A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Study Designed to Evaluate the Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Profile of Bertilimumab in Patients With Active Moderate to Severe Ulcerative Colitis
Phase: PHASE2
Conditions: Ulcerative Colitis, Active Moderate, Ulcerative Colitis, Active Severe
Sponsor: Alexion Pharmaceuticals, Inc.

CONFIDENTIAL 
Protocol: Immune/BRT/UC-01 
Page 1 of 58 
Final Version 8.0 
May 23, 2018 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 
Multi-Center Study Designed to Evaluate the Safety, Efficacy, 
Pharmacokinetic and Pharmacodynamic Profile of Bertilimumab in 
Patients with Active  
Moderate to Severe Ulcerative Colitis 
Study Product: 
Bertilimumab 
Indication: 
Active Moderate to Severe Ulcerative Colitis 
Protocol Number 
Immune/BRT/UC-01 
Phase: 
2a 
Principal Investigator: 
  
 
Israel  
Name and Address of Sponsor: 
Immune Pharmaceuticals Inc. 
550 Sylvan Avenue 
Suite 101 
Englewood Cliffs, New Jersey 07632 
USA 
Tel: 201-464-2677 
Fax: 201-608-5103 
GCP Statement: 
This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
Version Number and Date: 
Version 8.0 
May 23, 2018 
The information in this document is confidential and is proprietary to the Immune Pharmaceuticals Inc  
It is understood that information in this document shall not be disclosed to any third party, in any form, 
without prior written consent of Immune Pharmaceuticals Inc. 
1
NCT #: NCT01671956

 
 
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Final Version 8.0 
 
 
May 23, 2018 
PROTOCOL SIGNATURE PAGE 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-
Center Study Designed to Evaluate the Safety, Efficacy, Pharmacokinetic and 
Pharmacodynamic Profile of Bertilimumab in Patients with Active Moderate 
to Severe Ulcerative Colitis 
Protocol Number: 
Immune/BRT/UC-01 
Study Phase: 
2a 
Sponsor: 
Immune Pharmaceuticals, Inc. 
 
 
Sponsor Representative: 
I, the undersigned, have read this protocol and agree that it contains all necessary information required 
to conduct the trial and that the protocol is in compliance with International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP) guidelines. 
 
 
 
 
 
Name, Title 
Signature 
Date  
 
 
 
 
 
 
Principal Investigator  
By signing below, I, the Investigator, approve the protocol and agree to conduct the clinical trial 
according to all stipulations of the protocol as specified in both the clinical and administrative 
sections, CRF and any protocol-related documents. I agree to comply with the ICH-GCP, World 
Medical Association Declaration of Helsinki (and relevant updates) and applicable local regulations. I 
agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Immune Pharmaceuticals Inc. I understand that the study may be terminated or enrollment 
suspended at any time by the Sponsor, or by me, at my center, if it becomes necessary in my opinion, 
to protect the best interests of the study subjects. 
 
 
Name 
Investigator Signature 
Date 
 
 
 
Center’s Name 
 
City, Country 
2

 
 
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Final Version 8.0 
 
 
May 23, 2018 
PROTOCOL VERSION HISTORY  
Version 
Main Changes 
1 
Original  
Submitted to Shaare Tzedek only 
2.0 
• 
Study changed from 24 subject, dose escalation design exploring three 
bertilimumab dose levels vs placebo, to 42 subject, randomized, placebo-
controlled study with 2:1 randomization ratio exploring a single bertilimumab 
dose level (7 mg/kg).  
2.1 
Submitted to Shaare Tzedek only 
• 
Protocol number changed to Immune/BRT/UC-01 from C2a/BRT/UC-01 to 
reflect Sponsor name 
• 
Sponsor name (Immune Pharmaceuticals Inc/Ltd.) and address updated to reflect 
offices in USA and Israel 
• 
Sponsor representative changed to 
 
• 
Criteria for statistical evaluations changed throughout from a one-sided alpha 
level of 0.10 to a two-sided alpha level of 0.05.  
• 
Consequent increase in sample size to 105 evaluable subjects randomized 2:1 to 
active vs placebo, with 80% power to detect improvement of 30% in clinical 
response for active treatment over placebo. 
• 
Addition of 10-12 clinical sites in Europe and 2-4 in the US with flexibility to 
recruit additional sites in the event of slow recruitment 
• 
Clarification of study objectives 
• 
Clarification of allowed/prohibited pre-treatment and concomitant medications in 
exclusion criteria and sections 6.9.1 and 6.9.2 
• 
Addition of diverticulitis/diverticulosis and systemic fungal infection to 
exclusion criterion 16 
• 
Deletion of AUC from list of derived PK parameters 
• 
Incorporation of flexibility in visit dates 
• 
Addition of screening test for fecal calprotectin and Clostridium difficile toxin  
• 
Randomization of eligible subjects to treatment groups moved from Visit 2 to 
screening period for logistical reasons 
• 
Addition of information regarding randomization list, treatment allocation and 
emergency access to randomization codes to section 4.3 
• 
Clarification of definition of screen failure 
• 
Reduction of sampling time points for eosinophil shape change assay during 
treatment period 
• 
Screen for active/latent TB to be performed using Interferon Gamma Release 
Assay 
• 
Amendment to classification terminology of infusion site reactions 
• 
Clarification of procedure for collection of colonic biopsies during endoscopy at 
screening and on Day 42 
• 
Introduction of central endoscopy reading 
• 
Addition of details for analysis of eotaxin-1 and eosinophil count in biopsy tissue 
• 
Addition of pharmacy instructions for preparation of bertilimumab/matching 
placebo to section 6.6 
• 
Addition of section 6.8 describing blinding and randomization 
• 
Sponsor contact for notification of SAEs changed to 
 
• 
Section 8.2.2 deleted to allow for the possibility of an interim analysis 
• 
Section 10 updated due to incorporation of electronic data capture system 
• 
Appendix A, Schedule of Activities, updated to reflect changes in protocol 
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• 
Addition of Appendix D, Changes to the Protocol in Version 2.1 
• 
Definitions for additional acronyms added to the glossary  
• 
Typographical, punctuation and grammatical errors corrected throughout 
• 
Reference to “subjects” changed to “patients” throughout including study title 
• 
The order of some words, sentences and lists have been modified for consistency 
3.0 
• 
Sponsor addresses updated to reflect new offices in USA and Israel 
• 
Sponsor representative changed to 
 
