode 
exacerbation as long as taken during the 4 months prior to inclusion. 
14 The Subject Identification Card will be dispensed after the subject provides written informed consent and will 
be retrieved at the last visit. 
15 Study medication will be dispensed at visit 2 and visit 3 for the following planned administrations. After study 
completion, and if physician finds it beneficial to the subject, golimumab will continue to be dispensed 
according to SmPC. 
16 Prior to termination of study participation, all subjects should complete assessments indicated at Week 16 or 
Early Discontinuation. 
17 Samples of ST2,calprotectin, and plasma for future biomedical research will only be collected at the Early 
Discontinuation visit in case the investigator discontinued the subject due to golimumab’s lack of efficacy 
18 Informed consent for plasma samples for future biomedical research must be obtained before the plasma 
samples are drawn.  Plasma samples for analysis should be obtained pre-dose at Baseline/Day 1 and at Week 
16 as the last sample drawn, on enrolled subjects only. 
19 Golimumab levels and anti-golimumab antibodies will be measured in blood sample collected prior to study 
drug administration. Sample will be sent to a certified central laboratory for analysis. 
 
 
 
 
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3.0 TABLE OF CONTENTS 
1.0 TITLE PAGE ..................................................................................................... 3 
2.0 SYNOPSIS ........................................................................................................ 4 
2.1 
Trial Design Diagram .............................................................................. 7 
2.2 
Trial Flow Chart....................................................................................... 8 
3.0 TABLE OF CONTENTS .................................................................................. 10 
3.1 
List of Tables ........................................................................................ 12 
3.2 
List of Appendices ................................................................................ 13 
4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................... 14 
5.0 INTRODUCTION ............................................................................................. 16 
5.1 
Therapeutic Rationale .......................................................................... 16 
5.2 
Subject Population Rationale .............................................................. 18 
5.3 
Dose and Administration Rationale..................................................... 18 
5.4 
Rationale for Future Biomedical Research ......................................... 18 
6.0 TRIAL OBJECTIVES ...................................................................................... 19 
6.1 
Primary Trial Objectives ....................................................................... 19 
6.2 
Secondary Trial Objective(s)................................................................ 19 
6.3 
Exploratory Objective(s) ...................................................................... 20 
7.0 INVESTIGATIONAL AND ANALYSIS PLAN .................................................. 20 
7.1 
Overall Trial Design .............................................................................. 20 
7.2 
Beginning and End of the Trial ............................................................ 21 
7.3 
Trial Population..................................................................................... 22 
7.3.1 
Subject Inclusion Criteria ............................................................... 22 
7.3.2 
Subject Exclusion Criteria .............................................................. 25 
7.3.3 
Subject Discontinuation Criteria ..................................................... 27 
7.3.4 
Replacement of Subjects ............................................................... 30 
7.4 
Treatments ............................................................................................ 30 
7.4.1 
Trial Treatments ............................................................................. 30 
7.4.2 
Non-Trial Treatments ..................................................................... 33 
7.4.3 
Procedures for Monitoring Subject Compliance With 
Administration of Trial Treatments ................................................. 34 
7.5 
Trial Schedule ....................................................................................... 34 
7.6 
Trial Procedures ................................................................................... 35 
7.7 
Assessments ........................................................................................ 39 
7.7.1 
Efficacy Assessments .................................................................... 39 
7.7.2 
Safety Monitoring and Assessments .............................................. 39 
7.7.3 
Other Endpoints ............................................................................. 48 
 
 
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7.8 
Criteria for Early Termination of the Trial ........................................... 50 
8.0 STATISTICAL AND ANALYTICAL PLAN ...................................................... 50 
9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS ........................................................................................ 55 
9.1 
Ethical Conduct of the Trial ................................................................. 55 
9.1.1 
Independent Ethics Committee or Institutional Review Board ........ 55 
9.1.2 
Subject Information and Consent ................................................... 55 
9.1.3 
Subject Identification Card ............................................................. 56 
9.1.4 
Registration of the Trial .................................................................. 57 
9.2 
Reporting Trial Data to the Sponsor .................................................... 57 
9.2.1 
Data Collection Forms ................................................................... 57 
9.2.2 
Preparing Case Report Forms for All Subjects ............................... 57 
9.2.3 
Preparing Case Report Forms for Subjects Who Fail Screening .... 58 
9.3 
Publications and Other Rights ............................................................. 58 
9.3.1 
Rights to Publish by the Investigator .............................................. 58 
9.3.2 
Use of Proprietary or Confidential Information in a Publication ....... 59 
9.3.3 
Use of Trial Information in a Publication ......................................... 59 
9.3.4 
Authorship of Publications.............................................................. 59 
9.4 
Trial Documents and Records Retention ............................................ 60 
10.0 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ................. 61 
10.1 
Sponsor ................................................................................................. 61 
10.2 
Investigators ......................................................................................... 61 
10.2.1 
Selecting Investigators ................................................................... 61 
10.2.2 
Financial Disclosure Requirement .................................................. 61 
10.2.3 
Clinical Study Report Coordinator Investigator ............................... 62 
10.3 
Central Organizations........................................................................... 62 
11.0 REFERENCES ................................................................................................ 62 
 
 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
3.1 
List of Tables 
Table 1 Medications, Supplements, and Other Substances Prohibited During 
the Trial ........................................................................................................ 33 
Table 2 Medications, Supplements, and Other Substances Allowed During 
the Trial ........................................................................................................ 34 
Table 3 Laboratory Tests................................................................................... 38 
 
 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
3.2 
List of Appendices 
Appendix 1 Code of Conduct for Clinical Trials ............................................... 65 
Appendix 2 Specimen Handling and Shipping Instructions ............................. 68 
Detailed instructions for storage, labelling and shipment of all samples will be 
provided in the Laboratory Manual. .............................................................. 68 
Appendix 3 Mayo scoring system for assessment of ulcerative colitis activity . 69 
Appendix 4 Ulcerative Colitis Endoscopic Index Of Severity (UCEIS©) .......... 70 
Appendix 5 Geboes score for assessment of ulcerative colitis histologic 
disease activity............................................................................................. 71 
Appendix 6 Collection and Management of Specimens for Future 
Biomedical Research ................................................................................... 72 
Appendix 7 Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ............................................................................... 79 
 
 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
AE 
Adverse Event 
ALT 
Alanine aminotransferase (SGPT) 
ANCA 
Anti-neutrophil cytoplasmic antibodies 
Anti-OmpC 
anti-Outer membrane of porin C 
ASCA 
Anti-Saccharomyces cerevisiae antibodies 
AST 
Aspartate aminotransferase (SGOT) 
AZA 
azathioprine 
CHF 
chronic heart failure 
CO 
Country Operations; a local, country-wide, representative of the sponsor 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DBP 
Diastolic blood pressure 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EDC  
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration, USA 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
IBD 
Inflammatory bowel disease 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
ICMJE 
International Committee of Medical Journal Editors 
IL 
Interleukin 
IL-1RL1 
Interleukin-1 receptor like 1 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application; legal instrument in the USA that allows trial of 
unapproved, investigational new drugs in human subjects 
Investigational Product The drug, biologic, and/or device being investigated in the current trial 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA, N/A 
Not applicable 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
Term 
Definition 
RBC 
Red Blood Cell 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
(S)AE 
All Adverse Events, including Serious Adverse Events 
SBP 
Systolic blood pressure 
sc 
subcutaneous 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (ALT) 
SmPC 
Summary of Product Characteristics 
sST2 
Serum human Suppression of Tumorigenicity 2 
ST2 
human Suppression of Tumorigenicity 2 
TB 
Tuberculosis 
TNF 
Tumor necrosis factor 
UC 
Ulcerative colitis 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
USA 
United States of America 
WBC 
White Blood Cell 
 
 
 
 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
5.0 INTRODUCTION 
5.1 
Therapeutic Rationale 
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) causing continuous 
mucosal inflammation of the colon without granulomas characterized by a relapsing 
and remitting course (Silverberg et al., 2005). Currently, the classification of IBDs is 
based on clinical parameters (activity, localization and phenotype). However, due to 
the high percentage of non-classifiable IBD (10%-15%) and the difficulty of a 
differential diagnosis, it has become necessary to search for new markers for these 
diseases (Díaz-Jiménez et al., 2011). 
Ideally, a biomarker should be able to identify individuals at risk of developing the 
disease, detect the activity, monitor the effect of the treatment and, finally, have a 
prognostic value for the reactivation of the disease (Tibble and Bjarnason, 2001; 
Gisbert et al., 2007). Current biomarkers for IBD include serological levels of specific 
antibodies (ASCA, ANCA, anti-OmpC, anti-Cbir, antiglycans), serum C-reactive 
proteins (CRP) and cytokines and fecal proteins (calprotectin and lactoferrin). 
Nevertheless, the majority of these markers show a low sensitivity and/or specificity, 
and they cannot reflect the real intestinal damage (Díaz-Jiménez et al., 2011). 
IL-33 is the newest identified member of the IL-1 family and exerts its biological 
effects through binding of its receptor, ST2 (human Suppression of Tumorigenicity 
2).ST2 belongs to IL-1 receptor like 1 (IL-1RL1) super family, is coded by 
chromosome 2 and expressed mainly as 2 splice variants, namely transmembrane 
bound receptor, ST2L, that activates downstream signalling upon IL-33 recognition, 
and a serum soluble protein, sST2. Complex formation of IL-33 with sST2 leads to 
cytokine inactivation, suggesting a role for this variant form as a decoy receptor 
(Beltrán et al., 2010). The IL-33/ST2 axis is a intracellular signalling system that 
participates in processes as varied as the antigen/allergen response, autoimmunity, 
organ fibrosis and cardiac failure. Several studies reported an increase in plasma 
levels of sST2 in patients with inflammatory processes, including asthma, 
autoimmune, cardiovascular diseases, trauma and sepsis (Kuroiwa et al., 2001; 
Oshikawa et al., 2001; Weinberg et al., 2003; Brunner et al., 2004). Soluble ST2 
protein was recently identified as a new and reliable biomarker of heart failure (Kohli 
et al., 2012). 
There is an established role of IL-1 family members (such IL-1β and IL-18) in 
inflammatory bowel disease. Since 2010, several studies reported elevated 
expression of IL-33 in UC inflamed intestinal mucosa vs. healthy controls. Mucosal 
expression of IL-33 is mostly localized to non-hematopoietic cells, particularly to 
intestinal epithelial cells and myofibroblasts (Beltrán et al., 2010; Kobori et al., 2010; 
Pastorelli et al., 2010; Seidelin et al., 2011).In mucosal tissue, levels of IL-33 
showed to correlate positively with the severity of gut inflammation (Pastorelli et al., 
2010). Similary, the expression of its receptor, ST2, was shown to be increased in 
both colonic wall and serum of UC patients (Beltrán et al., 2010; Pastorelli et al., 
2010). In IBD, there is a recruitment of ST2 positive cells into the lamina propria, 
 
 
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while epithelial-derived ST2 expression is lost /decreased and redistributed. It was 
suggested that the global increase in ST2 in IBD represents the sST2 protein, 
produced by mucosal lamina propria mononuclear cells, intestinal epithelial cells and 
circulating mononuclear cells. ST2 could also be involved in a negative feedback 
mechanism to control inflammation (Beltrán et al., 2010).The IL-33/ST2 axis seems 
to have a dual and dichotomous role in the pathogenesis of IBD. On one hand, pro-
inflammatory cytokine stimuli, such as TNF, result in the increase of IL-33 in 
epithelial cells. On the other hand, IL-33 may be released by injured epithelial cells 
to induce pro-inflammatory cytokines production through activation of ST2L, in mast 
cells, macrophages, eosinophils and neutrophils. IL-33 may function as an 
endogenous danger signal or alarmin, to alert immune system of cell or tissue 
danger (Pastorelli et al., 2010).  
Recent data showed that sST2 levels correlate positively with the severity of colonic 
mucosal disease and inflammatory cytokines (IL-6, IL-33 and TNF) (Beltrán et al., 
2010; Pastorelli et al., 2010; Díaz-Jiménez et al., 2011). Diaz-Jimenez and his group 
demonstrated that sST2 has a good performance for discriminating between active 
and inactive UC in TNF inhibitors naïve patients, based on clinical, endoscopic and 
histopathological characteristics: active UC = 235.8 pg/mL (90.65-367.90); inactive 
UC = 33.19 pg/mL (20-65.32), for a cut-off value of 74.87 pg/mL (sensitivity=83%, 
specificity=83%; AUC=0.92 [0.86-0.97, p<0.0001]). This study also showed that 
sST2 serum levels from UC patients significantly correlate to endoscopic Mayo 
score (r=0.76, p<0.0001) as well as histopathological score (r=0.67, p<0.0001) 
(Díaz-Jiménez et al., 2011). 
Treatment with TNF inhibitors modulates circulating IL-33 and sST2 levels. In a 
small cohort of IBD patients, Pastorelli and his group evaluated Infliximab’s acute 
and long term effects and observed a decrease of IL-33 and an overall decrease in 
the IL-33/sST2 ratio, with a greater impact in UC patients (Pastorelli et al., 2010). 
In a rheumatoid arthritis study, serum levels of IL-33 were shown to decrease 
significantly in responders to TNF inhibitors vs. non responders, and sustained 
elevation of serum and/or synovial levels of IL-33 were suggested to have a possible 
association with poor response to TNF inhibitors (Matsuyama et al., 2012). 
TNF inhibitors have improved outcomes of patients with moderate to severe 
ulcerative colitis, in spite some patients do not respond to treatment. Approximately 
one third of IBD patients are primary non-responders and fail to improve after 
therapy induction. In UC, mucosal healing is one of the most important clinical 
targets in order to maintain long-term remission. As mucosal healing has become a 
goal of treatment in IBD, endoscopy is the "gold standard" for the assessment of 
inflammation of intestinal mucosa. Surrogate markers that reflect the severity of 
mucosal inflammation and could potentially replace endoscopy are being 
investigated. Fecal calprotectin levels correlate significantly with endoscopic disease 
activity in IBD and is currently the best surrogate marker for the presence of 
intestinal inflammation. Still, the use of nonsteroidal anti-inflammatory drugs 
(NSAIDs), occurrence of intercurrent intestinal infection and the presence of 
malignancy may cause elevation of calprotectin levels in the absence of IBD.  
 