• 
Deletion of Appendix D and replacement with Protocol Version History 
• 
Return to sample size to up to 42 subjects, randomized 2:1 to active treatment vs 
placebo 
• 
Amendment of statistical sections throughout to exploratory study with 
descriptive statistics and no pre-determined hypothesis for study success 
• 
Return to number of clinical sites specified in version 2.0 
• 
Increase of bertilimumab dose level to 10 mg/kg 
• 
Stratification of enrolled subjects for prior anti-TNF treatment 
• 
Addition of UCEIS as efficacy measure 
• 
Minor reclassification of efficacy and pharmacodynamic outcome measures 
• 
Amendment to pharmacy instructions  
• 
Appendix A, Schedule of Activities, updated to reflect changes in protocol 
• 
Addition of Appendix C, Ulcerative Colitis Endoscopic Index of Severity 
• 
Deletion of Appendix C, Declaration of Helsinki 
• 
Minor wording change to the protocol title and study objectives. 
• 
Definitions of additional acronyms added to the glossary 
• 
Typographical, punctuation and grammatical errors have been corrected 
throughout 
• 
The order of some words, sentences and lists have been modified for consistency 
4.0 
• 
Change in title of Sponsor Representative 
• 
Addition of flexibility to include European clinical sites in the event of slow 
recruitment (synopsis, sections 3.0, 9.2 and 11.1) 
• 
Visit 7 moved from Day 60 to Day 56 (8 weeks) 
• 
Timepoint for post-treatment endoscopy and measurement of primary and 
secondary efficacy endpoints moved from Visit 6 (Day 42) to Visit 7 (Day 56) 
• 
Removal of reference to 5 mg/kg bertilimumab dose from section 1.3 
5.0 
• 
Deletion of inclusion criterion 6 and addition of exclusion criterion 6 to exclude 
young, childless males or those planning to have more children in the future. 
• 
Amended exclusion criterion 9 to remove discrepancy with exclusion criterion 
20 (Hb level). 
• 
Administrative changes to sections 4.3 and 6.8 to remove erroneous reference to 
three treatment arms. 
• 
Administrative changes throughout to clarify stratification according to previous 
anti-TNF treatment. 
• 
Clarification in synopsis (Study Design section) and section 5.1 regarding 
collection of serology sample – previously only referred to in Schedule of 
Assessments. 
• 
Updated Appendix C to latest version of UCEIS. 
6.0 
• 
Change of the lead PI 
• 
Change in Sponsor Representative 
• 
Amended exclusion criterion 9 (Hb level) 
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Final Version 8.0 
 
 
May 23, 2018 
• 
Removal of drug preparation instructions from section 6 and insertion of 
reference to pharmacy manual.  
7.0 
• 
Modification of criteria regarding male reproduction to allow for entry of males 
as long as they use effective contraception for the duration of the study and for 
four months following completion of the study. 
• 
Addition of exclusion criteria to exclude subjects treated with integrin blockers 
(e.g., vedolizumab) within 60 days of the screening visit. 
• 
Updated Immune Pharmaceuticals Representative contact details for SAE 
reporting. 
7.1 
• 
Correction to Declaration of Helsinki version. Version only distributed in Russia. 
7.2 
• 
Screening period extended from up to 14 days to up to 28 days  
8.0 
• 
Cover page updated to include corrected Sponsor Address and contact 
information 
• 
Page 2- Protocol Signature Page- updated with new Sponsor representative 
information 
• 
SAE Reporting to Sponsor Representative contact information updated 
• 
Addition of a prophylactic pre-medication regimen to be administered 
prior to study drug (active or placebo) administration on Day 0, 14 and 28, 
to minimize the risk of infusion reactions. The pretreatment regimen for 
infusion reaction prophylaxis is as follows: 
o 
Dexamethasone 10 mg PO 24-18 hours prior to 
administration of study drug. 
o 
Acetaminophen 1000 mg PO 1 hour prior to 
administration of study drug. 
o 
Loratadine 10 mg PO or cetirizine 10 mg PO one hour 
prior to the administration of study drug. 
In the event that dexamethasone was not administered previously, 
then 10 mg dexamethasone IV may be administered one to three 
hours prior to study drug administration. 
• 
Addition of specific instructions for management of study drug infusion in the 
event of an infusion reaction. 
• 
Addition of hypersensitivity to any of the components of the pretreatment 
regimen as an exclusion criterion. 
• 
Removal of injection site reaction assessments (and grading) after each dosing 
(and the time frames for these assessments) and replacement with the more 
relevant assessment of general infusion reaction and a grading schedule for 
infusion reactions.   
• 
Clarification that the study drug and placebo formulations include the addition of 
polysorbate, a non-ionic surfactant added to prevent protein aggregation.  This 
surfactant has always been part of the bertilimumab and placebo formulations 
delivered to the subject; its inclusion, however, is now clearly noted in the 
protocol 
• 
Inclusion of more liberal time guidelines for various study procedure 
assessments (ex: blood sampling, EKG, vital signs, etc) to more closely reflect 
the clinical reality of executing multiple study tasks within a compressed time-
frame 
• 
The threshold for the eotaxin-1 level (inclusion criterion #3) in colonic biopsy 
tissue is lowered to 50 pg/mg protein to more closely reflect the data in the 
observational study (Importance of Intestinal Eotaxin-1, Adar T. et al, Dig 
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Disease Sci, July 2016)22 upon which this criterion is based, and allow otherwise 
eligible subjects to enroll.  The data for eotaxin-1 can be stratified by screening 
levels to assess the treatment effect (the relevant article has been added to the list 
of references). 
• 
Deletion of the eosinophil shape change assay and replacement with the 
eosinophil cationic protein (ECP) assay. 
• 
Addition of Cortiment (budesonide) as allowed concomitant study medication at 
screening and throughout the study owing to its limited systemic absorption 
• 
Clarification and correction of several study procedures to be more accurately 
described.  This includes the mechanism for  SAE reporting; statistical 
methodology to be employed; randomization code unblinding; direct data entry 
of source documents; assessment of study UCEIS and Mayo scores as compared 
to screening (not baseline) values; provision of study drug on an "as-needed 
basis" as subjects are enrolled and not to be provided to the sites as stock 
inventory; clarification of requirement for male contraception throughout the 
study and for 4 months following the last treatment; and removal of erroneously 
cited central assay laboratories.  
• 
Technical and editorial changes:  replaced "patients" with the more study 
relevant term "subjects" throughout the document, as appropriate; added 
Appendix D for grading of infusion reactions; updated Corticosteroid 
Comparison Table; updated List of Abbreviations, as appropriate; and removal 
of LTD from Sponsor name. 
 
 
 
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Final Version 8.0 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center 
Study Designed to Evaluate the Safety, Efficacy, Pharmacokinetic and 
Pharmacodynamic Profile of Bertilimumab in Patients with Active Moderate to 
Severe Ulcerative Colitis 
Protocol No. 
Immune/BRT/UC-01 
Clinical Sites 
Up to 10-12 sites in Israel. Additional sites in Europe may be added in the event 
of slow recruitment. 
Study Phase 
2a 
Indication 
Active moderate to severe ulcerative colitis (UC)  
Study Objectives 
Primary Objectives:  
• To evaluate, in patients with active moderate to severe UC, the safety and 
clinical efficacy of bertilimumab administered as 3 intravenous (IV) 
infusions over 4 weeks.  
Secondary Objectives: 
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of 
bertilimumab in patients with active moderate to severe UC. 
Study Design  
This is a randomized, double blind, placebo-controlled, parallel group multi-
center study in adult patients with active moderate to severe UCa. Eligible 
subjects will be randomly assigned in a 2:1 ratio to one of two treatment groups, 
bertilimumab 10 mg/kg or matching placebo, respectively. 
The study will consist of three periods: a screening period of up to four weeks, a 
4-week double-blind treatment period (three IV infusions at 2-week intervals), 
and a safety and efficacy follow-up period of approximately 9 weeks.  
Screening Period – Visit 1 (Days -28 to -1) 
Following signing of informed consent, subjects will be screened for study 
eligibility. The following assessments will be performed: demographic data, 
medical history, prior medications, physical examination, height and weight, vital 
signs, ECG, screening for active/latent tuberculosis (TB), screening for 
Clostridium difficile toxin in stool, flexible sigmoidoscopy with biopsies, 
Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Mayo scoreb, eotaxin-
1 levels and eosinophil count in tissue, calprotectin in fecal sample and 
laboratory evaluations (hematology, biochemistry, serology and serum pregnancy 
test [for females of childbearing potential]). The screening visit may be 
conducted over multiple days. Subjects who meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to treatment groups. 
 