 
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A simple, rapid, sensitive, specific, inexpensive, non-invasive marker to detect and 
monitor intestinal inflammation is still needed. If such biomarker could also predict 
the clinical response to therapeutic regimens, its importance and impact for the 
patient would be greater.  
Golimumab is a fully human anti-TNFα monoclonal antibody that binds with high 
affinity to human TNFα and inhibits TNFα bioactivity. A study recently conducted 
with 1228 patients (Sandborn et al., 2014a) has shown that golimumab induces 
clinical response in 51% of patients with moderate to severe UC at week 6, with 
remission and mucosal healing being achieved by 18% and 42% of patients, 
respectively. Among those patients on clinical response after induction with 
golimumab, 47-50%  were able to maintain response through week 54 (50-100mg). 
At both week 30 and week 54, 23-28% of patients were in remission and 42-42% 
had mucosal healing (50-100mg).  (Sandborn et al ., 2014b) 
No research so far correlated the levels of ST2 with endoscopic and histological 
activity in UC patients receiving anti-TNF-α therapy. 
This is an exploratory study aiming to evaluate the potential of serum soluble ST2  
as a surrogate biological marker of disease outcome and therapeutic response, in 
subjects with moderate to severe active UC who have an inadequate response to 
conventional therapies and who will start treatment with golimumab according to the 
SmPC. 
5.2 
Subject Population Rationale 
This study will include adult subjects with a diagnosis of moderate to severe active 
ulcerative colitis eligible for use of anti-TNF-α therapy, i.e., subjects who had an 
inadequate response to conventional therapy including corticosteroids and 6-
mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have 
medical contraindications for such therapies. 
Details about specific benefits and risks for subjects participating in this clinical trial 
may be found in the accompanying SmPC and Informed Consent documents. 
5.3 
Dose and Administration Rationale 
Golimumab will be used in this indication according to the SmPC. 
5.4 
Rationale for Future Biomedical Research 
Merck will conduct Future Biomedical Research on plasma specimens collected 
during this clinical trial. Such research is for biomarker testing to address emergent 
questions not described elsewhere in the protocol (as part of the main trial) and will 
only be conducted on specimens from appropriately consented subjects. The 
objective of collecting specimens for Future Biomedical Research is to explore and 
 
 
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identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The details of this Future Biomedical Research sub-trial are 
presented in Appendix 6:  Collection and Management of Specimens for Future 
Biomedical Research.  Additional informational material for institutional review 
boards/ethics committees (IRBs/ERCs) and investigational site staff is provided in 
Appendix 7. 
 
6.0 TRIAL OBJECTIVES 
6.1 
Primary Trial Objectives 
• To evaluate the correlation of serum soluble ST2 levels with endoscopic 
activity (endoscopic Mayo score) at week 6 in moderate to severe UC 
subjects under golimumab treatment.  
• 
To evaluate the correlation of serum soluble ST2 with histological activity 
(Geboes index) at week 6 in moderate to severe UC subjects under 
golimumab treatment. 
6.2 
Secondary Trial Objective(s) 
• To evaluate the correlation of serum soluble ST2 levels with endoscopic 
activity (endoscopic Mayo score) at week 16 in moderate to severe UC 
subjects under golimumab treatment. 
• To evaluate the correlation of serum soluble ST2 levels with histological 
activity (Geboes index) at week 16 in moderate to severe UC subjects under 
golimumab treatment. 
• To correlate serum soluble ST2 levels with fecal calprotectin at week 6 and 
week 16 in moderate to severe UC subjects under golimumab treatment. 
• To correlate serum soluble ST2 with clinical activity (total Mayo score) at 
week 6 and week 16 in moderate to severe UC subjects under golimumab 
treatment. 
• To evaluate the potential of serum soluble ST2 as a predictor of endoscopic 
response (endoscopic Mayo score) to golimumab in moderate to severe UC 
subjects. 
• To evaluate the correlation between serum soluble ST2 levels with 
maintenance of endoscopic response (endoscopic Mayo score) to 
golimumab.  
• To correlate Mayo endoscopic score with UCEIS overall score at week 6 and 
week 16 in moderate to severe UC subjects under golimumab treatment. 
 
 
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6.3 
Exploratory Objective(s) 
• To evaluate the relationships of serum levels of golimumab and the presence 
of anti-golimumab antibodies with clinical, endoscopic, and histological 
activities and with biomarker levels in subjects with moderate to severe UC 
 
7.0 INVESTIGATIONAL AND ANALYSIS PLAN 
7.1 
Overall Trial Design 
This is an exploratory, multi-site, nonrandomized, open label, prospective, 
interventional, single-arm, study to evaluate the correlation of serum soluble ST2 
levels with clinical, endoscopic and histological activity in subjects with moderate to 
severe active UC who received golimumab. During this study, golimumab will be 
used according to the SmPC. 
The overall study design is illustrated in the trial design diagram presented in 
Section 2.1.  Study procedures are outlined by visit in the trial flow chart in Section 
2.2. 
After signing the informed consent, subjects will enter a screening period of up to 42 
days. After confirmation of eligibility criteria, subjects will initiate treatment with 
golimumab according to SmPC (Baseline Visit – V2). Subjects will be followed for a 
period of 16 weeks for clinical assessments and data collection. Biomarker samples 
(ST2 and fecal calprotectin) will be collected at baseline and at all subsequent visits. 
All subjects will be evaluated for clinical, endoscopic (fibrosigmoidoscopy) and 
histologic activity at screening, week 6 and week 16. 
The trial design is appropriate for the indication studied. Validated methods of data 
collection, analysis, and evaluation will be used for the trial. 
The method of assessment of serum soluble ST2 is described in Section 7.6. 
In addition it will be evaluated the correlation between ST2 levels with fecal 
calprotectin, which is currently the best surrogate marker for the presence of 
intestinal inflammation. Fecal calprotectin has been demonstrated to be a sensitive 
and specific marker in identifying intestinal inflammation and response to treatment 
in subjects with IBD.  
The Geboes index is a validated instrument for evaluating histologic disease activity 
in UC (Geboes et al., 2000) - see more detailed information in Section 7.7.2.2. This 
index will be applied at screening, week 6 and week 16 in order to determine if a 
correlation exists between its overall score and serum soluble ST2 levels at the 
respective time points. 
 
 
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Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a 3-item validated tool for 
assessing endoscopic severity of UC (Travis et al., 2011) - see more detailed 
information in Section 7.7.2.2 and Appendix 4. This tool will be applied at screening, 
week 6 and week 16 in order to determine if a correlation exists between its overall 
score and the endoscopic Mayo score at the respective time points. 
 
At this moment, little is known about the benefit of measuring golimumab serum 
concentrations in daily practice. In the pivotal PURSUIT Induction trial, an exposure-
response relationship was observed for the change from baseline in Mayo score and 
rates of clinical response and clinical remission, with patients in the highest serum 
golimumab concentration quartiles having greater improvement in median Mayo 
scores and greater rates of clinical response and clinical remission when compared 
with those in the lower quartiles at week 6 (Sandborn et al., 2014a). A second study, 
also including UC patients from PURSUIT (Sandborn et al., 2016a and Sandborn et 
al., 2016b), assessed golimumab pharmacokinetics and exposure-response 
relationship. It was observed that serum golimumab concentrations are 
approximately dose proportional, and a positive serum golimumab concentration-
efficacy relationship exists during induction/maintenance golimumab treatment of 
adult UC patients (Adedokun et al., 2016). 
On the other hand, the presence of anti-drug antibodies may also be associated with 
low response to anti-TNFs since it is thought that anti-drug antibodies can neutralize 
the therapeutic antibodies or induce their rapid elimination (Vincent et al., 2013)To 
investigate these findings, comparisons of serum golimumab levels and the 
presence of anti-golimumab antibodies with clinical response and remission, 
endoscopic activity, fecal calprotectin and histological activity will be analysed as 
exploratory endpoints.  
Serum golimumab levels and the presence of anti-golimumab antibodies will be 
evaluated at week 6 and week 16 using an ELISA (enzyme-linked immunosorbent 
assay) technique (IDKmonitor® Golimumab drug level ELISA and IDKmonitor® 
golimumab free ADA ELISA, from Immundiagnostik AG, Germany). These analyses 
will be done at the end of the study and will not be available to the investigators 
during subjects’ participation in the study. 
Considering these study aims, there is no justification for including a comparative 
arm. 
7.2 
Beginning and End of the Trial 
Each subject is considered to be enrolled in the trial when he/she (or the subject’s 
legal representative) has provided written informed consent. 
Each subject is considered to have ended participation in the trial when he/she has 
completed the last protocol-specified contact (e.g., visits or telephone contacts) or 
prematurely discontinues from the trial. 
 
 
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A subject is considered to have discontinued after he/she has withdrawn consent or 
has been discontinued under the conditions specified in Section 7.3.3. 
A subject is considered to have been lost to follow-up if he/she is unable to be 
contacted by the investigator. The end of participation for a subject lost to follow-up 
is the last known contact (e.g., visit or telephone contact). 
Subjects may be rescreened one time only, and only for the reason of initially failing 
to meet the Visit 1 inclusion/exclusion criteria related with the severity of the disease.  
 
The overall trial begins when the first subject is enrolled (i.e., signs the informed 
consent form).  The overall trial ends when the last remaining subject has ended 
participation in the trial, by completing the trial, being discontinued from the trial, or 
being lost to follow-up. 
Each subject will be monitored for the occurrence of AEs immediately after he/she 
has signed informed consent and until the last protocol-specified visit. Follow-up 
procedures related to pregnancy or SAEs may continue beyond the end of the 
clinical trial. 
Each subject will participate in the trial for approximately 22 weeks from the time the 
subject signs the Informed Consent Form (ICF) until the final protocol-specified 
contact. After a screening phase of up to 6 weeks each subject will receive 
golimumab (Section 7.4.1.1) for 16 weeks. 
7.3 
Trial Population 
Adult subjects with a diagnosis of moderate to severe active ulcerative colitis who 
have had an inadequate response to conventional therapy including corticosteroids 
and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have 
medical contraindications for such therapies, and are considered candidates to TNF 
inhibitors, will be selected to participate in the trial. 
7.3.1 
Subject Inclusion Criteria 
To be eligible for the study, subjects must meet all of the following criteria: 
1. Are men or women of any race, ≥ 18 and ≤ 65 years of age; 
2. Had UC diagnosed prior to screening, based on results from a biopsy collected 
at an endoscopy procedure; 
3. Have moderate to severe active UC with total Mayo score of 6 to 12, inclusive at 
baseline, AND endoscopic Mayo subscore (fibrosigmoidoscopy), greater than or 
equal to 2; 
4. Regarding prior or current medication for UC:  
 
 
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4.1 Subjects must have responded inadequately to corticosteroids (at least 
40mg) with or without 5-ASA, or subjects must be steroid-dependent 
(unable to reduce steroids below 10mg within 3 months of starting 
steroids and/or have relapsed within 3 months of stopping steroids) 
AND 
4.2 Subjects must have responded inadequately to AZA or 6-MP (must have 
been receiving it for the last 12 weeks) or are intolerant or have medical 
contraindications to these agents 
5. Subjects must be naïve to TNF inhibitors; 
6. Subjects must be eligible to start golimumab treatment according to SmPC; 
7. All subjects must either have had a colonoscopy to assess for the presence of 
adenomatous polyps within 5 years of study inclusion or a colonoscopy to 
assess for the presence of adenomatous polyps at the screening visit. The 
adenomatous polyps must be removed prior to the first administration of 
golimumab; 
8. All subjects who have had extensive colitis for ≥ 8 years, or disease limited to 
the left side of the colon for ≥10 years, must either have had a colonoscopy to 
assess the presence of dysplasia within 1 year prior study inclusion or a 
colonoscopy to assess the presence of malignancy at the screening visit; 
9. The investigator has discussed with the subject the information contained in the 
informed consent regarding anti-TNF therapies and the potential risk of cancer, 
and has reviewed with the subject country-specific guidance (local practice) on 
cancer screening and the impact of life-style choices (e.g., smoking) on the risk 
of developing cancer.  
10.  Have an acceptable Tuberculosis Assessment: 
10.1. Have no history of untreated latent or active tuberculosis (TB) prior to 
screening.  An exception is made for subjects who have a history of latent 
TB and are currently receiving treatment for latent TB, or who will initiate 
treatment for latent TB prior to first administration of study agent, or have 
documentation of having completed appropriate treatment for latent TB 
within 5 years prior to the first administration of study agent.  It is the 
responsibility of the investigator to verify the adequacy of previous anti-
tuberculous treatment and provide appropriate documentation. 
10.2. Have no signs or symptoms suggestive of active TB upon medical history 
and/or physical examination. 
10.3. Have had no recent close contact with a person with active TB or, if there 
has been such contact, will be referred to a physician specializing in TB to 
undergo additional evaluations and receive appropriate treatment for 
latent TB prior to the first administration of study agent. 
 
 
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10.4. Within 2 months prior to study inclusion, have a negative result for 
QuantiFERON-TB Gold test; or have a newly identified positive result for 
QuantiFERON-TB Gold test in which active TB has been ruled out and for 
which appropriate treatment for latent TB has been initiated prior to the 
first administration of study agent.   
• 
The QuantiFERON®-TB Gold test is not required at screening for 
subjects with a history of latent TB and ongoing treatment for latent 
TB or documentation of having completed adequate treatment as 
described above; Subjects with documentation of having completed 
adequate treatment as described above are not required to initiate 
additional treatment for latent TB. 
10.5. Have a chest radiograph (both posterior-anterior and lateral views) within 
3 months prior to study inclusion and read by a qualified radiologist, with 
no evidence of current, active TB or old, inactive TB. 
11. Have negative stool results for enteric pathogens (including Clostridium difficile 
stool culture and toxin assay)  
12. During the study and for 6 months after receiving the last administration of 
golimumab, women of childbearing potential or men capable of fathering 
children must agree to use adequate birth control measures (eg, abstinence, 
oral contraceptives, intrauterine device, barrier method with spermicide, surgical 
sterilization). Women of childbearing potential must test negative for pregnancy 
at screening (V1). 
13. Have screening detailed laboratory test results: 
a. White blood cells 
≥ 2.5 x 103 cells/µL 
(SI: ≥ 2.5 x109 cells/L) 
b. Neutrophils 
≥ 1.5 x 103 cells/µL 
(SI: ≥ 1.5 x109 cells/L) 
c. Platelets 
≥ 100 x 103 cells/µL 
(SI: ≥ 100 x109 cells/L) 
d. Serum creatinine 
≤ 1.5 mg/dL    
(SI: ≤ 133 µmol/L)  
e. Serum ALT and AST levels not exceeding 2 times the ULN  
 
14. Must be able and willing to adhere to the study visit schedule and comply with 
other protocol requirements.  
15. Are capable of providing informed consent, which must be obtained prior to any 
study-related procedures. The subject may also provide consent for Future 
Biomedical Research.  However, the subject may participate in the main trial 
without participating in Future Biomedical Research 
 
 
 
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7.3.2 
Subject Exclusion Criteria 
A subject meeting any of the exclusion criteria listed below must be excluded from 
participating in the trial: 
1. Any contraindication as specified in golimumab’s SmPC, 
2. Have severe extensive colitis as evidenced by: 
a) Investigator judgment that the subject is likely to require a colectomy 
within 12 weeks of baseline (V2). 
OR  
b) Symptom complex at screening (V1) or baseline visit (V2) that includes 
at least 4 of the following:  
I. 
diarrhea with ≥ 6 bowel movements/day with macroscopic blood 
in stool 
II. 
focal severe or rebound abdominal tenderness 
III. 
persistent fever (≥ 37.5°C) 
IV. 
tachycardia (> 90 beats/minute)  
V. 
anemia (hemoglobin < 8.5 g/dL) 
 
3. Presence of symptomatic colonic or small bowel obstruction, confirmed by 
objective radiographic or endoscopic evidence of a stricture with resulting 
obstruction (dilation of the colon or small bowel proximal to the stricture on 
barium radiograph or an inability to traverse the stricture at endoscopy). 
4. History of colonic mucosal dysplasia in flat mucosa. 
5. Presence on screening endoscopy of adenomatous colonic polyps, if not 
removed prior to study entry, or history of adenomatous colonic polyps that were 
not removed.  
Concomitant or previous medical therapies received:  
6. Have ever received biologic therapy targeted at TNFα.  
7. Have received natalizumab within 12 months prior to study inclusion.  
8. Have received agents that deplete B or T cells (e.g., rituximab, alemtuzumab, or 
visilizumab) within 12 months prior to study inclusion, or continue to manifest 
depletion of B or T cells more than 12 months after completion of therapy with 
lymphocyte-depleting agents. 
9. Have received cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil 
(MMF) within 8 weeks prior to study inclusion. .  
 