                                                 
a A Mayo Score of 6 to 12 (inclusive); Endoscopic evidence of active UC (i.e., Mayo Endoscopic Finding Sub-
score of ≥2) as assessed by flexible sigmoidoscopy unless colonoscopy is clinically indicated; Mayo Rectal 
Bleeding Sub-score of ≥1; Physician’s Global Assessment (PGA) of at least moderate disease (Mayo Sub-score 
≥2). 
b Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, et al. (2005 Dec) Infliximab for induction and 
maintenance therapy for ulcerative colitis. N Engl J Med. 8;353(23):2462-76. 
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Treatment Periodc – Visit 2 (Day 0), Visit 3 (Day 14), Visit 4 (Day 28) 
At Visit 2, inclusion and exclusion criteria will be reviewed. The following 
assessments will be performed at each treatment visit pre-dose: physical 
examination, vital signs, ECG, partial Mayo score, eosinophil count, serum 
eotaxin-1, high-sensitivity C-reactive protein (hs-CRP),  eosinophil cationic 
protein (ECP), pre-dose blood samples for PK (bertilimumab concentration), 
calprotectin in fecal samples, urine pregnancy test (for females of childbearing 
potential) and safety laboratory evaluations (hematology, biochemistry, 
antibodies to bertilimumab). A regimen for infusion reaction prophylaxis, 
described below (see section "Prophylaxis for Prevention of Infusion Reaction"), 
will be administered.  
At each treatment visit, following completion of the pre-dose assessments, and 
administration of the pre-treatment regimen according to the timeframes noted, 
bertilimumab/matching placebo will be administered by IV infusion over 30 
minutes. Vital signs will be recorded at 15 minutes (during infusion), 30 (+15) 
minutes (immediately post infusion), 2 hr (±20 minutes) and 4 hr (±20 minutes) 
following initiation of study drug infusion. ECG will be performed at 30 (+15) 
minutes (immediately post infusion). Blood samples for bertilimumab 
concentration (PK analysis) will be collected 30 (+15) minutes and 4 hours (±20 
minutes) following initiation of study drug infusion. I Adverse events (AE) and 
concomitant medications will be recorded.   
Follow-Up Periodd – Visit 5 (Day 35), Visit 6 (Day 42), Visit 7 (Day 56) and 
Visit 8 (Day 90)  
The following assessments will be performed at the follow-up visits: physical 
examination, vital signs, ECG, AE and concomitant medication recording, partial 
Mayo score (Visits 5, 6 and 8), safety laboratory evaluations (hematology, 
biochemistry, antibodies to bertilimumab), blood samplescollection for 
bertilimumab concentration (PK analysis), ECP, eosinophil count, serum eotaxin-
1 and hs-CRP. Calprotectin will be evaluated in fecal samples. Visit 7 (Day 56) 
will also include flexible sigmoidoscopy with biopsies, and evaluation of UCEIS, 
Mayo score, eotaxin-1 and eosinophil count in tissue samples. 
Study Duration 
Study duration for each subject will be approximately 118 days ±12 days (~16-19 
weeks) as follows: 
Screening period:  
Up to 28 days  
Treatment period:  
28 days (±3 days) 
Follow-up period:  
62 days (±9 days) 
Planned Sample 
Size 
Up to 42 subjects are planned to be recruited to this study, randomized to the two 
arms using a 2:1 active drug to placebo ratio and stratified by previous anti-TNF 
treatment. Investigators are encouraged to recruit subjects who have not received 
previous anti-TNF treatment. 
Inclusion Criteria 1. Males or females, 18 to 70 years of age inclusive.  
2. Diagnosed with active moderate to severe UC per standard diagnostic criteria 
for a minimum of 3 months The subject must present with the following at 
the screening visit: 
• Mayo score of 6-12 (inclusive).  
                                                 