 
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10. Have a known hypersensitivity to human immunoglobulin proteins or other 
components of golimumab. 
11. Have used any investigational drug within 4 weeks prior to prior to study 
inclusion or within 5 half-lives of the investigational drug, whichever is longer. 
12. Have used apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to study 
inclusion.  
13.  Have rectal corticosteroids or 5–ASA compounds administered to the rectum or 
sigmoid colon via foam or enema or suppository within 2 weeks prior to study 
inclusion.  
Infection or predisposition to infections: 
14. Have a history of latent or active granulomatous infection, histoplasmosis, or 
coccidioidomycosis, prior to screening (for TB refer to inclusion criteria 10). 
15. Have a history of, or ongoing, chronic or recurrent infectious disease, including 
but not limited to, chronic renal infection, chronic chest infection (e.g., 
bronchiectasis), sinusitis, recurrent urinary tract infection (e.g., recurrent 
pyelonephritis, chronic cystitis), an open, draining, or infected skin wound, or an 
ulcer. 
16. Have immune deficiency syndrome (eg, severe combined immunodeficiency 
syndrome [SCIDS], T cell deficiency syndromes, B cell deficiency syndromes, 
and chronic granulomatous disease).  
17. Are known to be infected with HIV, hepatitis B, or hepatitis C.  
18. Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of 
screening.  
19. Have had a nontuberculous mycobacterial infection or opportunistic infection 
(e.g., cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months prior 
to screening.  
20. Have a chest radiograph within 3 months prior to study inclusion that shows an 
abnormality suggestive of a malignancy or current active infection, including TB.  
21. Have received, or are expected to receive, any live virus or bacterial vaccination 
within 3 months prior to study inclusion, or during the study,  
22. Have had a serious infection (e.g., hepatitis, pneumonia, or pyelonephritis), have 
been hospitalized for an infection, or have been treated with parenteral 
antibiotics for an infection within 2 months prior to study inclusion. Less serious 
infections (e.g., acute upper respiratory tract infection, simple urinary tract 
infection) need not be considered exclusionary at the discretion of the 
investigator.  
 
 
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Malignancy or increased potential for malignancy:  
23. Presence or history of any malignancy within 5 years of screening (with 
exception of nonmelanoma skin cancer that has been treated with no evidence 
of recurrence).  
24. Presence or history of lymphoproliferative disease including lymphoma, or signs 
and symptoms suggestive of possible lymphoproliferative disease, such as 
lymphadenopathy of unusual size or location (e.g., nodes in the posterior 
triangle of the neck, infraclavicular, epitrochlear, or periaortic areas), or clinically 
significant hepatomegaly or splenomegaly.   
Coexisting medical conditions or past medical history of: 
25. Concomitant diagnosis or history of chronic heart failure (CHF), including 
medically controlled asymptomatic CHF.  
26. Have signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematologic, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral 
diseases.  
27. History of systemic lupus erythematosus.  
28. Have a transplanted organ (with the exception of a corneal transplant performed 
> 3 months prior to study inclusion).  
29. History of demyelinating disease, such as multiple sclerosis or optic neuritis.  
30. Have or have had a substance abuse (drug or alcohol) problem within the 
previous 3 years.  
31. Are participating in another study with an investigational product or procedure.  
32. Are pregnant, nursing, or planning pregnancy (both men and women) within 6 
months following the last administration of investigational product. 
33. Coexisting medical conditions or medical history of: hypertension, asthma.  
34. The subject or a family member is among the personnel of the investigational or 
sponsor staff directly involved with this trial. 
7.3.3 
Subject Discontinuation Criteria 
A subject may discontinue from the clinical trial at any time for any reason. 
It is the right and the duty of the investigator or sub investigator to stop treatment in 
any case in which emerging effects are of unacceptable risk to the individual subject. 
In addition, the investigator or sub investigator is to stop treatment of any subject 
with unmanageable factors that may interfere significantly with the trial procedures 
and/or the interpretation of results. 
 
 
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Discontinuation is “permanent”: once a subject is discontinued, he/she shall not be 
enrolled again. 
At a minimum, collect the following information when a subject discontinues: 
1. The reason the subject discontinued; 
2. The date of the last dose of test product from the trial; 
3. The date of the last assessment and/or contact.  A follow-up contact 
(telephone or visit) will be arranged as appropriate; 
4. (Serious) Adverse events; 
5. Compliance with the test product administration as specified in this protocol; 
6. Final Assessments: 
7. Every effort should be made to ensure that all procedures and evaluations 
scheduled for the Early Discontinuation visit is performed (Section 2.2, Trial 
Flow Chart). Samples of ST2 and calprotectin will only be collected at the 
Early Discontinuation visit in case the investigator discontinued the subject 
due to golimumab’s lack of efficacy.  
8. Retrieve all investigative product(s) and test articles from the subject. 
A subject must be discontinued from the trial for any of the following reasons: 
1. The subject or legal representative (such as a parent or legal guardian) 
withdraws consent; 
2. The subject shows lack of compliance with the trial or treatment evaluations. 
3. Lost to follow-up 
4. Reaction resulting in bronchospasm with wheezing and/or dyspnea requiring 
ventilatory support, or symptomatic hypotension that occurs following the 
administration of investigational product. 
5. Reaction resulting in myalgia and/or arthralgia with fever and/or rash 
(suggestive of serum sickness and not representative of signs and symptoms 
of other recognized clinical syndromes) occurring 1-14 days after injection of 
investigational product. These may be accompanied by other events including 
pruritus, facial, hand, or lip edema, dysphagia, urticaria, sore throat, and/or 
headache 
6. Opportunistic infection 
7. Malignancy, excluding nonmelanoma skin cancer 
8. Pregnancy, or pregnancy planned within the study period or within 6 months 
after the last study agent administration 
 
 
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9. CHF 
10. Demyelinating disease 
11. Subject is deemed ineligible according to the following TB screening criteria: 
11.1 A diagnosis of active tuberculosis is made 
11.2 A subject receiving treatment for latent TB who discontinues 
prematurely or is non-compliant 
11.3 A subject has symptoms suggestive of active TB 
11.4 A subject with active TB 
12. Initiation of protocol prohibited medications (thalidomide or related agents, 
tacrolimus or sirolimus, investigational products, other immunomodulators 
biologic agents: anakinra, rituximab, natalizumab, vedolizumab, etanercept, 
adalimumab, infliximab) 
 
7.3.3.1 
Withdrawal From Future Biomedical Research  
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any 
time by writing to the principal investigator for the main trial.  If medical records for 
the main trial are still available, the Investigator will contact the Sponsor using the 
designated mailbox 
, and a form will 
be provided by the Sponsor to obtain appropriate information to complete specimen 
withdrawal.  Subsequently, the subject's specimens will be removed from the bio 
repository and be destroyed.  A letter will be sent from the Sponsor to the 
investigator confirming the destruction. It is the responsibility of the Investigator to 
inform the subject of completion of destruction.  Any analyses in progress at the time 
of request for destruction or already performed prior to the request being received by 
the Sponsor will continue to be used as part of the overall research trial data and 
results.   No new analyses would be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (e.g., if 
the investigator is no longer required by regulatory agencies to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer 
be a link between the subject’s personal information and their specimens.  In this 
situation, the request for specimen destruction cannot be processed.   
 
 
 
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7.3.4 
Replacement of Subjects 
A subject who discontinues from the study without performing at least one valid post 
baseline assessment for the primary endpoint correlating ST2 with endoscopic 
activity may be replaced at the discretion of the sponsor. 
7.4 
Treatments 
7.4.1 
Trial Treatments 
Golimumab (Simponi; CNTO-148) is a high affinity, fully humanised monoclonal 
antibody, directed against tumour necrosis factor-α (TNF-α). Golimumab inhibits the 
interaction between TNF-α and the p55 and p75 cell surface receptors, neutralising 
its biological effects. 
Golimumab has been shown to be effective to treat moderate to severe UC 
(Sandborn et al., 2014ab). 
The treatment with golimumab will follow the SmPC. 
7.4.1.1 
Treatments Administered 
The first dose of subcutaneous (sc) golimumab will be administered at the trial site at 
Visit 2 (Day 1). Subsequent dosing will be done by the subject (i.e., unsupervised at 
his/her home) at week 2 and every 4 weeks thereafter (approximately the same time 
as the first administration), according to SmPC. 
7.4.1.2 
Method of Treatment Assignment, Randomization, and/or 
Stratification 
This is a single-arm study. No stratification based on age, sex, or other 
characteristics will be performed. 
7.4.1.3 
Selection and Timing of Dose for Each Subject 
7.4.1.3.1 
Selecting the Dose for Each Subject 
The rationale for the selection of induction and maintenance doses to be used in this 
trial is presented in golimumab’s SmPC. 
 
 
 
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7.4.1.3.2 
Determining the Timing of Dose Administration for Each Subject 
The rationale for the selection of timings of doses to be used in this trial is presented 
in golimumab’s SmPC.  
7.4.1.4 
Blinding Trial Treatments 
This will be an open label trial. 
7.4.1.5 
Investigational Medicinal Product 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, handling, storage, distribution, 
and usage of these materials in accordance with the protocol and any applicable 
laws and regulations. 
7.4.1.5.1 
Identity of Investigational Medicinal Product 
The Investigational Medicinal Product to be used in this trial is as follows: 
• Golimumab 50mg/0.5 mL in a single-use, ready-to-use autoinjector 
7.4.1.5.2 
Source 
The sponsor will provide the investigational medicinal product as described above in 
Section 7.4.1.5.1. 
7.4.1.5.3 
Labelling 
The carton containing the pre-filled pen autoinjector will be labeled in accordance 
with local regulations.  
7.4.1.5.4 
Packaging 
Each clinical supply device will be packaged into a medication kit. 
7.4.1.5.5 
Storage 
Trial treatment supplies must be stored in a secure, limited-access location under 
the storage conditions specified on the supply label.  Site storage conditions should 
be monitored by the site personnel for adherence to label specifications and 
reviewed during site visits. 
 
 
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7.4.1.5.6 
Dispensing 
The investigator or qualified designee(s) will dispense trial treatments at the 
designated site(s) to subjects who have provided written informed consent and have 
met the entry criteria. Clinical supplies may not be used for any purpose other than 
that which is stated in this protocol. 
See the Trial Flow Chart in Section 2.2 for a schedule of when clinical supplies are 
to be dispensed to the subjects. First administration of golimumab will be performed 
at the trial site during Baseline (V2), under supervision of the investigator or qualified 
designee(s). At this visit golimumab will dispensed to the subject, for self-injection 
two weeks after the first administration. At week 6 (V3) golimumab will be dispensed 
in order to be administrated at the day of this visit and at weeks 10 and 14, 
according to SmPC. Each subject will be instructed by the investigator or designee 
to return all unused and partially used investigational product to the site at week 6 
(V3) and week 16 (V4). After study completion, and if physician finds it beneficial to 
the subject, golimumab will continue to be dispensed according to SmPC. 
 
7.4.1.5.7 
Replacement of Investigational Product 
Clinical supplies provided by the sponsor will be replaced, where required. 
Provisions that govern this activity extend to clinical supplies that have short 
expiration dating, and/or inadequate inventory levels. The sponsor and investigator 
should monitor the clinical supplies for adequate inventory levels and/or expiration 
date. 
 
7.4.1.5.8 
Investigational Medicinal Product Accountability 
Accurate and current accounting of the dispensing and return of investigational 
product will be maintained on an ongoing basis by a member of the trial site staff: 
• Investigational medicinal product dispensed to each site will be recorded in 
the trial-specific Site Investigational Medicinal Product (IMP) Accountability 
Log (or equivalent document approved by the sponsor); 
• Investigational medicinal product dispensed to each subject will be recorded 
in the trial-specific Subject IMP Accountability Log (or equivalent document 
approved by the sponsor). 
The Site IMP Accountability Log and Subject IMP Accountability Log will be verified 
by the sponsor's trial monitor. The original Site IMP Accountability Log and Subject 
IMP Accountability Log will be approved by the investigator and retained at the trial 
site and a copy supplied to the sponsor when the trial is complete. 
 
 
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Each subject will be instructed by the investigator or designee to return all unused 
and partially used test articles to the site at all protocol-specified visits. 
The sponsor’s trial monitor will instruct the site on the return of all investigational 
product(s) supplies.  A final inventory of the total amount of investigational product(s) 
received at each trial site against the amount used and returned must be recorded in 
the Site IMP Accountability Log.  Inventory records must be readily available for 
inspection by the trial monitor and/or auditor, and open to government inspection at 
any time. 
7.4.2 
Non-Trial Treatments 
7.4.2.1 
Prior and Concomitant Medications 
7.4.2.1.1 
Medications, Supplements, and Other Substances Prohibited 
Prior to Screening and During the Trial 
The subject must not take the treatments listed in table 1 during the trial after the 
Screening visit (V1). 
 
Table 1 Medications, Supplements, and Other Substances Prohibited During the Trial 
Protocol No. MK 8259-022-03 
Topical 5-ASA and topical corticoids  
Thalidomide or related agents, investigational products 
Tacrolimus or sirolimus 
Other immunomodulators biologic agents: anakinra, rituximab, natalizumab, 
vedolizumab, etanercept, adalimumab, infliximab tacrolimus or sirolimus 
 
The medications, supplements, and other substances prohibited prior to Screening 
are listed in Section 7.3.2 with the subject exclusion criteria. 
 
 
7.4.2.1.2 
Concomitant Medications, Supplements, and Other Substances 
Allowed During the Trial 
The following medications, supplements, and other substances are allowed during 
the trial: 
 
 
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Table 2 Medications, Supplements, and Other Substances Allowed During the Trial 
Protocol No. MK 8259-022-03 
Oral 5-ASA: Dose must be maintained throughout the study according to clinical 
practice 
AZA or 6-MP 
Oral Corticosteroids - Subjects in clinical response to golimumab who were 
receiving oral corticosteroids should begin tapering the daily dose of corticosteroids 
by 5mg per week after 6 week. In case of clinical relapse  corticosteroids can be re-
initiated or the dose increased 
 
Note that the use of any concomitant medication must relate to the documented 
medical history, prophylaxis, or an adverse event of the subject. 
7.4.2.2 
Other Treatments 
None. 
7.4.3 
Procedures for Monitoring Subject Compliance With Administration of 
Trial Treatments 
At all protocol-specified visits, the investigator or qualified designee is to record 
whether treatment had been taken per protocol in the preceding interval.  If not, the 
date(s) and reason for each dosing noncompliance must be recorded. 
A diary will be dispensed to the subject at Baseline (V2), with the expected dates for 
next golimumab administrations provided by the investigator or designee. In this 
diary the subject will record/confirm the date of golimumab administration. The 
subject should be instructed to return the diary at each study visit for investigator or 
designee to check compliance with defined administrations.  
7.5 
Trial Schedule 
The visit-by-visit schedule of trial activities is provided in the Trial Flow Chart in 
Section 2.2. 
The timing of each visit is relative to Day 1, which is defined as the baseline and 
corresponds to the administration of the first dose of trial medication, Visit 2 
(Section 7.4.1.1). 
All visits should be performed within the windows specified in Section 2.2 (Trial Flow 
Chart). Every attempt should be made to have each subject attend each visit as 
scheduled. However, if a subject is unable to attend a visit within the specified 
 
 
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windows, the visit should be scheduled as closely as possible to these windows. A 
subject should not miss a protocol-specified visit due to scheduling difficulties. 
7.6 
Trial Procedures 
The Trial Flow Chart in Section 2.2 summarizes the trial procedures to be 
performed at each visit. Individual trial procedures are described below. 
In order to minimize variability of evaluations, it is preferred that the same individuals 
perform the same types of evaluations for all subjects at each trial site. 
1. Explain Trial and Obtain Written Informed Consent 
The investigator or qualified designee will explain the trial to the subject, 
answer all of his/her questions, and obtain written informed consent before 
performing any trial-related procedure.  A copy of the informed consent will be 
given to the subject (see Section 9.1.2 for further description of the Informed 
Consent). 
2. Consent and Collection of Specimens for Future Biomedical Research 
The investigator or qualified designee will explain the Future Biomedical 
Research consent to the subject, answer all of his/her questions, and obtain 
written informed consent before performing any procedure related to the 
Future Biomedical Research sub-trial.  A copy of the informed consent will be 
given to the subject.  
3. Issue or Collect Subject Identification Card 
The investigator or qualified designee will provide the subject with a Subject 
Identification Card after the subject provides written informed consent. The 
investigator or qualified designee will retrieve the card from the subject at the 
last contact (see Section 9.1.3 for further description of the Subject 
Identification Card). 
4. Obtain Demography and Medical History 
Demographic information and medical history will be obtained by the 
investigator or qualified designee.   
5. Review Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria will be reviewed by the investigator or 
qualified designee to ensure that the subject qualifies for the trial. 
6. Review Prior Medications 
Review of appropriate prior medications, including the necessary washout 
times, with the subject. A record of prior medication taken by the subject 
within 6 months before starting the trial is to be obtained. 
 