c Visits 3 and 4 during the Treatment Period have a ±2 day window. 
d Visits during the Follow-Up Period have a ±3 day window. 
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• Endoscopic evidence of active mucosal disease, as assessed by 
flexible sigmoidoscopy, with an Endoscopic Finding Sub-score of ≥2 
(assessed centrally). 
• Rectal Bleeding Sub-score of ≥1.  
• Physician’s Global Assessment (PGA) Sub-score of ≥2. 
3. Levels of eotaxin-1 in biopsied colon tissue of ≥50 pg/mg protein. 
4. Adequate cardiac, renal and hepatic function as determined by the 
Investigator and demonstrated by screening laboratory evaluations and 
physical examination results; these findings must all be within normal limits 
or judged not clinically significant by the Investigator. 
5. Females of childbearing potential must agree to use effective contraception 
consistently throughout the study (such as hormonal contraception or two 
forms of barrier contraception) and have a negative serum pregnancy test at 
screening and a negative urine pregnancy test before administration of each 
study treatment. 
6. Males of childbearing potential must agree to use effective contraception 
consistently throughout the study and for a period of four months following 
the last treatment 
7. Willing and able to adhere to the study visit schedule and other protocol 
requirements. 
8. Willing and able to provide voluntary written informed consent. 
Exclusion criteria 
1. History of colonic or rectal surgery other than hemorrhoidal surgery or 
appendectomy. 
2. Currently receiving total parenteral nutrition (TPN). 
3. Positive Clostridium difficile toxin stool assay. 
4. Tested positive for active/latent mycobacterium tuberculosis (TB) infection. 
5. Pregnant or breast-feeding, or plan to become pregnant during the study. 
6. Known hypersensitivity to bertilimumab or any of the drug excipients, or to 
any components of the pretreatment regimen. 
7. History of infection requiring administration of any IV antibiotic, antiviral or 
antifungal medication within 30 days of Screening or any oral anti-infective 
agent within 14 days of Screening. 
8. Acute or fulminant UC requiring immediate surgery or severe UC evidenced 
by the following signs of toxicity: toxic megacolon, abscess, heart rate >100 
beats/min at rest, temperature >38.2°C, hemoglobin <8.0 g/dL.  
9. Ulcerative proctitis, defined as disease limited to less than 15 cm from the 
anal verge. 
10. Received a vaccine or other immunostimulator within 4 weeks prior to 
screening.  
11. Use of >4.8 g mesalazine or equivalent within 2 weeks prior to the screening 
visit.  Mesalazine ≤4.8 g is allowed if the dose during the 2 weeks prior to 
the screening visit was stable. 
12. Use of systemic corticosteroids exceeding the equivalent of 20 mg/day of 
prednisone within four weeks prior to the screening visit (see Section 6.9.1). 
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13. Change in dose of immunosuppressive drugs (e.g., corticosteroids, 6-
mercaptopurine [6-MP], azathioprine) within four weeks prior to the 
screening visit. 
14. Use of TNF-blockers (e.g., infliximab or adalimumab) within 60 days of the 
screening visit.  
15. Use of integrin blockers (e.g., vedolizumab) within 60 days of the screening 
visit.   
16. Use of chronic non-steroidal anti-inflammatory (NSAID) therapy. 
Occasional use of NSAIDs or acetaminophen for headache, arthritis, 
myalgias, menstrual cramps, etc., or daily use of low dose (81-162 mg) 
aspirin for cardiovascular prophylaxis is allowed.  
17. Subjects diagnosed with: 
• 
Crohn’s disease. 
• 
Diverticulitis or diverticulosis. 
• 
Indeterminate colitis (inability to distinguish between UC and 
Crohn’s disease [as assessed by the Investigator]). 
• 
Microscopic colitis (collagenous or lymphocytic colitis). 
• 
Ischemic or infectious colitis. 
• 
Clostridium difficile colitis within 90 days of the screening visit. 
• 
Parasitic disease within 90 days of the screening visit. 
• 
Systemic fungal infection within 90 days of the screening visit. 
18. Current or history of positive serology of hepatitis B or C, or human 
immunodeficiency virus (HIV) infection. 
19. Congenital or acquired immunodeficiency (e.g., common variable 
immunodeficiency, organ transplantation). 
20. Clinically significant abnormal laboratory test results, unless regarded by the 
Investigator as related to UC, including but not limited to: 
• 
Hemoglobin level <10.0 g/dL. 
• 
White blood cell count < 3 x 103/µL. 
• 
Lymphocyte count < 0.5 x 103/µL. 
• 
Platelet count <100 x 103/µL or >1200 x 103/µL. 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3  the upper limit of normal (ULN). 
• 
Alkaline phosphatase >3  ULN. 
• 
Serum creatinine >2  ULN. 
21. Active abuse of alcohol or drugs. 
22. Known malignancy or history of malignancy that could reduce life 
expectancy. 
23. Any condition, which in the opinion of the Investigator, would place the 
subject at an unacceptable risk if participating in the study protocol. 
24. Participation in a clinical trial of an investigational (unapproved) product 
within 1 month of the screening visit.  
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Investigational 
Product, Route 
and Dosage Form 
Bertilimumab is a recombinant human IgG4 monoclonal antibody that neutralizes 
human eotaxin-1 (eotaxin). The drug product consists of bertilimumab 
formulated in phosphate buffered saline (PBS) at a concentration of 10 mg/mL, 
presented as a sterile, clear, colorless solution in 10 mL clear glass vials. 
Polysorbate 20, a non-ionic surfactant to prevent protein aggregation, is added to 
the study drug vial during manufacture or to the saline infusion bag prior to 
subject dosing.  
Bertilimumab 10 mg/kg will be administered by IV infusion over 30 minutes. 
Reference 
Therapy 
A matching phosphate buffered saline (PBS) placebo containing polysorbate 20 
will be administered by IV infusion over 30 minutes. 
Prophylaxis for 
Prevention of 
Infusion 
Reactions 
Subjects will be administered a pre-treatment regimen consisting of 
dexamethasone 10 mg PO 18-24 hours prior to administration of study drug (i.e., 
bertilimumab or placebo).  One hour prior to administration of study drug, 
subjects will receive acetaminophen 1000 mg PO and either loratadine 10 mg PO 
or cetirizine 10 mg PO.  In the event that dexamethasone was not administered 
previously, then 10 mg dexamethasone IV may be administered one to three 
hours prior to study drug administration. 
Outcome 
Measures 
EFFICACY ENDPOINTS 
Primary Endpoint 
• 
Change in Mayo Score from screening to Day 56 (Visit 7), where 
clinical response at Day 56e is defined as: 
• 
A decrease from the pre-treatment screening Mayo score of at 
least 3 points and at least 30%  
       AND 
• 
Either a decrease from the pre-treatment screening sub-score for 
rectal bleeding of at least 1 point, or Rectal Bleeding Sub-score 
of 0 or 1. 
Secondary Endpoints 
• 
Change in UCEIS score from screening to Day 56. 
• 
Clinical remission at Day 56, defined as a total Mayo score of 2 points or 
lower, with no individual sub-score exceeding 1 point.  
• 
Mucosal healing at Day 56, defined as an absolute sub-score for 
endoscopy of 0 or 1.  
• 
Change in partial Mayo score from Day 0 to all scheduled measurement 
timepoints (efficacy follow up). 
PHARMACOKINETICS (PK) ENDPOINTS 
• 
PK analysis for bertilimumab concentration: blood samples will be 
collected on dosing days (pre-dose and at 30 minutes (+ 15 minutes) and 
4 hours (± 20 minutes) following initiation of study drug infusion) and at 
the follow-up visits. The following PK parameters will be calculated, to 
the degree possible given the number of timepoints: Cmax, Tmax, Cavg, Cmin 
and t1/2. Additional standard and exploratory PK parameters will be 
calculated if deemed necessary. 
PHARMACODYNAMIC (PD) ENDPOINTS 
                                                 
e This and all other follow-up visits have a window of ±3 days. 
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• 
Fecal calprotectin change from Day 0 (baseline) to all scheduled 
measurement timepoints. 
• 
Change in eosinophil count, ECP, serum eotaxin-1 and hs-CRP from Day 
0 to all scheduled measurement timepoints.   
• 
Change in eotaxin-1 concentration and eosinophil count in biopsy tissue 
from Screening to Day 56. 
SAFETY ENDPOINTS 
Safety will be evaluated on the basis of the following parameters: 
• 
Adverse events (AE) 
• 
Infusion reactions 
• 
Physical examination  
• 
Vital signs (blood pressure, heart rate, temperature and respiratory rate) 
• 
ECG  
• 
Concomitant medications  
• 
Laboratory evaluation (hematology, biochemistry, anti-bertilimumab 
antibodies).  
Statistical 
Methods  
 