 
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7. Record Concomitant Medications 
A record of medication taken by the subject during the trial is to be obtained. 
8. Record (Serious) Adverse Events 
See Section 7.7.2.4, for instructions on the assessment and reporting of 
(Serious) Adverse Events and Section 7.7.2.5 for instructions on the 
reporting of (Serious) Adverse Events to the sponsor. 
9. Physical Examination 
A partial physical examination will be performed. Ulcerative colitis clinical 
activity will be assessed by partial Mayo score and Montreal classification 
(Silverberg et al., 2005) of extent of ulcerative colitis performed at every study 
visit. If the subject is discontinued for any reason during the treatment phase, 
every attempt should be made to perform a final physical examination. 
10. Sigmoidoscopies  
Fibrosigmoidoscopies will be performed at the visits indicated in the study 
Flowchart. The subject preparation for the exam should be done only with 
water. Endoscopic activity will be assessed by Endoscopic Mayo score and 
UCEIS index at every study visit indicated. 
11. Histology  
Four biopsies will be collected from distinct areas (2 rectum and 2 sigmoid) 
from each subject at every study visit indicated. The samples will be prepared 
and sent to Central Laboratory. The formalin fixed and Hematoxylin & Eosin-
stained specimens will be assessed according to the Geboes index (Geboes 
et al., 2000) – see Appendix 5 
12. Pregnancy Assessment 
Assess whether a subject is pregnant with a medically acceptable test (Serum 
Pregnancy Test - Beta-hCG at Screening visit and urine hCG at visits 3 and 
4). 
13. Tuberculosis Evaluation 
For this protocol, a chest X-ray and QuantiFERON-TB Gold test are 
mandatory. All subjects must at least perform a postero-anterior and lateral 
chest x-rays (unless a chest x-ray has been performed within 3 months prior 
to study inclusion), and QuantiFERON-TB Gold test (unless performed within 
two months of study inclusion).  
If not available within 2 months prior to study inclusion, latent TB must be 
evaluated at screening by specialized, trained, and licensed personnel, either 
at the participating trial site or at an external unit (e.g. Lung Disease 
Diagnostic Centers (CDPs)), as according to local guidelines. When this 
 
 
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evaluation is performed at any site other than the investigator’s facility, the 
results must be made available in written form as source documentation.  
If TB is suspected at any time during the study, chest x-ray and 
QuantiFERON-TB Gold test should be performed and latent TB must be re-
evaluated. 
 
14. Laboratory Tests 
• Laboratory tests for hematology, blood chemistry, and urinalysis are 
specified in Table 3. Blood samples for laboratory tests are to be taken 
prior to investigational product(s) administration. If judged necessary by 
investigator, laboratory tests may be repeated during Screening period, 
and results should be obtained prior to first administration of 
investigational product. 
• CRP is a useful marker of inflammation in patients with IBD. CRP will be 
assayed using a validated, high sensitivity CRP assay. Serum CRP 
evaluation will be done at the visits indicated. 
• Levels of serum soluble ST2 (human Suppression of Tumorigenicity 2).   
Serum ST2 evaluation will be done at the visits indicated and analysed by 
a central laboratory.  
• Levels of serum golimumab and the presence of anti-golimumab 
antibodies will be evaluated at the visits indicated and analysed by a 
central laboratory.  
• Stools collection for culture and Clostridium difficile assay for toxin must 
be performed at screening visit (local laboratory) or in the case of episode 
exacerbation as long as taken during the last 4 months prior study 
inclusion. 
• Stools collection for fecal calprotectin assessments should be performed 
at the same timings of ST2, according to the study flowchart. Calprotectin 
will be done at the visits indicated and analysed by a central laboratory.  
• Plasma for Future Biomedical Research will be collected pre-dose at 
Baseline/Day 1 and Week 16 (or Early Discontinuation) from subjects who 
consent to Future Biomedical Research. See Appendix 6 for further 
information concerning Future Biomedical Research. 
 
 
 
 
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Table 3 Laboratory Tests 
Protocol No. MK-8259-022-03 
Hematology 
Chemistry 
Faeces 
Basophils 
Albumin 
calprotectin 
Eosinophils 
Alkaline phosphatase 
Culture and Clostridium difficile 
assay for toxin, if applicable 
Hematocrit 
ALT (SGPT) 
 
Hemoglobin 
AST (SGOT) 
 
Lymphocytes 
Calcium 
 
Monocytes 
Chloride 
 
Neutrophils 
Creatinine 
 
Platelets 
Phosphate 
 
RBC 
Potassium 
 
WBC 
CRP  
 
Golimumab 
levels 
Sodium 
 
Anti-golimumab 
antibodies 
Serum ST2 
 
 
Total Bilirubin 
 
 
Total protein 
 
 
Urea 
 
 
Urinalysis (proteins, glucose, 
nitrates, WBC, ketone bodies, 
hemoglobin, urobilinogen, bilirubin) 
 
 
Serum Pregnancy Test - Beta-hCG 
 
 
15. Dispensing Diary Card 
Each subject will be provided with a diary card to collect the date of each 
Golimumab administration. This information will be recorded in the card by the 
subject for all Golimumab doses administered out-of-site, or also by site 
personnel when Golimumab is administered at the site. The subject must 
bring his/her diary card at all trial visits. At each visit, the site will collect the 
diary card, record the new information in the CRF, and return the card to the 
subject. Subjects will be instructed to return the completed card in their final 
visit. 
 
 
 
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7.7 
Assessments 
7.7.1 
Efficacy Assessments 
7.7.1.1 
Coprimary Efficacy Endpoint(s) 
There are no efficacy-related endpoints in this study. 
 
7.7.1.2 
Secondary Efficacy Endpoint(s) 
There are no efficacy-related endpoints in this study. 
 
7.7.2 
Safety Monitoring and Assessments 
7.7.2.1 
Safety Endpoints 
There are no safety-related endpoints in this study. 
Hematology and blood chemistry assessments will be performed according to the 
study schedule of events (Section 2.2).  
Hematology assessments in this study include: basophils, eosinophils, hematocrit, 
hemoglobin, lymphocytes, monocytes, neutrophils, platelets, RBC, WBC. 
Blood chemistry assessments in this study include: total bilirubin, ALT, AST, alkaline 
phosphatase, albumin, total protein, calcium, phosphate, sodium, potassium, 
chloride, urea and creatinine), CRP. 
7.7.2.2 
Definition of Terms 
• Moderate to severe active UC is defined in this study as a total Mayo score of 
6 to 12, inclusive. 
• The total Mayo Score, is a scale for assessing UC activity, it is the sum of 4 
subscores and has values that range from 0 to 12. It includes assessment of 
Stool frequency (0–3) + Rectal bleeding (0–3) + Physician’s global 
assessment (0–3) + Findings of endoscopy (0–3). Clinical remission: ≤2 
points with no individual subscore > 1 ; Mildly active disease: 3-5 points; 
Moderately active disease: 6-10 points; Severely active disease: 11-12 points 
• Endoscopic Mayo score (0-3): 0 = Normal or inactive disease, 1 = Mild 
disease (erythema, decreased vascular pattern, mild friability); 2 = Moderate 
disease (marked erythema, absent vascular pattern, friability, erosions); 3 = 
Severe disease (spontaneous bleeding, ulceration) - See Appendix 3.  
 
 
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• Partial Mayo score: Mayo score excluding the endoscopy subscore and has 
values that range from 0 to 9. 
• Mucosal healing in this study will be determined by the endoscopy subscore 
of the Mayo score. Mucosal healing corresponds to endoscopy subscore of 0 
or 1. 
• Geboes index, is a validated score for evaluating histologic disease activity in 
UC as follows: grade 0, structural and architectural changes; grade 1, chronic 
inflammatory infiltrate; grade 2, lamina propria neutrophils and eosinophils; 
grade 3, neutrophils in the epithelium; grade 4, crypt destruction; grade 5, 
erosions or ulceration ; a higher score indicating more severe disease. Active 
histologic disease can be defined as a Geboes score ≥3.1 (presence of 
epithelial neutrophils with or without crypt destruction or erosions) (Geboes et 
al., 2000). - See Appendix 5 
• Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a 3-item (vascular 
pattern, bleeding and erosion/ulceration) validated tool for assessing 
endoscopic severity of UC. Each item with three or four levels of severity, 
yielding a 9-point scale that accounts for 94% of the variance between 
observers in the overall assessment of severity (Travis et al., 2011) - See 
Appendix 4 
• Clinical response is defined as a reduction in the Mayo score of at least 3 
points and a decrease of at least 30% from the baseline score, accompanied 
by a decrease of at least 1 point in the rectal bleeding scale or an absolute 
rectal bleeding score of 0 or 1.  
• Clinical remission is defined as Mayo score ≤ 2, with no individual subscore 
exceeding 1. 
 
7.7.2.2.1 
Adverse Event 
Per the International Conference on Harmonization (ICH), an adverse event (AE) is 
defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to this medicinal product. 
 
 
 
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7.7.2.2.2 
Serious Adverse Event 
Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at 
any dose: 
Results in death; 
Is life-threatening;  
Requires hospitalization or prolongation of existing inpatients’ hospitalization; 
Results in persistent or significant disability or incapacity; and/or 
Is a congenital anomaly or birth defect; 
Is a cancer; 
Is associated with an overdose; 
Is an Other Important Medical Event. 
 
Life-threatening in the definition of a serious adverse event refers to an event in 
which the subject was at risk of death at the time of event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an adverse 
event/reaction is serious in other situations.  Important adverse events/ reactions 
that are not immediately life-threatening or do not result in death or hospitalization, 
but may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious.  
These are considered “Other Important Medical Events”. 
7.7.2.2.3 
Events of Clinical Interest 
An "Event of Clinical Interest" is a non-serious adverse event or occurrence that is 
designated to be of special interest and must be reported to the sponsor as though it 
were a serious adverse event – as described in Section 7.7.2.5.1. 
The following events are considered events of clinical interest for this trial: 
 
 
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1. An overdose of Sponsor's product, as defined in Section 7.7.2.2.4, Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results is 
to be reported as a non-serious ECI, using the terminology "accidental or 
intentional overdose without adverse effect.” 
2. An elevated AST or ALT lab value that is ≥3 x the upper limit of normal (ULN) 
and an elevated total bilirubin lab value that is ≥2 x ULN and, at the same 
time, an alkaline phosphatase lab value that <2 x ULN, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing is to 
be reported as a non-serious ECI. 
Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology. 
3. Infections (including serious infections: sepsis, TB (frequently disseminated or 
extrapulmonary), invasive fungal and opportunistic infections) 
4. Demyelinating disorders 
5. Lymphoma 
6. HBV reactivation 
7. CHF 
8. Autoimmune processes (lupus-like syndrome) 
9. Hypersensitivity reactions 
10. Immunogenicity 
 
7.7.2.2.4 
Overdose 
An overdose is a significant variation above the recommended/scheduled dosage for 
a product. In this current trial an overdose of the investigational product golimumab 
is any dose higher than the dose specified in Section 7.4.1.1 of this protocol. 
 
7.7.2.2.5 
Clinical Supply Complaint 
A clinical supply complaint is defined as any communication concerning 
manufacturing, packaging, labelling or distribution (including adverse storage at 
depots) of a clinical supply that describes a potential defect related to its identity, 
strength, quality or purity after it is released and left the control of a Merck-approved 
packaging facility for distribution.  A clinical supply GCP inquiry is defined as any 
 
 
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communication of an event taking place at a trial site after the product was 
satisfactorily received at the trial site, which puts product disposition in question.  
Examples include adverse storage of product at the trial site and dosing past 
expiration.  Alleged Counterfeit, Diversion and Tampering (CDT), adverse events 
and trial site errors/issues which do not put product disposition in question should 
not be reported. 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution 
and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations. This responsibility includes reporting of all clinical 
supply complaints and/or clinical supply GCP inquiries to the Sponsor. 
Clinical supplies complaints and GCP inquiries, as defined above, must be reported 
to the Sponsor within 1 business day of first becoming aware of the issue. Sponsor 
Contact information and related reporting details can be found in the Investigator 
Trial File Binder. 
 
7.7.2.2.6 
Incident 
A device-related incident is any product complaint that led to or might have led to 
death or serious deterioration of health/serious injury/serious illness for the user of 
the product or any other person. 
 
7.7.2.3 
Monitoring 
7.7.2.3.1 
Monitoring Adverse Events 
Each subject will be monitored for the occurrence of AEs immediately after the 
subject has signed informed consent through after the last protocol-specified visit as 
described in Section 7.2. 
Subjects will be questioned and/or examined by the investigator or a qualified 
designee for evidence of AEs. The questioning of subjects with regard to the 
possible occurrence of adverse events will be generalized such as, "How have you 
been feeling since your last visit?” The presence or absence of specific AEs should 
not be elicited from subjects. 
Subjects having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the investigator. 
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the 
Case Report Forms (Section 9.2.1), as well as in the subject's source 
documentation. Follow-up laboratory results should be filed with the subject's source 
documentation. 
 
 
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For all AEs that require the subject to be discontinued from the trial and SAEs, 
relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate, until final resolution or stabilization of the event(s). 
 
7.7.2.3.2 
Monitoring Laboratory Assessments 
Serum ST2, fecal calprotectin, serum golimumab levels and anti-golimumab 
antibodies assessments will be performed by a certified central laboratory selected 
by the sponsor.   
Histological assessment will be performed at a certified laboratory selected by the 
sponsor. 
The routine laboratory tests (hematology, chemistry) will be performed at local 
certified hospital laboratory in each center. 
The routine laboratory tests (hematology, chemistry) and histological assessment 
will be reported to the investigator by the laboratories and he/she will review them for 
significance and consideration as an AE. 
Serum ST2 and fecal calprotectin assessments will not be provided to the 
investigator during the clinical trial. 
 