Analysis Sets 
Analysis in this trial include safety, modified intent-to-treat (mITT) and per-
protocol (PP). 
General Analysis Methods and Data Display 
All measured variables and derived parameters will be listed individually. 
Outcomes will be summarized by treatment group, depending on their nature, as 
follows: 
For dichotomous variables: Categorization into success/failure-like categories; 
then incidence of failure and relative risk of failure in the active group compared 
to placebo with 95% confidence interval.   
For numeric continuous endpoints: Descriptive statistics and summary tables will 
include sample size, arithmetic mean, standard deviation, median, minimum and 
maximum, and 95% Confidence Interval (CI) for mean at the relevant time points 
by treatment and placebo corrected for the active treatment group. 
For ordered categories endpoints: incidences in the different categories and, after 
dichotomization into success/failure-like categories, incidence of failure and 
relative risk of failure in the active group towards placebo with 95% confidence 
intervals.  
This is an exploratory trial whose main analyses will be descriptive in nature. 
Where statistical testing will be applied, an alpha of 0.1 will be considered 
significant. At the same time, this being an exploratory trial, there will be no 
correction for overall Type I Error. The data will be analyzed using the SAS® 9.1 
(or higher) software package (SAS Institute, Cary, North Carolina). 
Safety Endpoint Analysis 
Safety endpoint analysis will be descriptive in nature and done on the safety 
anlysis set. 
Effiacy Endpoints Analysis 
Analysis of all efficacy endpoints will be performed on the mITT set. The PP set 
will be used as supplementary analyses to test the robustness of the results. 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ..................................................................................................................... 2 
PROTOCOL VERSION HISTORY ................................................................................................................... 3 
PROTOCOL SYNOPSIS ..................................................................................................................................... 7 
TABLE OF CONTENTS ................................................................................................................................... 13 
GLOSSARY ........................................................................................................................................................ 16 
1. 
INTRODUCTION ...................................................................................................................................... 18 
1.1 ULCERATIVE COLITIS ........................................................................................................................... 18 
1.1.1 
The Role of Eotaxin and Eosinophils in Inflammatory Bowel Disease ............................. 18 
1.2 INVESTIGATIONAL THERAPY ................................................................................................................ 18 
1.2.1 
Nonclinical Studies ............................................................................................................ 18 
1.2.2 
Clinical Studies .................................................................................................................. 19 
1.3 STUDY RATIONALE .............................................................................................................................. 19 
1.3.1 
Rationale for Dose Selection .............................................................................................. 19 
1.3.2 
Allergic and Infusion Reactions ......................................................................................... 20 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 20 
2.1 STUDY OBJECTIVES .............................................................................................................................. 20 
2.2 STUDY ENDPOINTS AND OUTCOMES .................................................................................................... 20 
2.2.1 
Efficacy Endpoints ............................................................................................................. 20 
2.2.2 
Pharmacokinetic Endpoints ................................................................................................ 21 
2.2.3 
Pharmacodynamic Endpoints ............................................................................................. 21 
2.2.4 
Safety Endpoints ................................................................................................................ 21 
3. 
STUDY DESIGN ........................................................................................................................................ 21 
4. 
STUDY POPULATION ............................................................................................................................ 22 
4.1 INCLUSION CRITERIA ........................................................................................................................... 22 
4.2 EXCLUSION CRITERIA .......................................................................................................................... 22 
4.3 SUBJECT IDENTIFICATION AND TREATMENT ALLOCATION................................................................... 24 
4.4 SCREENING FAILURES .......................................................................................................................... 24 
4.5 REMOVAL, REPLACEMENT, OR EARLY DISCONTINUATION OF SUBJECTS FROM THERAPY OR 
ASSESSMENT ........................................................................................................................................ 24 
4.5.1 
Handling of Early Discontinuation ..................................................................................... 25 
4.5.2 
Adverse Events ................................................................................................................... 25 
4.6 SPONSOR'S TERMINATION OF STUDY .................................................................................................... 25 
5. 
STUDY PROCEDURES AND ASSESSMENTS..................................................................................... 25 
5.1 SCREENING PERIOD (VISIT 1, DAY -28 TO DAY -1) .............................................................................. 25 
5.2 TREATMENT PERIOD: VISIT 2 (DAY 0), VISIT 3 (DAY 14) AND VISIT 4 (DAY 28) ................................. 26 
5.3 FOLLOW-UP PERIOD: VISIT 5 (DAY 35), VISIT 6 (DAY 42), VISIT 7 (DAY 56) AND VISIT 8 (DAY 90) ... 27 
5.4 EARLY DISCONTINUATION STUDY VISIT .............................................................................................. 28 
5.5 UNSCHEDULED VISIT ........................................................................................................................... 28 
5.6 SAFETY ASSESSMENTS ......................................................................................................................... 28 
5.6.1 
Adverse Events (AEs) ........................................................................................................ 28 
5.6.2 
Concomitant Medications ................................................................................................... 29 
5.6.3 
Vital Signs .......................................................................................................................... 29 
5.6.4 
Electrocardiogram .............................................................................................................. 29 
5.6.5 
Physical Examination ......................................................................................................... 29 
5.6.6 
Infusion Reactions .............................................................................................................. 29 
5.6.7 
Safety Laboratory Assessments .......................................................................................... 30 
5.7 EFFICACY ASSESSMENTS ...................................................................................................................... 30 
5.7.1 
Sigmoidoscopy ................................................................................................................... 30 
5.7.2 
Mayo score ......................................................................................................................... 31 
5.8 PD ASSESSMENTS ................................................................................................................................ 31 
5.8.1 
Fecal calprotectin ............................................................................................................... 31 
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5.8.2 
Eosinophil count, serum eotaxin-1, hs-CRP and ECP ........................................................ 31 
5.8.3 
Eosinophil count and eotaxin-1 concentrations in biopsy tissue ........................................ 31 
5.9 PK ASSESSMENTS ................................................................................................................................ 31 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................................... 32 
6.1 IDENTITY OF INVESTIGATIONAL PRODUCT ........................................................................................... 32 
6.2 STUDY DRUG ADMINISTRATION AND DOSAGE ..................................................................................... 32 
6.3 MANUFACTURING OF STUDY MEDICATION .......................................................................................... 32 
6.4 PACKAGING AND LABELLING OF STUDY MEDICATION ......................................................................... 32 
6.5 DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION ....................................................................... 32 
6.6 STORAGE AND INSTRUCTIONS FOR PREPARATION AND INFUSION OF THE INVESTIGATIONAL PRODUCT 33 
6.7 ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT ................................................ 33 
6.8 BLINDING AND RANDOMIZATION ......................................................................................................... 34 
6.9 CONCOMITANT THERAPY ..................................................................................................................... 34 
6.9.1 
Allowed Medications ......................................................................................................... 34 
6.9.2 
Prohibited Prior and Concomitant Medication ................................................................... 35 
7. 
SAFETY AND PHARMACOVIGILANCE ............................................................................................ 35 
7.1 ADVERSE EVENT .................................................................................................................................. 35 
7.2 SERIOUS ADVERSE EVENT ................................................................................................................... 36 
7.3 DEFINITION OF AN UNEXPECTED ADVERSE EVENT .............................................................................. 37 
7.4 NOTIFICATION ABOUT SERIOUS OR UNEXPECTED ADVERSE EVENTS ................................................... 37 
8. 
PLANNED STATISTICAL ANALYSES AND METHODS ................................................................. 38 
8.1 DESIGN CONSIDERATIONS .................................................................................................................... 38 
8.2 DETERMINATION OF SAMPLE SIZE ....................................................................................................... 38 
8.3 STATISTICAL METHODS ....................................................................................................................... 39 
8.3.1 
Analysis Sets ...................................................................................................................... 39 
8.3.2 
Subject Disposition ............................................................................................................ 40 
8.3.3 
Demographics and Baseline Characteristics ....................................................................... 40 
8.3.4 
Efficacy Endpoints Analysis .............................................................................................. 40 
8.3.5 
Pharmacokinetic Analysis .................................................................................................. 41 
8.3.6 
Pharmacodynamic Analysis ............................................................................................... 41 
8.3.7 
Safety Analysis ................................................................................................................... 41 
8.3.8 
Interim Analysis ................................................................................................................. 43 
9. 
ETHICS ...................................................................................................................................................... 43 
9.1 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ............................................. 43 
9.2 ETHICAL CONDUCT OF THE STUDY ...................................................................................................... 43 
9.3 PROTOCOL REVISIONS AND/OR DEVIATIONS ........................................................................................ 43 
9.4 STUDY SUBJECT INFORMATION AND CONSENT .................................................................................... 43 
9.5 STUDY SUBJECT INSURANCE ................................................................................................................ 44 
9.6 PERSONAL DATA PROTECTION ............................................................................................................. 44 
10. QUALITY CONTROL AND QUALITY ASSURANCE ....................................................................... 44 
10.1 AUDITS AND INSPECTIONS .................................................................................................................... 44 
10.2 STUDY MONITORING ............................................................................................................................ 44 
10.2.1 
Source Data and Records ................................................................................................... 44 
10.2.2 
Original Records ................................................................................................................ 45 
10.2.3 
Target e*CRF® (Electronic Data Capture) ......................................................................... 45 
10.2.4 
Target e*CTR® Viewer (Target e*Clinical Trial Record Viewer) ..................................... 45 
10.2.5 
Certified Copies of Original Data ....................................................................................... 45 
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10.3 QUALITY LABORATORY STANDARDS ................................................................................................... 46 
10.4 DATA MANAGEMENT ........................................................................................................................... 46 
11. STUDY ADMINISTRATION ................................................................................................................... 47 
11.1 PARTICIPATING CENTERS ..................................................................................................................... 47 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION ......................................................................... 47 
11.3 CLINICAL TRIAL SUPPLIES ................................................................................................................... 48 
11.4 INVESTIGATOR SITE FILE ..................................................................................................................... 48 
11.5 STUDY COMPLETION ............................................................................................................................ 48 
11.6 FINAL REPORT...................................................................................................................................... 49 
11.7 RETENTION OF STUDY RECORDS .......................................................................................................... 49 
11.8 CONFIDENTIALITY AND PUBLICATION .................................................................................................. 49 
12. REFERENCES ........................................................................................................................................... 50 
13. APPENDICES ............................................................................................................................................ 52 
 