7.7.2.4 
Assessment of Adverse Events 
7.7.2.4.1 
Assessment of Severity 
Where the determination of adverse event severity rests on medical judgment, the 
determination of severity must be made with the appropriate involvement of a 
medically-qualified investigator. 
The severity of AEs will be graded according to the following definitions: 
 
Mild: 
awareness of sign, symptom, or event, but easily tolerated; 
Moderate: 
discomfort enough to cause interference with usual activity and 
may warrant intervention; 
Severe: 
incapacitating with inability to do normal daily living activities or 
significantly affects clinical status, and warrants intervention; 
 
 
 
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7.7.2.4.2 
Assessment of Causality 
A medically-qualified investigator must assess the relationship of any AE (including 
SAEs) to the use of the investigational product using the guidelines listed below: 
• Yes, there is reasonable possibility of drug relationship.  There is evidence of 
exposure to test drug.  The temporal sequence of the AE onset relative to the 
administration of the test drug is reasonable.  The AE is more likely explained by 
the test drug than by another cause. 
• No, there is not a reasonable possibility of drug relationship.  Subject did not 
receive the test drug OR temporal sequence of the AE onset relative to 
administration of the test drug is not reasonable OR there is another obvious 
cause of the AE.  (Also entered for a subject with overdose without an associated 
AE.) 
 
7.7.2.4.3 
Reference Safety Information (RSI) for the Assessment of 
Expectedness of Adverse Events 
The Reference Safety Information (RSI) for assessing the expectedness of an 
adverse event for the investigational product in this current trial is to be the most 
recent SmPC. 
 
7.7.2.4.4 
Known Potential Toxicities of Investigational Products 
The following observations are known potential toxicities of the investigational 
product golimumab: 
1. Infections (including serious infections: sepsis, TB (frequently disseminated or 
extrapulmonary), invasive fungal and opportunistic infections) 
2. Demyelinating disorders 
3. Lymphoma 
4. HBV reactivation 
5. CHF 
6. Autoimmune processes (lupus-like syndrome) 
7. Hematologic reactions 
8. Hypersensitivity reactions 
9. Immunogenicity 
 
 
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Refer to the approved labelling for additional information on AEs related to toxicities 
observed to date. 
 
7.7.2.4.5 
Known Adverse Events Relating to the Underlying Clinical 
Condition 
Some common AEs associated with ulcerative colitis include: 
1. ulcerative colitis 
2. abdominal pain 
3. hematochezia 
4. diarrhoea 
 
7.7.2.5 
Reporting Safety Observations by the Investigator to the Sponsor 
7.7.2.5.1 
Expedited Reporting of Safety Observations by the Investigator to 
the Sponsor 
Any occurrence of the following events or outcomes in a subject in the trial must be 
reported by the investigator or qualified designee to the sponsor – either by 
electronic media or paper – within 24 hours of learning of the event. 
1. SAE (including SAEs associated with pregnancy or exposure during pregnancy 
or lactation – including the pregnancy of a male subject’s female partner who has 
provided written informed consent to provide information regarding pregnancy); 
2. Events of clinical interest; 
3. Incidents associated with the device. 
 
If the investigator is unsure about when to report an observation from the lists above, 
the event or outcome should be reported to the sponsor or designee. 
Any observation reported to the sponsor or designee that is also an AE, is to be 
recorded in the eCRF (Section 9.2), as well as in the subject's source 
documentation, along with any actions taken as a result of AE and follow-up results. 
If an autopsy is performed, available results should be provided to the sponsor. 
The investigator must assess causality of the event as relative to the investigational 
product administered in the trial as described in Section 7.7.2.4.2. 
 
 
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There will be a follow-up from the Sponsor to the Investigator for all malignancies 
occurring in patients 30 years of age or younger. This will be done via a dedicated 
Malignancy Follow-up Questionnaire, which needs to be completed by the 
Investigator(s) and submitted to the Sponsor within 2 weeks of receipt via a 
designated fax number. The Investigator must make at least 2 attempts to contact 
the patient or guardian to complete the Malignancy Follow -up Questionnaire. If the 
attempts are not successful, the reason for each unsuccessful attempt must be 
documented (e.g., patient lost-to-follow-up, patient refuses to supply the additional 
information, etc.). 
The Sponsor will review the study AE database for possible premalignant conditions 
twice a year, occurring in patients 30 years of age or younger. If any are reported, 
the Sponsor will contact the Investigator with a dedicated follow-up request that 
needs to be completed. In case a pre-malignant condition has progressed to a 
malignancy, the Investigator will need to complete the Malignancy Follow-Up 
Questionnaire. 
 
7.7.2.5.2 
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority 
Global Safety will monitor data for safety.  The Sponsor will manage the expedited 
reporting of relevant safety information to concerned health authorities, competent 
authorities, and IRBs/IECs in accordance with local laws and regulations. 
7.7.2.6 
Discontinuation, Treatment Interruption, and Unblinding of Blinded 
Treatment Due to Safety Observations 
7.7.2.6.1 
Discontinuation 
See Section 7.3.3 for the criteria by which a subject must be discontinued.  Should 
a subject be discontinued from the trial, complete the visit activities as specified for 
discontinuation in the Trial Flow Chart in Section 2.2. 
 
7.7.2.6.2 
Temporary Interruption of Treatment for a Subject 
A Subject may not temporarily interrupt and then restart treatment.  The investigator 
is to discontinue a subject as necessary according to the criteria provided in 
Section 7.3.3. 
 
 
 
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7.7.2.6.3 
Modification of Dose and/or Administration of Investigational 
Product for a Subject 
The dose and administration to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 7.3.3.  
 
7.7.2.6.4 
Unblinding Treatment for a Subject During the Trial 
No treatments in this current trial are blinded. 
 
7.7.3 
Other Endpoints 
7.7.3.1 
Primary endpoints  
• To correlate serum soluble ST2 levels with endoscopic activity of disease 
(assessed by endoscopy subscore of Mayo score) at week 6 in moderate to 
severe UC subjects under golimumab treatment.  
• To correlate serum soluble ST2 levels with histological activity (assessed by 
Geboes index) at week 6 in moderate to severe UC subjects under 
golimumab treatment. 
 
See Section 7.7.2.2 for the definition of endoscopic and histological activity of 
disease.   
 
7.7.3.2 
Secondary endpoints  
• To correlate serum soluble ST2 levels with endoscopic activity (assessed by 
endoscopy subscore of Mayo score) at week 16 in moderate to severe UC 
subjects under golimumab treatment. 
• To correlate serum soluble ST2 levels with histological activity (assessed by 
Geboes index) at week 16 in moderate to severe UC subjects under 
golimumab treatment. 
• To correlate serum soluble ST2 levels with fecal calprotectin levels at week 6 
and week 16. 
• To correlate serum soluble ST2 levels with clinical activity (assessed by total 
Mayo score) at week 6 and week 16. 
 
 
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• To evaluate the potential of serum soluble ST2 as a predictor of endoscopic 
response to golimumab by comparing Mayo endoscopic activity (activity 
[subscore ≥ 2] or no activity [subscore 0 or 1]) with ST2 at baseline and 
change of ST2 between baseline and Week 6.  
• To correlate serum soluble ST2 levels with maintenance of endoscopic 
response to golimumab by comparing subjects who achieved endoscopic 
response at week 6 [subscore 0 or 1] and maintained through week 16 versus 
subjects who did not maintain response throughout the same period, 
regarding serum soluble ST2 at baseline, week 6 and change between 
baseline and week 6. 
• To correlate Mayo endoscopic score with UCEIS overall score at week 6 and 
week 16 in moderate to severe UC subjects under golimumab treatment. 
 
7.7.3.3 
Exploratory endpoints  
• To compare serum golimumab levels with clinical activity (total Mayo score) at 
weeks 6 and 16. 
• To compare serum golimumab levels in subjects with endoscopic active 
disease (total Mayo score >2) and subjects with inactive disease (total Mayo 
score ≤2 points with no individual subscore >1) at week 6 and 16. 
• To compare the presence of anti-golimumab antibodies (+ or -) and clinical 
activity (total Mayo score) at weeks 6 and 16. 
• To compare the presence of anti-golimumab antibodies in subjects with 
endoscopic active disease (total Mayo score >2) and subjects with inactive 
disease (total Mayo score ≤2 points with no individual subscore >1) at week 6 
and 16. 
• To compare serum golimumab levels with endoscopic activity (endoscopic 
Mayo score) at weeks 6 and 16. 
• To compare the presence of anti-golimumab antibodies (+ or -) and 
endoscopic activity (endoscopic Mayo score) at weeks 6 and 16.  
• To compare serum golimumab levels with faecal calprotectin at weeks 6 and 
16. 
• To compare the presence of anti-golimumab antibodies (+ or -) and faecal 
calprotectin at weeks 6 and 16. 
• To compare  serum golimumab levels with histological activity (Geboes index) 
at weeks 6 and 16. 
• To compare the presence of anti-golimumab antibodies (+ or -) and 
histological activity (Geboes index) at weeks 6 and 16. 
 
 
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• To compare quartile serum golimumab levels with rates of clinical response 
and clinical remission  
• To compare serum golimumab levels between subjects who achieved 
response at week 6 and subjects who did not. 
• To compare serum golimumab levels among subjects who achieved response 
at week 16 and subjects who did not. 
• To compare the presence of anti-golimumab antibodies among subjects who 
achieved response at week 6 and subjects who did not. 
• To compare the presence of anti-golimumab antibodies who achieved 
response at week 16 and subjects who did not. 
• To compare serum golimumab levels between subjects who achieved 
remission at week 6 and subjects who did not. 
• To compare serum golimumab levels among subjects who achieved 
remission at week 16 and subjects who did not. 
• To compare the presence of anti-golimumab antibodies among subjects who 
achieved remission at week 6 and subjects who did not. 
• To compare the presence of anti-golimumab antibodies who achieved 
remission at week 16 and subjects who did not. 
 
See Section 7.7.2.2 for the definitions of interest. 
 
7.8 
Criteria for Early Termination of the Trial 
There are no pre-specified criteria for terminating the trial early. 
In addition, further recruitment in the trial or at (a) particular site(s) may be stopped 
due to insufficient compliance with the protocol, GCP and/or other applicable 
regulatory 
requirements, 
procedure-related 
problems, 
or 
the 
number 
of 
discontinuations for administrative reasons is too high. 
 
8.0 STATISTICAL AND ANALYTICAL PLAN 
All quantitative variables will be summarize through descriptive statistics namely 
mean, median, standard deviation and range (minimum and maximum) and 
qualitative variables though absolute (n) and relative frequencies (%) and 95% 
confidence intervals (if applicable). The statistical analysis will be performed through 
frequency tables for qualitative variables and tables with descriptive statistics for 
quantitative variables.  
 
 
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The association between two quantitative variables will be performed through 
Pearson correlation coefficient or Spearman correlation coefficient, in case the 
normality assumption was not verified. 
The association of two categorical variables will be tested through the Chi-Square 
test or Fisher Exact test (if applicable). Cohen's kappa coefficient will be performed. 
The comparison of two independent samples in respect to quantitative variables will 
be performed through t-test for independent samples or the Mann-Whitney non-
parametric test, according to the assumption validations of the statistical test. 
ROC curve analysis will be performed as well as sensitivity, specificity, and positive 
and negative predictive values. 
The primary analysis is to investigate the correlation between serum soluble ST2 
and: 
• endoscopic activity of disease (measured by Endoscopy Mayo subscore) at 6 
weeks in UC subjects receiving golimumab, through the Spearman correlation 
coefficient;  
• histological activity (measured by Geboes index score) at 6 weeks in UC 
subjects receiving golimumab, through the Spearman correlation coefficient. 
 
Additionally, it will be obtained the cut-off of serum soluble ST2 levels at week 6 that 
optimizes sensitivity and specificity in the identification of disease activity through 
ROC curve analysis supplemented with analysis of sensitivity, specificity, and 
positive and negative predictive values. Endoscopic activity will be classified 
according to endoscopy subscore of Mayo score and histological activity will be 
classified according to Geboes index score. 
For the analysis of the secondary endpoints the following analysis will be performed: 
• the correlation between serum soluble ST2 with endoscopic activity of 
disease (measured by Endoscopy Mayo subscore) at 16 weeks in UC 
subjects receiving golimumab, through the Spearman correlation coefficient;  
• the correlation between serum soluble ST2 histological activity (measured by 
Geboes index score) at 16 weeks in UC subjects receiving golimumab, 
through the Spearman correlation coefficient. 
• Correlations will also be performed between serum soluble ST2 levels and 
endoscopic and histological activity at baseline.   
• Serum soluble ST2 levels at baseline, Week 6 and Week 16 will be correlated 
with fecal calprotectin levels at baseline, week 6 and week 16 through 
Pearson correlation coefficient or Spearman correlation coefficient in case the 
normality assumption was not verified. The two biomarkers will be categorized 
by the cut-offs and Cohen's kappa coefficient will be obtained.  
 
 
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• Serum soluble ST2 levels at baseline, week 6 and week 16 will be correlated 
with clinical activity (total Mayo score), through Spearman correlation 
coefficient. 
• Comparative analyses of means (active disease versus inactive disease at 
week 6) with serum ST2 at baseline and change between baseline and week 
6. 
• Comparative analyses of subjects who achieved response at week 6 and 
maintained through week 16 versus subjects who did not maintain response, 
regarding serum soluble ST2 at baseline, week 6 and change between 
baseline and week 6. ROC curve analysis of the serum soluble ST2 at week 6 
regarding maintenance of response between week 6 and 16 will be 
performed. This exploratory analysis will detect the cut-off levels of the serum 
soluble ST2 at week 6 associated with maintenance of response. 
• It will be investigated the correlation of Mayo endoscopic score at baseline, 
week 6 and week 16 with UCEIS overall score at baseline, week 6 and week 
16, through the Spearman correlation coefficient. 
 
For the exploratory endpoints the following analysis will be performed:  
• Serum golimumab levels at week 6 and week 16 will be correlated with 
clinical activity (total Mayo score) at the same time points, through Spearman 
correlation coefficient. 
• Mean serum golimumab levels will be compared between patients with active 
disease (total Mayo score >2) and patients with inactive disease (total Mayo 
score ≤2 points with no individual subscore > 1) at week 6 and 16 through T-
test for independent groups or Mann-Whitney test according to the 
assumption validations of the statistical test. 
• The association between the presence of anti-golimumab antibodies at week 
6 and week 16 and clinical activity (total Mayo score) at the same time points 
will be tested through t-test for independent samples or the Mann-Whitney 
non-parametric test, according to the assumption validations of the statistical 
test. 
• Presence of anti-golimumab antibodies will be compared between patients 
with active disease (total Mayo score >2) and patients with inactive disease 
(total Mayo score ≤2 points with no individual subscore > 1) at week 6 and 16 
through Chi-Square test or Fisher exact test. 
• Serum golimumab levels at week 6 and week 16 will be correlated with 
endoscopic activity (endoscopic Mayo score) at the same time points, through 
Spearman correlation coefficient. 
 