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GLOSSARY 
Abbreviation/Term 
Definition 
5-ASA 
5-aminosalicylic acid  
6-MP 
6-mercaptopurine 
AE 
 
Adverse event 
ALT 
Alanine aminotransferase 
ASI 
Application Setup Instructions 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification) 
Cavg 
Average bertilimumab serum concentration 
CDM 
Clinical Data Management 
CDMoP 
Clinical Data Monitoring Plan 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum serum concentration 
Cmin 
Minimum serum concentration 
CRF 
Case report form (also eCRF for electronic CRF) 
CRO 
Contract research organization 
CV% 
Coefficient of variance 
DEHP 
Di (2-ethyl hexyl) phthalate also known as Di-octyl phthalate (DOP) 
DM 
Data Management 
EDC 
Electronic Data Capture 
ECP 
Eosinophil cationic protein 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
Hr 
Hour 
hs-CRP 
High sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G  
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LOCB 
Last observation carried backward 
LOCF 
Last observation carried forward 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
Multiple imputation 
mITT 
Modified intent to treat 
mL 
Milliliter 
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Abbreviation/Term 
Definition 
mM 
Millimolar 
MOH 
Ministry of Health 
NSAID 
Non-steroidal anti-inflammatory 
PBS 
Phosphate buffered saline 
PD 
Pharmacodynamic 
PGA 
Physician’s Global Assessment 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per protocol 
PPD 
Purified protein derivative 
PVC 
Polyvinyl chloride 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
T1/2 
Half-live of bertilimumab in serum 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to reach maximum bertilimumab serum concentration 
TNF 
Tumor necrosis factor 
TPN 
Total parenteral nutrition 
UC 
Ulcerative colitis 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 
 
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1. INTRODUCTION 
1.1 ULCERATIVE COLITIS 
Ulcerative colitis (UC) is a chronic and relapsing inflammatory disease characterized by 
diffuse mucosal inflammation limited to the colon and rectum without evidence of any 
specific causative pathogens [1]. The disease course is characterized by exacerbations 
(including symptoms of diarrhea, abdominal pain, and rectal bleeding) and remissions [2, 3]. 
The worldwide incidence rates of UC range between 1.25 to 20.3 new cases per 
100,000/year, with approximately 10–12 new cases per 100,000/year in North America and 
Europe [4-7]. 
The goal of the medical treatment in UC is to rapidly induce a steroid-free remission while at 
the same time preventing complications of the disease itself and its treatment. The choice of 
treatment depends on severity, localization and the course of the disease. More extensive or 
severe disease is treated with oral and local 5-ASA compounds and corticosteroids to induce 
remission. Patients who do not respond to this treatment require hospitalization, intravenous 
(IV) steroids or, when refractory, calcineurin inhibitors (cyclosporine, tacrolimus), tumor 
necrosis factor-α antibodies (infliximab, adalimumab) or immunomodulators (6-
mercaptopurine [6-MP], azathioprine) [3, 8-10]. 
1.1.1 The Role of Eotaxin and Eosinophils in Inflammatory Bowel Disease 
Eotaxin-1 is an eosinophil-selective chemokine that is constitutively expressed in the 
intestine and various other tissues [11]. It is produced by a variety of cell types including 
eosinophils, epithelial cells, fibroblasts, endothelial cells, T-lymphocytes, monocytes and 
macrophages following induction by pro-inflammatory mediators [12].  Eotaxin is known to 
play a significant role in the tissue accumulation of eosinophils that accompanies allergic 
inflammation. While eosinophils are an important component of innate immunity, the 
accumulation of eosinophils in tissues can be detrimental.  Eosinophil degranulation products 
have significant cytotoxic effects on tissues, and cytokines known to be released by 
eosinophils enhance inflammatory signaling. 
An association between eosinophils and the initiation of mucosal injury and clinical relapse 
in UC [13, 14] and Crohn’s disease [15] has been documented, and serum eotaxin levels are 
increased in patients with these diseases [16, 17].  These studies provide strong rationale for 
the use of therapeutic agents targeting eosinophils and molecules that regulate eosinophil 
function such as eotaxin-1 in the treatment of UC. 
1.2 INVESTIGATIONAL THERAPY 
Bertilimumab is a human monoclonal immunoglobulin G (IgG) 4 antibody that neutralizes 
human eotaxin-1 and inhibits its function. The product is manufactured in a mammalian cell   
line engineered using recombinant DNA technology to produce the antibody. 
1.2.1 Nonclinical Studies 
A single-dose toxicity study with bertilimumab was conducted in Rhesus monkeys (6 per 
dose group). Monkeys were administered a single IV infusion of bertilimumab at a dose of 10 
or 100 mg/kg and observed for 28 and 7 days, respectively. No effects on morbidity or 
mortality were observed. Body weights and food consumption were not impacted by 
bertilimumab treatment and all clinical chemistry and hematological parameters examined 
were unaffected. In a repeat-dose toxicity study, Rhesus monkeys (6 per dose group) were 
administered 10, 30 or 100 mg/kg bertilimumab twice weekly by IV infusion for 28 days. 
There were no deaths or significant morbidity following treatment with bertilimumab. No 
effects on clinical chemistry, ophthalmoscopic or hematological parameters or body weight 
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were observed. At sacrifice (end of study period), there were no treatment-related changes in 
organ weight or macroscopic/microscopic observations. For detailed information on pre-
clinical studies, please refer to the Investigator’s Brochure. 
1.2.2 Clinical Studies 
Three clinical studies of bertilimumab were conducted in Europe: a Phase 1 study in healthy 
volunteers (study CAT-213-0101), and Phase 2 studies in patients with allergic rhinitis and 
allergic conjunctivitis (studies CAT-213-0103 and CAT-213-0203, respectively).  Ninety-
nine (99) individuals have received bertilimumab: 45 via the intravenous (45/99, 45%), eight 
(8) via the intranasal (8/99, 8%), and 46 via the topical ocular (46/99, 46%) route of 
administration. Thirteen individuals received IV bertilimumab at doses ≥500 mg (maximum 
dose administered: 770 mg).  In these studies, bertilimumab was well tolerated and no dose-
related adverse events (AEs) were noted.  To date, no clinical studies of bertilimumab have 
been conducted in patients with UC. For additional information on these clinical studies, 
please refer to the Investigator’s Brochure. 
1.3 STUDY RATIONALE 
Bertilimumab is the first monoclonal antibody to specifically neutralize human eotaxin-1. 
Bertilimumab has been shown to interrupt the eotaxin-stimulated migration of cells and may 
therefore be useful in the treatment of human diseases such as UC, where eosinophil 
accumulation is an important feature. 
The purpose of this study is to evaluate the safety and efficacy of bertilimumab compared to 
placebo in adult patients with active moderate to severe UC. The treatment period will 
include three IV infusions of bertilimumab (10 mg/kg) or placebo at two-week intervals, on 
study Days 0, 14 (±2 days) and 28 (±2 days).  Subjects will be followed for an additional 9 
weeks after the end of treatment on study Days 35, 42, 56 and 90 (±3 days per follow-up 
visit). The study design will allow evaluation of the safety and efficacy of bertilimumab over 
the treatment and follow-up periods using validated assessment tools. In addition, the 
pharmacokinetics (PK) and pharmacodynamics (PD) of bertilimumab will be assessed 
throughout the study. 
1.3.1 Rationale for Dose Selection 
Immune Pharmaceuticals has chosen to evaluate an IV dose of 10 mg/kg bertilimumab every 
2 weeks based on the following safety, PK and PD data: 
• No safety concerns were identified in Study CAT-213-0101, in which subjects 
received a single IV bertilimumab dose of up to 10 mg/kg (corresponding to absolute 
doses of 570 to 770 mg in four subjects), or in Study CAT-213-0103, in which 
subjects received a single IV bertilimumab dose of up to 500 mg. 
• The PD endpoint in Study CAT-213-0101, eotaxin-induced eosinophil shape change, 
was inhibited by serum from all subjects who received bertilimumab doses of 1 
mg/kg and higher, with nearly 100% inhibition in the 5 mg/kg and 10 mg/kg dose 
groups. A shape change in eosinophils is considered a requisite process in 
chemotaxis, and can be taken as evidence of an impending migratory response. 
Maximum inhibition occurred at concentrations of ~40 μg/mL. At 35 days post-dose, 
high levels of inhibition were still observed despite low concentrations of 
bertilimumab, suggesting that the PD response was prolonged when compared with 
the bertilimumab plasma concentrations. 
• In Study CAT-213-001, after a single dose of 5 mg/kg, unbound bertilimumab had a 
mean half-life of 211 hours (CV% 30.5); the mean half-life after a single 10 mg/kg 
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dose was 194 hours (CV% 27.1). The half-life of total bertilimumab (bound plus 
unbound) is estimated to be 16-20 days. The data from this study also suggest dose 
proportionality in bertilimumab exposure between these two doses. 
• No antibodies to bertilimumab were detected in any of the three previous single-dose 
clinical trials. 
Systemic markers of bertilimumab activity (peripheral blood eosinophil count, serum levels 
of eotaxin-1, ECP, and hs-CRP), as well as eosinophil count and eotaxin level in intestinal 
tissue, and their correlation with the therapeutic response in UC patients will be also assessed. 
1.3.2 Allergic and Infusion Reactions 
Monoclonal antibodies, including fully human antibodies, can cause allergic or non-allergic 
infusion reactions when administered intravenously, and three subjects in bertilimumab 
clinical trials have experienced infusion reactions, one serious.  Accordingly, several 
precautions have been instituted in the protocol to decrease the risk of infusion reactions and 
possible anaphylaxis, including the administration of study drugf in a controlled setting with 
ready availability of antihistamines, fluids, epinephrine, and staff trained in the management 
of anaphylaxis and a pre-study drug regimen with antihistamines, acetaminophen and 
corticosteroids. 
Grading of infusion reactions will be made according to the criteria set forth in Appendix D, 
as are criteria for anaphylaxis, by definition, a grade 4 reaction. Management of-study drug 
infusion in the event of an infusion reaction is set forth in Appendix D as well; if additional 
interventions beyond interruption of- study drug infusion are indicated, then the investigator 
should manage the reaction according to his or her clinical judgement and any applicable 
institutional protocols. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 STUDY OBJECTIVES 
Primary Objective  
• To evaluate, in patients with active moderate to severe UC, the safety and clinical 
efficacy of bertilimumab administered as 3 IV infusions over 4 weeks.  
Secondary Objectives  
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of 
bertilimumab in patients with active moderate to severe UC. 
2.2 STUDY ENDPOINTS AND OUTCOMES 
2.2.1 Efficacy Endpoints 
Primary 
• Change in Mayo Score from screening to Day 56 (Visit 7). Clinical response at Day 
56g will be defined as: 
o A decrease from the pre-treatment screening Mayo score of at least 3 points 
and at least 30%  
 