 
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• The association between the presence of anti-golimumab antibodies at week 
6 and week 16 and endoscopic activity (endoscopic Mayo score) at the same 
time points will be tested through t-test for independent samples or the Mann-
Whitney non-parametric test, according to the assumption validations of the 
statistical test. 
• Serum golimumab levels at Week 6 and Week 16 will be correlated with 
faecal calprotectin levels at the same time points through Pearson correlation 
coefficient or Spearman correlation coefficient in case the normality 
assumption was not verified.  
• The association between the presence of anti-golimumab antibodies at Week 
6 and Week 16 and faecal calprotectin levels at the same time points will be 
tested through will be tested through t-test for independent samples or the 
Mann-Whitney non-parametric test, according to the assumption validations 
of the statistical test. 
Both measurements will be categorized by the cut-offs and Cohen's kappa 
coefficient will be obtained. 
• The correlation between serum golimumab levels at week 6 and 16 and 
histological activity (measured by Geboes index score) at the same time 
points will be performed through the Spearman correlation coefficient. 
• The association between the presence of anti-golimumab antibodies at week 
6 and 16 and histological activity (measured by Geboes index score) at the 
same time points will be tested through Mann-Whitney non-parametric test. 
• Subjects who achieved response / remission at week 6 versus subjects who 
did not will be compared regarding serum golimumab levels at this time point 
through T-test for independent groups or Mann-Whitney test according to the 
assumption validations of the statistical test.  
• Subjects who achieved response / remission at week 16 versus subjects who 
did not will be compared regarding serum golimumab levels at this time point 
through T-test for independent groups or Mann-Whitney test according to the 
assumption validations of the statistical test.  
• Subjects who achieved response / remission at week 6 versus subjects who 
did not will be compared regarding the presence of anti-golimumab antibodies 
at this time point through the Chi-Square test or Fisher Exact test (if 
applicable).  
• Subjects who achieved response / remission at week 16 versus subjects who 
did not will be compared regarding the presence of anti-golimumab antibodies 
at this time point through the Chi-Square test or Fisher Exact test (if 
applicable).  
 
 
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• ROC curve analysis of the serum golimumab levels at week 6 regarding 
maintenance of response between week 6 and 16 will be performed. This 
exploratory analysis will allow to detect the cut-off for serum golimumab levels 
at week 6 associated with maintenance of response.  
In addition, CRP at baseline, week 6 and week 16 will be correlated with endoscopic 
activity (measured by Endoscopy Mayo subscore) and histological activity at the 
same time points, through Spearman correlation coefficient. 
Bivariate correlation analysis will be carried out for ST2, calprotectin, CRP and 
endoscopy Mayo score. 
The incidence of adverse events (percentage of subjects with at least one adverse 
event) and serious adverse events (overall and with reasonable relationship) will be 
presented as well as the frequency distribution of AEs and SAEs (overall and with 
reasonable relationship) by means of total number of observations (n) and relative 
frequency (%). Frequency distribution of adverse events by grade and relationship 
with study drug will be summarized by total number of observations (n) and relative 
frequency (%). 
Adverse events will be listed individually with severity, grade, relationship with study 
drug, duration (for solved AEs and calculated as the difference between end date 
and start date), measures taken and outcome.  
All deaths will be listed, regardless of being caused by adverse events. 
Results 
for 
hematology 
(basophils, 
eosinophils, 
hematocrit, 
hemoglobin, 
lymphocytes, monocytes, neutrophils, platelets, RBC, WBC); blood chemistry (total 
bilirubin, ALT, AST, alkaline phosphatase, albumin, total protein, calcium, 
phosphate, sodium, potassium, chloride, urea and creatinine and CRP; urinalysis 
(proteins, glucose, nitrates, WBC, ketone bodies, hemoglobin, urobilinogen, bilirubin) 
will be summarized by total number of observations (n), mean, median, standard 
deviation, minimum and maximum. 
Based on the recruitment capacity of sites it is expected to include a total of 37 
subjects for analysis. With this sample size there is a probability of 80% that the 
lower limit of a one-sided 95% confidence interval is higher than 0.50, if the 
observed correlation coefficient is at least 0.75. 
The primary analysis is to be performed on the Full Analysis Set, defined as all 
subjects who had received study medication and had at least one valid post baseline 
assessment for the primary endpoint that correlates ST2 with endoscopic activity.  
In addition, a Per Protocol Set is defined as subjects receiving study medication, 
who meet key eligibility and evaluability criteria (without major protocol deviations). 
Sensitivity analyses will be based on this Per Protocol Set. 
All safety analyses will be performed on the All Treated Set, comprising all subjects 
who received at least one dose of study medication. 
 
 
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No interim analysis is planned. 
9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
The trial must be conducted in accordance with Good Clinical Practice (GCP) as 
outlined in the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, 
E6 Good Clinical Practice:  Consolidated Guidance and other applicable laws and 
regulations.  In addition, the trial must be conducted in accordance with:  (i) the USA 
Code of Federal Regulations (CFR) if the trial is conducted under a USA IND, 
regardless of the country involved; (ii) the European Union (EU) Clinical Trial 
Directive (CTD) and local regulations if the trial is conducted in the EU; and (iii) any 
specific local regulations if the trial is conducted elsewhere. 
9.1 
Ethical Conduct of the Trial 
9.1.1 
Independent Ethics Committee or Institutional Review Board 
Prior to initiation of the trial at any site, the trial, including the protocol, informed 
consent, and other trial documents must be approved by an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).  The IRB/IEC must be 
constituted according to applicable regulatory requirements.  As appropriate, 
amendments to the protocol must also be approved by the IRBs/IECs before 
implementation at the sites, unless warranted to eliminate an immediate hazard.  
The IRB/IEC approval should be obtained in writing, clearly identifying the trial, the 
documents reviewed (including informed consent), and the date of the review.  The 
trial as described in the protocol (or amendment), informed consent, and other trial 
documentation may be implemented only after all the necessary approvals have 
been obtained and the sponsor has confirmed that it is acceptable for the 
investigator to do so. 
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be 
advised and must approve the changes prior to implementation.  The investigator 
shall not modify the trial described in the protocol once finalized and after approval 
by the IRB/IEC without the prior written approval of sponsor. 
In countries where the investigator submits the trial protocol and statement of 
informed consent to the IRB/IEC, the investigator or qualified designee will forward 
the approvals to the sponsor. 
9.1.2 
Subject Information and Consent 
The details of the protocol must be provided in written format and discussed with 
each potential subject, and written informed consent must be obtained for all 
subjects before any trial-related procedure is performed.  In obtaining informed 
 
 
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consent, the information must be provided in language and terms understandable to 
the subject.  The subject, or the subject's legal representative, must give their written 
consent to participate in the trial.  The signed and dated consent form itself must be 
retained by the investigator as part of the trial records.  A copy of the signed and 
dated consent form must be given to the subject.  The consent form must include all 
of the required elements of informed consent in accordance with ICH Guidelines E6 
and local laws.  In addition, the sponsor specifically requests that the consent form 
identify it as the sponsor and state that use of the investigational product(s) is 
experimental and the side effects of the investigational product(s)are not completely 
known.  The consent form must be approved by the appropriate IRB/IEC and 
sponsor before trial initiation at a trial site.  Any subsequent changes to the approved 
informed consent form must be reviewed and approved by the appropriate IRB/IEC 
and sponsor before implementation. 
9.1.3 
Subject Identification Card 
A Subject Identification Card is provided to each subject to carry on his or her 
person (e.g., in a wallet) at all times while the subject is participating in the trial. The 
Subject Identification Card must be provided to the subject no later than when IMP is 
dispensed. The card is to be shown to caregivers in the event of an emergency. 
At a minimum, the card must contain the following information: 
1. Protocol number; 
2. The subject’s protocol identification number; 
3. A statement identifying the card-carrier as a participant in a clinical trial (e.g., 
“This person is participating in a clinical research trial.”); 
4. A statement indicating the person might be taking an investigational drug 
(e.g., “This person is taking an experimental drug which could have 
interactions with other medications, or placebo”); and 
5. Contact information in the event of an emergency or hospitalization. The 
contact information on the card is to be the investigator or a designated site 
contact, rather than a contact from within the sponsor; 
The cards may also include other trial-specific information to assist with treatment 
decisions in the event of an emergency, such as types of concomitant therapies that 
may, or may not be, permitted as part of emergency treatment. As with any other 
information provided to subjects, the Subject Identification Card must be approved 
by the IRB/IEC. Monitors will request that Investigators provide Subject Identification 
Cards to each subject. Investigators will be asked to request that subjects carry the 
cards with them while they are participating in the trial. 
The Investigator/site should collect the cards at the end of the trial and retain them 
with other clinical trial documents. 
 
 
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9.1.4 
Registration of the Trial 
The trial will be registered by the sponsor on a publicly accessible database. The 
results will be disclosed by the sponsor on a publicly accessible database. 
 
9.2 
Reporting Trial Data to the Sponsor 
9.2.1 
Data Collection Forms 
The Sponsor will provide the site with data collection forms, be they Case Report 
Forms (CRF), either in paper format or electronic Case Report Forms (eCRF); 
diaries; Electronic Data Capture (EDC) screens; or other appropriate data collection 
forms as the trial requires.  The investigator is to provide subject data according to 
the Sponsor’s instructions, in the designated data collection form, compliant with 
GCP practices.  The Sponsor will also provide the site with instructions for assisting 
other parties - such as a central laboratory - to collect data.  As instructed by the 
Sponsor, a designated central laboratory may collect data in a database and provide 
the completed database to sponsor. All data collection forms and the databases 
from the trial are the exclusive property of sponsor. 
The investigator must maintain records and data during the trial in compliance with 
all applicable legal and regulatory requirements. Each data point must be supported 
by a source document at the trial site. Any records or documents used as the source 
of information (called the “subject source data”) are to be retained for review by 
authorized representatives of the sponsor or a regulatory agency. 
The investigator will ensure that there are sufficient time, staff, and facilities available 
for the duration of the trial to conduct and record the trial as described in the protocol 
and according to all applicable guidances, laws, and regulations. 
All data collection forms (e.g., CRFs, diaries; EDC screens), electronic database 
entries, etc., should be completed as soon as possible after the evaluation has 
occurred.  All dates appearing on the sponsor's subject data collection forms for 
laboratory tests, cultures, and other data collected, must be the dates on which the 
specimens were obtained, or the procedures performed. 
 
9.2.2 
Preparing Case Report Forms for All Subjects 
A CRF must be completed for all subjects who have given informed consent. The 
Sponsor must not collect subject names, initials, or other personal information that is 
beyond the scope of the trial from any subject. Subjects are not to be identified by 
 
 
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name or initials on the CRF or any trial documents. The only acceptable 
identification for a subject who may appear on a CRF or trial document is the unique 
subject identification number. The investigator must maintain contact information for 
each participant so that all can be quickly contacted by the investigator, if necessary. 
All entries into CRFs are the responsibility of the investigator and must be completed 
by the investigator or a qualified designee. The investigator will acknowledge in 
writing that he/she has verified the accuracy of the recorded data. 
 
9.2.3 
Preparing Case Report Forms for Subjects Who Fail Screening 
Data are to be collected from the time the informed consent form is signed until the 
subject is determined to have failed screening.  A CRF with a minimum of the 
following information must be completed for subjects who fail screening:  
(1) demographics, (2) subject status, (3) reason for screen failure, and (4) serious 
adverse events. 
 
9.3 
Publications and Other Rights 
9.3.1 
Rights to Publish by the Investigator 
The investigator has the right to publish or publicly present the results of the trial in 
accordance with this Section 9.3 of the protocol.  In the event that the protocol is a 
part of a multi-site trial, it is understood that it is the intent of the sponsor and the 
investigator to initially only publish or present the trial results together with the other 
sites, unless specific written permission is obtained in advance from the sponsor to 
publish separate results.  The sponsor shall advise as to the implications of timing of 
any publication in the event clinical trials are still in progress at sites other than the 
investigator's site. 
The investigator agrees not to publish or publicly present any interim results of the 
trial without the prior written consent of the sponsor.  The investigator further agrees 
to provide to the sponsor 45 days prior to submission for publication or presentation, 
review copies of abstracts or manuscripts for publication (including, without 
limitation, slides and texts of oral or other public presentations and texts of any 
transmission through any electronic media, eg, any computer access system such 
as the Internet, World Wide Web, etc) that report any results of the trial.  The 
sponsor shall have the right to review and comment with respect to publications, 
abstracts, slides, and manuscripts and the right to review and comment on the data 
analysis and presentation with regard to the following concerns: 
 
 
 
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1. Proprietary information that is protected by the provisions contained in 
Section 9.3.2; 
The accuracy of the information contained in the publication; and 
To ensure that the presentation is fairly balanced and in compliance with FDA 
regulations. 
 
If the parties disagree concerning the appropriateness of the data analysis and 
presentation, and/or confidentiality of the sponsor's confidential information, 
investigator agrees to meet with the sponsor's representatives at the clinical trial site 
or as otherwise agreed, prior to submission for publication, for the purpose of 
making good faith efforts to discuss and resolve any such issues or disagreement. 
 
9.3.2 
Use of Proprietary or Confidential Information in a Publication 
No publication or manuscript shall contain any trade secret information of the 
sponsor or any proprietary or confidential information of the sponsor and shall be 
confined to new discoveries and interpretations of scientific fact.  If the sponsor 
believes there is patentable subject matter contained in any publication or 
manuscript submitted for review, the sponsor shall promptly identify such subject 
matter to investigator.  If sponsor requests and at sponsor’s expense, investigator 
shall use its best efforts to assist sponsor to file a patent application covering such 
subject matter with the USA Patent and Trademark Office or through the Patent 
Cooperation Treaty prior to any publication. 
 
9.3.3 
Use of Trial Information in a Publication 
Investigator is granted the right subject to the provisions of this protocol to use the 
results of all work provided by investigator under this protocol, including but not 
limited to, the results of tests and any raw data and statistical data generated for 
investigator's 
own 
teaching, 
research, 
and 
publication 
purposes 
only.  
Investigator/Institution agrees, on behalf of itself and its employees, officers, 
trustees, and agents, not to cause said results to be knowingly used for any 
commercial purpose whatsoever except as authorized by the sponsor in writing. 
 
9.3.4 
Authorship of Publications 
Authors of publications must meet the International Committee of Medical Journal 
Editors (ICMJE) guidelines for authorship and must satisfy the 3 criteria that follow: 
 
 
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1. Authors must make substantial contributions to the conception and design of the 
trial, acquisition of data, or analysis of data and interpretation of results; 
2. Authors must draft the publication or, during draft review, provide contributions 
(data analysis, interpretation, or other important intellectual content) leading to 
significant revision of the manuscript with agreement by the other authors; 
3. Authors must provide written approval of the final draft version of the publication 
prior to submission. 
 
All contributors who do not meet the 3 criteria for authorship should be listed in an 
acknowledgments section within the publication, if allowed by the journal, per the 
ICMJE guidelines for acknowledgment. 
Appearance of the name of authors in the publications will follow the order stated 
below, in accordance with International Committee of Medical Journal Editors 
(ICMJE) guidelines criteria for authorship of Publications or the scientific journal 
specific rules: the first author is the national study coordinator, followed by the list of 
names of  the principal investigators and co-investigators of the centers according to 
their contribution to the trial, and the last author is the investigator responsible for the 
analysis and interpretation of histologic data. 
 