AND 
                                                 
f In this protocol, “study drug” refers to either bertilimumab or placebo. 
g This and all other follow-up visits have a window of ±3 days. 
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o Either a decrease from the pre-treatment screening sub-score for rectal 
bleeding of at least 1 point, or Rectal Bleeding Sub-score of 0 or 1. 
Secondary  
• Change in UCEIS score from screening to Day 56.  
• Clinical remission at Day 56, defined as a total Mayo score of 2 points or lower, with 
no individual sub-score exceeding 1 point.  
• Mucosal healing at Day 56, defined as an absolute sub-score for endoscopy of 0 or 1.  
• Change in partial Mayo score from Day 0 to all scheduled measurement timepoints 
(efficacy follow up).     
2.2.2 Pharmacokinetic Endpoints 
• Blood samples will be collected on dosing days (pre-dose and at 30 minutes (+ 15 
minutes) and 4 hours (±20 minutes) following the initiation of study drug infusion) 
and at the follow-up visits. The following PK parameters will be calculated: Cmax, 
Tmax, Cavg, Cmin, and t1/2. Additional standard and exploratory PK parameters will be 
calculated if deemed necessary. 
2.2.3 Pharmacodynamic Endpoints 
• Fecal calprotectin change from Day 0 (baseline) to all scheduled measurement 
timepoints. 
• Change in eosinophil count, serum eotaxin-1,hs-CRP and ECP from Day 0 to all 
scheduled measurement timepoints.   
• Change in eotaxin-1 concentration and eosinophil count in biopsy tissue from 
Screening to Day 56. 
2.2.4 Safety Endpoints 
Safety will be evaluated on the basis of the following parameters: 
• Adverse events (AE) 
• Infusion reactions 
• Physical examination  
• Vital signs (blood pressure, heart rate, temperature and respiratory rate) 
• ECG  
• Concomitant medications  
• Laboratory evaluation (hematology, biochemistry, anti-bertilimumab antibodies).  
3. STUDY DESIGN 
This is a randomized, double blind, placebo-controlled, parallel group multi-center study in 
adult patients with active moderate to severe UCh. Eligible subjects will be randomly 
assigned in a 2:1 ratio to one of two treatment groups, bertilimumab 10 mg/kg or matching 
placebo, stratified by previous anti-TNF treatment. Approximately the same proportion of 
subjects who received previous anti-TNF treatment will be included in each arm. The study 
                                                 