9.4 
Trial Documents and Records Retention 
During the trial and after termination of the trial – including after early termination of 
the trial – the investigator must maintain copies of all documents and records 
relating to the conduct of the trial.  This documentation includes, but is not limited to, 
protocols, CRFs and other data collection forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with health authorities 
and IRBs/IECs, consent forms, investigator’s curricula vitae/biosketch, monitor visit 
logs, laboratory reference ranges, and laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  Subject files and other source 
data must be kept for the maximum period of time permitted by the hospital, 
institution or private practice, or as specified below.  The sponsor must be consulted 
if the investigator wishes to assign the files to someone else, remove them to 
another location, or is unable to retain them for the specified period. 
The investigator must retain trial records for the amount of time specified by 
applicable laws and regulations.  At a minimum, trial records must be retained for the 
amount of time specified by ICH Guidelines, the EU Good Clinical Practices 
Directive, or applicable local laws, whichever is longer: 
 
 
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1. The ICH Guidelines specify that records must be retained for a minimum of 
2 years after a marketing application for the indication is approved (or not 
approved) or 2 years after notifying the appropriate regulatory agency that an 
investigation is discontinued. 
The European Union (EU) Commission Directive 2003/63/EC which requires that 
Essential Documents (including Case Report Forms) other than subjects’ medical 
files, are retained for at least fifteen (15) years after completion or discontinuation of 
the trial, as defined in the protocol. 
 
All trial documents shall be made available if required by relevant health authorities.  
The investigator should consult with the sponsor prior to discarding trial and/or 
subject files. 
Sponsor will retain all sponsor-required documentation pertaining to the trial for the 
lifetime of the investigational product.  Archived data may be held on microfiche or 
electronic record, provided that a back-up exists and that a paper copy can be 
obtained from it, if required. 
 
10.0 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
10.1 Sponsor 
The sponsor of this trial is indicated in Section 1.0, Title Page. 
 
10.2 Investigators 
10.2.1 
Selecting Investigators 
Only investigators qualified by training and experience to perform a clinical 
investigation with golimumab are selected. The sponsor will contact and select all 
investigators (i.e., the legally responsible party(ies) at each trial site), who, in turn, 
will select their staff. 
 
10.2.2 
Financial Disclosure Requirement 
In connection with the clinical trial described in the protocol, the investigator certifies 
that, if asked, the investigator will read and answer the Certification/Disclosure Form 
or equivalent document truthfully and to the best of investigator's ability.  Investigator 
 
 
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also certifies that, if asked, the investigator will have any other applicable party(ies) 
(eg, subinvestigators) read and answer the Certification/Disclosure Form as a 
condition of their participation in the trial. 
If the financial interests reported on the Certification/Disclosure Form change during 
the course of the trial or within 1 year after the last subject has completed the trial as 
specified in the protocol, the investigator and the other applicable party(ies) are 
obligated to inform the sponsor of such financial change. 
 
10.2.3 
Clinical Study Report Coordinator Investigator 
A Clinical Study Report (CSR) will be prepared by the sponsor or its qualified 
designee to describe the results of the trial.  One of the investigators shall be 
selected by the sponsor to review the CSR and provide approval of the final CSR in 
writing.  The investigator chosen to review and approve the CSR is to be called the 
CSR Coordinating Investigator.  A second investigator shall be selected as the 
Alternate CSR Coordinating Investigator.  The Alternate CSR Coordinating 
Investigator is to review and approve the CSR should the first CSR Coordinating 
Investigator be unable to do so.  The sponsor is to select the CSR Coordinating 
Investigator and Alternate CSR Coordinating Investigator from the investigators 
using the following criteria: 
1. Must be the Principal Investigator at a trial site actively enrolling subjects and 
participating in the trial; 
2. Must be willing and capable of completing the necessary reviews and 
providing approval of the CSR in writing; 
 
10.3 Central Organizations 
Central organizations to be used in the conduct, monitoring, and/or evaluation or 
other activities as appropriate of this trial are provided on the Contact List. 
 
11.0 REFERENCES 
Adedokun OJ, Xu Z, Marano CW, Strauss R, Zhang H, Johanns J, Zhou H, Davis 
HM, Reinisch W, Feagan BG, Rutgeerts P, Sandborn WJ., 2017. 
Pharmacokinetics and Exposure-response Relationship of Golimumab in 
Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from 
Phase 2/3 PURSUIT Induction and Maintenance Studies. J Crohns Colitis 11, 
35-46. 
 
 
 
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Beltrán, C.J., Núñez, L.E., Díaz-Jiménez, D., Farfan, N., Candia, E., Heine, C., 
López, F., González, M.J., Quera, R., Hermoso, M.A., 2010. Characterization 
of the novel ST2/IL-33 system in patients with inflammatory bowel disease. 
Inflamm. Bowel Dis. 16, 1097–1107. 
Brunner, M., Krenn, C., Roth, G., Moser, B., Dworschak, M., Jensen-Jarolim, E., 
Spittler, A., Sautner, T., Bonaros, N., Wolner, E., Boltz-Nitulescu, G., 
Ankersmit, H.J., 2004. Increased levels of soluble ST2 protein and IgG1 
production in patients with sepsis and trauma. Intensive Care Med 30, 1468–
1473. 
Díaz-Jiménez, D., Núñez, L.E., Beltrán, C.J., Candia, E., Suazo, C., Alvarez-Lobos, 
M., González, M.-J., Hermoso, M.A., Quera, R., 2011. Soluble ST2: a new and 
promising activity marker in ulcerative colitis. World J. Gastroenterol. 17, 2181–
2190. 
Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T., Löfberg, R., 2000. A 
reproducible grading scale for histological assessment of inflammation in 
ulcerative colitis. Gut 47, 404–409. 
Gisbert, J.P., González-Lama, Y., Maté, J., 2007. [Role of biological markers in 
inflammatory bowel disease]. Gastroenterol Hepatol 30, 117–129. 
Kobori, A., Yagi, Y., Imaeda, H., Ban, H., Bamba, S., Tsujikawa, T., Saito, Y., 
Fujiyama, Y., Andoh, A., 2010. Interleukin-33 expression is specifically 
enhanced in inflamed mucosa of ulcerative colitis. J. Gastroenterol. 45, 999–
1007. 
Kohli, P., Bonaca, M.P., Kakkar, R., Kudinova, A.Y., Scirica, B.M., Sabatine, M.S., 
Murphy, S.A., Braunwald, E., Lee, R.T., Morrow, D.A., 2012. Role of ST2 in 
non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. Clin. 
Chem. 58, 257–266. 
Kuroiwa, K., Arai, T., Okazaki, H., Minota, S., Tominaga, S., 2001. Identification of 
human ST2 protein in the sera of patients with autoimmune diseases. 
Biochem. Biophys. Res. Commun. 284, 1104–1108. 
Matsuyama, Y., Okazaki, H., Hoshino, M., Onishi, S., Kamata, Y., Nagatani, K., 
Nagashima, T., Iwamoto, M., Yoshio, T., Ohto-Ozaki, H., Tamemoto, H., 
Komine, M., Sekiya, H., Tominaga, S.-I., Minota, S., 2012. Sustained 
elevation of interleukin-33 in sera and synovial fluids from patients with 
rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible 
association with persistent IL-1β signaling and a poor clinical response. 
Rheumatol. Int. 32, 1397–1401. 
Oshikawa, K., Kuroiwa, K., Tago, K., Iwahana, H., Yanagisawa, K., Ohno, S., 
Tominaga, S.I., Sugiyama, Y., 2001. Elevated soluble ST2 protein levels in 
sera of patients with asthma with an acute exacerbation. Am. J. Respir. Crit. 
Care Med. 164, 277–281. 
Pastorelli, L., Garg, R.R., Hoang, S.B., Spina, L., Mattioli, B., Scarpa, M., Fiocchi, C., 
Vecchi, M., Pizarro, T.T., 2010. Epithelial-derived IL-33 and its receptor ST2 
are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven 
enteritis. Proc. Natl. Acad. Sci. U.S.A. 107, 8017–8022. 
Sandborn, W., Feagan, B., Marano, C., Strauss, R., Johanns, J., Zhang, H., 
Colombel, J., Reinisch, W., Gibson, P., Collins, J., Jarnerot, G., Rutgeerts, P., 
 
 
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Subcutaneous Golimumab Induces Clinical Response and Remission in 
Patients With Moderate-to-Severe Ulcerative Colitis. Gastroenterology 
2014a;146:85–95 
Sandborn,  W.,  Feagan,  B.,  Marano,  C.,  Strauss,  R.,  Johanns,   J.,  Zhang,  H.,   
 
   Colombel,  J., Reinisch, W.,  Gibson, P., Collins, J.,  Jarnerot,  G.,  Rutgeerts, 
 
     P., Subcutaneous Golimumab Maintains Clinical Response in Patients With   
 
 
Moderate-to-Severe Ulcerative Colitis. Gastroenterology  2014b;146:96–109 
Seidelin, J.B., Rogler, G., Nielsen, O.H., 2011. A role for interleukin-33 in T(H)2-
polarized intestinal inflammation? Mucosal Immunol 4, 496–502. 
Silverberg, M.S., Satsangi, J., Ahmad, T., Arnott, I.D., Bernstein, C.N., Brant, S.R., 
Caprilli, R., Colombel, J.-F., Gasche, C., Geboes, K., Jewell, D.P., Karban, A., 
Loftus Jr, E.V., Peña, A.S., Riddell, R.H., Sachar, D.B., Schreiber, S., 
Steinhart, A.H., Targan, S.R., Vermeire, S., Warren, B.F., 2005. Toward an 
integrated clinical, molecular and serological classification of inflammatory 
bowel disease: Report of a Working Party of the 2005 Montreal World 
Congress of Gastroenterology. Can. J. Gastroenterol. 19 Suppl A, 5–36. 
Tibble, J.A., Bjarnason, I., 2001. Non-invasive investigation of inflammatory bowel 
disease. World J. Gastroenterol. 7, 460–465. 
Travis, S.P.L., Schnell, D., Krzeski, P., Abreu, M.T., Altman, D.G., Colombel, J.-F., 
Feagan, B.G., Hanauer, S.B., Lemann, M., Lichtenstein, G.R., Marteau, P.R., 
Reinisch, W., Sands, B.E., Yacyshyn, B.R., Bernhardt, C.A., Mary, J.-Y., 
Sandborn, W.J., 2011. Developing an instrument to assess the endoscopic 
severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of 
Severity (UCEIS). Gut 61, 535–542. 
Weinberg, E.O., Shimpo, M., Hurwitz, S., Tominaga, S., Rouleau, J.-L., Lee, R.T., 
2003. Identification of serum soluble ST2 receptor as a novel heart failure 
biomarker. Circulation 107, 721–726. 
 
 
 
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Appendix 1 
Code of Conduct for Clinical Trials 
Merck* 
Code of Conduct for Clinical Trials 
I. Introduction 
A. Purpose 
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate 
the safety and effectiveness of our products.  As such, we are committed to 
designing, implementing, conducting, analyzing and reporting these studies in 
compliance with the highest ethical and scientific standards.  Protection of 
subject safety is the overriding concern in the design of clinical trials.  In all 
cases, Merck clinical studies will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki. 
B. Scope 
Such standards shall be endorsed for all clinical interventional investigations 
sponsored by Merck irrespective of the party (parties) employed for their 
execution (eg, contract research organizations, collaborative research 
efforts).  This Code is not intended to apply to studies which are observational 
in nature, or which are retrospective.  Further, this Code does not apply to 
investigator-initiated studies (eg, Medical School Grant Program), which are 
not under the control of Merck. 
II. Scientific Issues 
A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation studies, clinical trial protocols will be 
hypothesis-driven to assess safety, efficacy and/or pharmacokinetic or 
pharmacodynamic indices of Merck or comparator products.  Alternatively, 
Merck may conduct outcomes research trials, studies to assess or validate 
various endpoint measures, or studies to determine patient preferences, 
etc. 
The design (ie, subject population, duration, statistical power) must be 
adequate to address the specific purpose of the trial.  Research subjects 
must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection 
Merck selects investigative sites based on medical expertise, access to 
appropriate 
patients, 
adequacy 
of 
facilities 
and 
staff, 
previous 
performance in Merck studies, as well as budgetary considerations.  Prior 
to trial initiation, sites are evaluated by Merck personnel to assess the 
ability to successfully conduct the trial. 
 
 
 
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3. Site Monitoring/Scientific Integrity 
Trial sites are monitored to assess compliance with the trial protocol and 
general principles of Good Clinical Practice.  Merck reviews clinical data 
for accuracy, completeness and consistency.  Data are verified versus 
source documentation according to standard operating procedures.  Per 
Merck policies and procedures, if fraud, misconduct or serious GCP-non-
Compliance are suspected, the issues are promptly investigated.  When 
necessary, the clinical site will be closed, the responsible regulatory 
authorities and ethics review committees notified and data disclosed 
accordingly. 
D. Publication and Authorship 
To the extent scientifically appropriate, Merck seeks to publish the results of 
studies it conducts.  Some early phase or pilot studies are intended to be 
hypothesis-generating rather than hypothesis testing.  In such cases, 
publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues of 
multiplicity. 
Merck’s policy on authorship is consistent with the requirements outlined in 
the ICH-Good Clinical Practice guidelines.  In summary, authorship should 
reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  
All named authors must be able to defend the trial results and conclusions.  
Merck funding of a trial will be acknowledged in publications. 
III. Subject Protection 
A. IRB/ERC Review 
All clinical trials will be reviewed and approved by an independent IRB/ERC 
before being initiated at each site.  Significant changes or revisions to the 
protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be 
enacted in anticipation of IRB/ERC approval.  For each site, the IRB/ERC and 
Merck’s Consent Form Review department (U.S. studies) or Clinical 
Research Director (non-U.S. studies) will approve the subject informed 
consent form. 
B. Safety 
The guiding principle in decision-making in clinical trials is that subject welfare 
is of primary importance.  Potential subjects will be informed of the risks and 
benefits of, as well as alternatives to, trial participation.  At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never 
denied access to appropriate medical care based on participation in a Merck 
clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only 
after providing informed consent for participation.  Subjects may withdraw 
from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them. 
 
 
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C. Confidentiality 
Merck is committed to safeguarding subject confidentiality, to the greatest 
extent possible.  Unless required by law, only the investigator, sponsor (or 
representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research subject by name. 
D. DNA Research 
DNA sequence analyses, including use of archival specimens collected as 
part of a clinical trial, will only be performed with the specific informed consent 
of the subject.  With IRB approval, an exception to this restriction on use of 
archival specimens may be possible (for instance, if specimens are de-
identified and are not referable to a specific subject). 
IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work 
performed in support of Merck studies.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly 
challenging, additional payments may be made to compensate for the time 
spent in extra recruiting efforts. 
Merck does not pay for subject referrals.  However, Merck may compensate 
referring physicians for time spent on chart review to identify potentially 
eligible subjects. 
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and 
that the investigator or sponsoring institution is being paid or provided a grant 
for performing the trial.  However, the local IRB/ERC may wish to alter the 
wording of the disclosure statement to be consistent with financial practices at 
that institution.  As noted above, publications resulting from Merck studies will 
indicate Merck as a source of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by investigators and support staff (eg, to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and 
practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment 
Investigators will be expected to review Merck’s Code of Conduct as an 
attachment to the trial protocol, and in signing the protocol, agree to support 
these ethical and scientific standards. 
 
* In this document, "Merck" refers to Merck Sharp & Dohme Corp, which is a subsidiary of Merck & Co., Inc.  
Merck is known as MSD outside of the United States and Canada.  As warranted by context, Merck also includes 
affiliates and subsidiaries of Merck & Co., Inc." 
 
 
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Appendix 2 
Specimen Handling and Shipping Instructions 
Detailed instructions for storage, labelling and shipment of all samples will be 
provided in the Laboratory Manual. 
 
 
 
 
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Appendix 3 
Mayo scoring system for assessment of ulcerative colitis 
activity  
Stool frequencya  
0 = Normal number of stools for this patient 
1 = 1-2 stools more than normal   
2 = 3-4 stools more than normal   
3 = 5 or more stools more than normal   
 
Rectal bleedingb  
0 = No blood seen   
1 = Streaks of blood with stool less than half the time   
2 = Obvious blood with stool most of the time   
3 = Blood alone passed   
 
Findings of endoscopy   
0 = Normal or inactive disease   
1 = Mild disease (erythema, decreased vascular pattern, mild friability)   
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)   
3 = Severe disease (spontaneous bleeding, ulceration)   
 
Physician’s global assessmentc 
0 = Normal   
1 = Mild disease   
2 = Moderate disease   
3 = Severe disease   
 
a Each patient serves as his or her own control to establish the degree of abnormality of the 
stool frequency. 
b The daily bleeding score represents the most severe bleeding of the day. 
c The physician’s global assessment acknowledges the 3 other criteria, the patient’s recall of 
abdominal discomfort and general sense of well-being, and other observations, such as 
physical findings and the patient’s performance status.  
 
 
 
 
 
 
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Appendix 4 
Ulcerative Colitis Endoscopic Index Of Severity (UCEIS©)   
Descriptors and definitions: UCEIS = sum of scores, which accounts for 91% of the variance 
between observers in the overall assessment of endoscopic severity 
Descriptor (Score  
most severe lesions) 
Likert Scale 
anchor points 
Definition 
Vascular pattern 
Normal (1) 
Normal vascular pattern with arborisation 
of capillaries clearly defined, or with 
blurring or patchy loss of capillary margins 
Patchy obliteration 
(2) 
Patchy obliteration of vascular pattern 
Obliterated (3) 
Complete obliteration of vascular pattern 
Bleeding 
None (1) 
No visible blood 
Mucosal (2) 
Some spots or streaks of coagulated blood 
on the surface of the mucosa ahead of the 
scope, which can be washed away 
Luminal mild (3) 
Some free liquid blood in the lumen 
Luminal moderate 
or severe (4) 
Frank blood in the lumen ahead of 
endoscope or visible oozing from mucosa 
after washing intra-luminal blood, or visible 
oozing from a haemorrhagic mucosa 
Erosions & Ulcers 
None (1) 
Normal mucosa, no visible erosions or 
ulcers 
Erosions (2) 
Tiny (< 5mm) defects in the mucosa, of a 
white or yellow colour with a flat edge 
Superficial ulcer (3) Larger (>5mm) defects in the mucosa, 
which are discrete fibrin-covered ulcers 
when compared to erosions, but remain 
superficial 
Deep ulcer (4) 
Deeper excavated defects in the mucosa, 
with a slightly raised edge 
For the UCEIS© Working Group 2011 (Travis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, 
Colombel JF, Feagan BG, Hanauer SB, Lémann M, Lichtenstein GR, Marteau PR, Reinisch W, 
Sands BE, Yacyshyn BR, Bernhardt CA, Mary JY, Sandborn WJ). The trademark is registered to 
Warner Chilcott Pharmaceuticals.  
 
 
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Appendix 5 
Geboes 
score 
for 
assessment 
of 
ulcerative 
colitis 
histologic disease activity      
Grade 0           
Structural (architectural changes) 
Subgrades   
 
0.0   
No abnormality        
0.1   
Mild abnormality        
0.2   
Mild or moderate diffuse or multifocal abnormalities        
0.3   
Severe diffuse or multifocal abnormalities      
 
 
Grade 1     
Chronic inﬂammatory inﬁltrate       
Subgrades 
 
1.0   
No increase        
1.1   
Mild but unequivocal increase        
1.2   
Moderate increase        
1.3   
Marked increase      
 
 
Grade 2 
Lamina propria neutrophils and eosinophils       
2A Eosinophils 
 
2A.0   
No increase        
2A.1   
Mild but unequivocal increase        
2A.2   
Moderate increase        
2A.3   
Marked increase      
2B Neutrophils         
 
2B.0   
No increase        
2B.1   
Mild but unequivocal increase        
2B.2   
Moderate increase        
2B.3   
Marked increase      
 
 
Grade 3     
Neutrophils in epithelium       
Subgrades 
 
3.0         
None 
3.1       
<  5 %  Crypts involved        
3.2       
<  50 %  Crypts involved        
3.3       
>  50 %  Crypts involved      
 
 
Grade 4 
Crypt destruction       
Subgrades 
 
4.0         
None 
4.1  
Probable - local excess of neutrophils in part of crypt        
4.2   
Probable - marked attenuation        
4.3   
Unequivocal crypt destruction      
 
 
Grade 5     
Erosion or ulceration       
Subgrades 
 
5.0   
No erosion, ulceration, or granulation tissue        
5.1   
Recovering epithelium + adjacent inﬂammation           
5.2   
Probable erosion focally stripped        
5.3   
Unequivocal erosion        
5.4   
Ulcer or granulation tissue 
 
 
 
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AMENDMENT NO.3, 13Mar2017 
 
 
 
 
Appendix 6 
Collection and Management of Specimens for Future 
Biomedical Research  
6.1  
Scope of Future Biomedical Research 
The plasma specimen(s) will be stored to provide a resource for future studies 
conducted by Merck focused on the study of biomarkers responsible for how a drug 
enters and is removed by the body, how a drug works, other pathways a drug may 
interact with, or other aspects of disease.   
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how 
individuals respond to drugs, enhance our understanding of human disease and 
ultimately improve public health through development of novel treatments targeted to 
populations with the greatest need.  All specimens will be used by Merck or 
designees and research will be monitored and reviewed by a committee of our 
scientists and clinicians. 
6.2  
Definitions 
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues 
that is a sign of a normal or abnormal process or of a condition or disease.  A 
biomarker may be used to see how well the body responds to a treatment for a 
disease or condition.a 
b. Pharmacogenomics: The investigation of variations of DNA and RNA 
characteristics as related to drug response.b 
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.b 
d. DNA: Deoxyribonucleic acid. 
e. RNA: Ribonucleic acid. 
6.3  
Summary of Procedures for Future Biomedical Research 
a. Subjects for Enrolment 
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-study. 
                                                 
a National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker 
b International Conference on Harmonization: Definitions For Genomic Biomarkers, Pharmacogenomics, 
Pharmacogenetics, Genomic Data and Sample Coding Categories - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf. 
 
 
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b. Informed Consent 
Informed consent for specimens (i.e., DNA, RNA, protein, etc) will be obtained 
during screening for protocol enrolment from all subjects or legal guardians, at a 
study visit by the investigator or his or her designate.  Informed consent for 
Future Biomedical Research should be presented to the subjects on Visit 1.  If 
delayed, present consent at next possible Subject Visit.  Informed consent must 
be obtained prior to collection of all Future Biomedical Research specimens. 
Subjects are not required to participate in the Future Biomedical Research sub-
study in order to participate in the main trial.  
Consent forms signed by the subject will be kept at the clinical trial site under 
secure storage for regulatory reasons.  Information contained on the consent 
form alone cannot be traced to any specimens, test results, or medical 
information once the specimens have been rendered de-identified.  Subjects 
who decline to sign the Future Biomedical Research informed consent will not 
have the specimen collected nor will they be discontinued from the main study.  
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.   
Each informed consent approved by an ethics committee is assigned a unique 
tracking number.  The tracking number on this document will be used to assign 
specimen permissions for each specimen into the Entrusted Keyholder’s 
Specimen Database. 
c. eCRF Documentation for Future Biomedical Research Specimens 
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-study's research purposes. Any 
specimens for which such an informed consent cannot be verified will be 
destroyed. 
d. Future Biomedical Research Specimen Collections  
Blood specimens will usually be obtained at a time when the subject is having 
blood drawn for other study purposes.  Specimens like tissue and bone marrow 
will usually be obtained at a time when the subject is having such a procedure for 
clinical purposes.  
 
 
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Specimens will be collected and sent to the laboratory designated for the trial 
where they will be processed following the Merck approved policies and 
procedures for specimen handling and preparation. 
6.4  
Confidential Subject Information for Future Biomedical Research 
 
In order to optimize the research that can be conducted with Future Biomedical 
Research specimens, it is critical to link subject' clinical information with future test 
results. In fact little or no research can be conducted without connecting the clinical 
study data to the specimen. The clinical data allow specific analyses to be 
conducted. Knowing subject characteristics like gender, age, medical history and 
treatment outcomes are critical to understanding clinical context of analytical results. 
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below.  
At the clinical site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number 
which does not contain any personally identifying information embedded within it.  
The link (or key) between subject identifiers and this first unique code will be held at 
the study site.  No personal identifiers will appear on the specimen tube.   
This first code will be replaced with a second code at a Merck designated 
storage/lab facility.  The second code is linked to the first code via a second key. 
The specimen is now double coded.  Specimens with the second code are 
sometimes referred to as de-identified specimens. The use of the second code 
provides additional confidentiality and privacy protection for subjects over the use of 
a single code.  Access to both keys would be needed to link any data or specimens 
back to the subject's identification. 
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the 
second code to the first code to allow clinical information collected during the course 
of the study to be associated with the specimen.  This second key will be transferred 
under secure procedures by the Merck designated facility to an Entrusted Keyholder 
at Merck.  The second code will be logged into the primary biorepository database at 
Merck and, in this database, this identifier will not have identifying demographic data 
or identifying clinical information (i.e., race, sex, age, diagnosis, lab values) 
associated with it. The specimen will be stored in a designated biorepository site 
with secure policies and procedures for specimen storage and usage. 
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done 
by the Merck Entrusted Keyholder under strict security policies and procedures.  The 
Merck Entrusted Keyholder will link the information and then issue a de-identified 
 
 
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data set for analysis.  The only other circumstance by which future biomedical 
research data would be directly linked to the full clinical data set would be those 
situations mandated by health authorities (e.g., EMEA, FDA), whereby this 
information would be directly transferred to the health authority. 
6.5  
Biorepository Specimen Usage 
 
Specimens obtained for the Merck Biorepository will be used for analyses using 
good scientific practices.  However, exploratory analyses will not be conducted 
under the highly validated conditions usually associated with regulatory approval of 
diagnostics.  The scope of research performed on these specimens is limited to the 
investigation of the variability in biomarkers that may correlate with a clinical 
phenotype in subjects. 
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by 
Merck.  The investigator conducting the analysis will be provided with double coded 
specimens.  Re-association of analysis results with corresponding clinical data will 
only be conducted by the Merck Entrusted Keyholder.  Any contracted third party 
analyses will conform to the specific scope of analysis outlined in this sub-study.  
Future Biomedical Research specimens remaining with the third party after the 
specific analysis is performed will be returned to the sponsor or destroyed and 
documentation of destruction will be reported to Merck. 
6.6  
Withdrawal from Future Biomedical Research 
 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any 
time by writing to the principal investigator for the main study.  If medical records for 
the main study are still available, the Investigator will contact MERCK using the 
designated mailbox 
 and a form will be 
provided by MERCK to obtain appropriate information to complete specimen 
withdrawal.  Subsequently, the subject's specimens will be removed from the 
biorepository and be destroyed.  A letter will be sent from MERCK to the investigator 
confirming the destruction.  It is the responsibility of the Investigator to inform the 
patient of completion of destruction.  Any analyses in progress at the time of request 
for destruction or already performed prior to the request being received by the 
sponsor will continue to be used as part of the overall research study data and 
results.  No new analyses would be generated after the request is received. 
In the event that the medical records for the main study are no longer available (e.g., 
if the investigator is no longer required by regulatory agencies to retain the main 
study records) or the specimens have been completely anonymized, there will no 
longer be a link between the patient’s personal information and their specimens. In 
this situation, the request for specimen destruction cannot be processed.  
 
 
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6.7  
Retention of Specimens 
 
Future Biomedical Research specimens will be stored in the biorepository for 
potential analysis for up to 20 years from acquisition.  Specimens may be stored for 
longer if a regulatory or governmental agency has active questions that are being 
answered.  In this special circumstance, specimens will be stored until these 
questions have been adequately addressed. 
Specimens from the site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and 
procedures and this destruction will be documented in the biorepository database. 
6.8  
Data Security 
 
Separate databases for specimen information and for results from the Future  
Biomedical Research sub-study will be maintained by Merck.  This is done to 
separate the future exploratory test results (which include genetic data) from the 
clinical trial database thereby maintaining a separation of subject number and these 
results.  The separate databases are accessible only to the authorized sponsor and 
the designated study administrator research personnel and/or collaborators.  
Database user authentication is highly secure, and is accomplished using network 
security policies and practices based in international standards (e.g., ISO17799) to 
protect against unauthorized access.  The Merck Entrusted Keyholder maintains 
control over access to all specimen data.  These data are collected for future 
biomedical research purposes only as specified in this sub-study will not be used for 
any other purpose. 
6.9  
Reporting of Future Biomedical Research Data to Subjects 
 
There is no definitive requirement in either authoritative ethical guidelines or in 
relevant laws/regulations globally that research results have to be, in all 
circumstances, returned to study participant.  Some guidelines advocate a proactive 
return of data in certain instances.  No information obtained from exploratory 
laboratory studies will be reported to the subject or family, and this information will 
not be entered into the clinical database maintained by Merck on subjects.  Principle 
reasons not to inform or return results to the subject include: lack of relevance to 
subject health, limitations of predictive capability, concerns of misinterpretation, and 
absence of good clinical practices standards in exploratory research typically used 
for diagnostic testing. 
If any exploratory results are definitively associated with clinical significance for 
subjects while the clinical trial is still ongoing, investigators will be contacted with 
information as to how to offer clinical diagnostic  testing (paid for by Merck) to 
 
 
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subjects enrolled and will be advised that counselling should be made available for 
all who choose to participate in this diagnostic testing.  
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all sites who participated in the Merck clinical trial, and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., Disease societies who have primary interest in the results) in 
order that physicians and patients may pursue clinical diagnostic testing if they wish 
to do so. 
6.10 Gender, Ethnicity and Minorities 
 
Although many diagnoses differ in terms of frequency by ethnic population and 
gender, every effort will be made to recruit all subjects diagnosed and treated on 
Merck clinical trials for future biomedical research.  When studies with specimens 
are conducted and subjects identified to serve as controls, every effort will be made 
to group specimens from subjects and controls to represent the ethnic and gender 
population representative of the disease under current investigation. 
6.11 Risks versus Benefits of Future Biomedical Research 
 
For future biomedical research, risks to the subject have been minimized.  Risks 
include those associated with venipuncture to obtain the whole blood specimen.  
This specimen will be obtained at the time of routine blood specimens drawn in the 
main study.  
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused. 
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and 
dosage, age, toxicities, etc.) to be reassociated to double coded specimens at the 
time of data analysis.  These subject data will be kept in a separate, secure Merck 
database, and all specimens will be stripped of subject identifiers.  No information 
concerning results obtained from future biomedical research will be entered into 
clinical records, nor will it be released to outside persons or agencies, in any way 
that could be tied to an individual subject. 
6.12  Self-Reported Ethnicity 
 
Subjects who participate in future biomedical research will be asked to provide self 
reported ethnicity.  Subjects who do not wish to provide this data may still participate 
in future biomedical research. 
 
 
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6.13 Questions 
 
Any questions related to the future biomedical research should be e-mailed directly 
to
 
 
 
 
 
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Appendix 7 
Understanding the Intent, Scope and Public Health Benefits 
of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff 
 
 
 
 
 
 
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