h A Mayo Score of 6 to 12 (inclusive); Endoscopic evidence of active ulcerative colitis (i.e., Endoscopic Finding 
Sub-score of ≥2) as assessed by flexible sigmoidoscopy unless colonoscopy is clinically indicated; Rectal 
Bleeding Sub-score of ≥1; Physician’s Global Assessment (PGA) of at least moderate disease (Mayo Sub-score 
≥2). 
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will consist of three periods: a screening period of up to four weeks, a 4-week double-blind 
treatment period (three IV infusions at two-week intervals), and a safety and efficacy follow-
up period of approximately 9 weeks. A schedule of events for this study is shown in 
Appendix A. The total duration of subject participation will be ~16-19 weeks. The study will 
be conducted in up to 10-12 sites in Israel. Additional sites in Europe may be added in the 
event of slow recruitment.  
4. STUDY POPULATION 
The study will be conducted in patients aged 18 to 70 years diagnosed with active moderate 
to severe UC. Subjects who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized to treatment groups. 
4.1 INCLUSION CRITERIA 
1. 
Males or females, 18 to 70 years of age inclusive. 
2. 
Diagnosed with active moderate to severe UC per standard diagnostic criteria for a 
minimum of 3 months.  The subject must present with the following at the screening 
visit: 
• Mayo score of 6-12 (inclusive).   
• Endoscopic evidence of active mucosal disease, as assessed by flexible 
sigmoidoscopy, with an Endoscopic Finding Sub-score of ≥2 (assessed centrally). 
• Rectal Bleeding Sub-score of ≥1.  
• Physician’s Global Assessment (PGA) Sub-score of ≥2. 
3. 
Levels of eotaxin-1 in biopsied colon tissue of ≥50 pg/mg protein. 
4. 
Adequate cardiac, renal and hepatic function as determined by the Investigator and 
demonstrated by screening laboratory evaluations and physical examination results; 
these findings must all be within normal limits or judged not clinically significant by 
the Investigator. 
5. 
Females of childbearing potential must agree to use effective contraception consistently 
throughout the study (such as hormonal contraception or two forms of barrier 
contraception) and have a negative serum pregnancy test at screening and a negative 
urine pregnancy test before administration of each study treatment. 
6. 
Males of childbearing potential must agree to use effective contraception consistently 
throughout the study and a period of four months following the end of the study treatment- 
7. 
Willing and able to adhere to the study visit schedule and other protocol requirements. 
8. 
Willing and able to provide voluntary written informed consent. 
4.2 EXCLUSION CRITERIA 
1. 
History of colonic or rectal surgery other than hemorrhoidal surgery or appendectomy. 
2. 
Currently receiving total parenteral nutrition (TPN). 
3. 
Positive Clostridium difficile toxin stool assay. 
4. 
Tested positive for active/latent mycobacterium tuberculosis (TB) infection. 
5. 
Pregnant or breast-feeding, or plan to become pregnant during the study. 
6. 
Known hypersensitivity to bertilimumab or any of the drug excipients or to any 
components of the pretreatment regimens. 
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7. 
History of infection requiring administration of any IV antibiotic, antiviral or antifungal 
medication within 30 days of Screening or any oral anti-infective agent within 14 days 
of Screening. 
8. 
Acute or fulminant UC requiring immediate surgery or severe UC evidenced by the 
following signs of toxicity: toxic megacolon, abscess, heart rate >100 beats/min at rest, 
temperature >38.2°C, hemoglobin <8.0 g/dL.  
9. 
Ulcerative proctitis, defined as disease limited to less than 15 cm from the anal verge. 
10. 
Received a vaccine or other immunostimulator within 4 weeks prior to screening.  
11. 
Use of>4.8 g mesalazine or equivalent within 2 weeks prior to the screening visit.  
Mesalazine ≤4.8 g is allowed if the dose during the 2 weeks prior to the screening visit 
was stable. 
12. 
Use of systemic corticosteroids exceeding the equivalent of 20 mg/day of prednisone 
(see Section 6.9.1) within four weeks prior to the screening visit. 
13. 
Change in dose of immunosuppressive drugs (e.g., corticosteroids, 6-MP, azathioprine) 
within four weeks prior to the screening visit. 
14. 
Use of TNF-blockers (e.g., infliximab, adalimumab) within 60 days of the screening 
visit. 
15. 
Use of integrin blockers (e.g., vedolizumab) within 60 days of the screening visit.   
16. 
Use of chronic non-steroidal anti-inflammatory (NSAID) therapy. Occasional use of 
NSAID and acetaminophen for headache, arthritis, myalgias, menstrual cramps etc., 
daily use of low-dose (81-162 mg) aspirin for cardiovascular prophylaxis is permitted. 
17. 
Subject diagnosed with: 
• Crohn’s disease 
• Diverticulitis or diverticulosis 
• Indeterminate colitis (inability to distinguish between UC and Crohn’s disease [as 
assessed by the Investigator]) 
• Microscopic colitis (collagenous or lymphocytic colitis) 
• Ischemic or infectious colitis 
• Clostridium difficile colitis within 90 days of the screening visit 
• Parasitic disease within 90 days of the screening visit 
• Systemic fungal infection within 90 days of the screening visit. 
18. 
Current or history of positive serology of hepatitis B or C, or human immunodeficiency 
virus (HIV) infection. 
19. 
Congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, 
organ transplantation). 
20. 
Clinically significant abnormal laboratory test results, unless regarded by the 
Investigator as related to UC, including but not limited to: 
• Hemoglobin level < 10.0 g/dL 
• White blood cell count < 3 x 103/µL 
• Lymphocyte count < 0.5 x 103/µL 
• Platelet count < 100 x 103/µL or > 1200 x 103/µL 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3  the 
upper limit of normal (ULN) 
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• Alkaline phosphatase >3  ULN 
• Serum creatinine > 2  ULN. 
21. 
Active abuse of alcohol or drugs. 
22. 
Known malignancy or history of malignancy that could reduce life expectancy. 
23. 
Any condition, which in the opinion of the Investigator, would place the subject at an 
unacceptable risk if participating in the study protocol. 
24. 
Participation in a clinical trial of an investigational (unapproved) product within 1 month 
of the screening visit. 
4.3 SUBJECT IDENTIFICATION AND TREATMENT ALLOCATION 
At screening, all subjects who signed informed consent will be identified by a screening 
number, their initials and birth date. Subjects who meet all inclusion criteria and none of the 
exclusion criteria will be randomized to treatment groups. Subjects will be block randomized 
centrally (i.e., not within each center) and stratified by previous anti-TNF treatment. 
Specifically, the randomization scheme will ensure that approximately equal proportions of 
subjects who received previous anti-TNF treatment will be in each of the two treatment arms. 
The randomization list specifying treatment assignments will be generated by the Clinical 
Research Organization (CRO). Within each anti-TNF treatment strata, each eligible subject 
will be assigned a treatment corresponding to the randomization number specified on the 
randomization list in the order in which they are enrolled; i.e. separate block randomization 
sequences will be generated for each anti-TNF strata and each subject will be given a 
randomization number in sequence within his or her strata. The randomization number 
assigned to the subject will be recorded by the pharmacist on the infusion bag when the dose 
is prepared. 
In the event of a medical emergency requiring knowledge of the study drug assignment, the 
Investigator will be provided access to the randomization code in the secured database by the 
data management team.   
4.4 SCREENING FAILURES 
Subjects who fail to meet the eligibility criteria at any stage prior to randomization are 
defined as screen failures. All screen failures will be documented on the screening log, which 
documents the screening number, subject’s initials, birth date and reason(s) for screen failure. 
The screening log will be kept in the Investigator’s Site File. Screen failure subjects will not 
be enrolled in the study and will receive the local standard-of-care.  
4.5 REMOVAL, REPLACEMENT, OR EARLY DISCONTINUATION OF SUBJECTS 
FROM THERAPY OR ASSESSMENT 
Subjects are free to discontinue their participation in the study at any time and without 
prejudice to further treatment.  The Investigator must withdraw any subject from the study if 
that subject requests to be withdrawn, or if it is determined that continuing in the study would 
result in a significant safety risk to the subject.  Withdrawn subjects will not be replaced. 
The subject’s participation in this study may be discontinued due to the following reasons: 
• Subject withdraws consent. 
• Intolerable adverse event (any subject experiencing a grade 3 or 4 infusion reaction 
will be withdrawn from the study). 
• Subject’s need for medication prohibited by the protocol. 
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• The Investigator decides that continuing in the study would not be in the subject’s 
best interest. 
• The subject is noncompliant with the protocol. 
• The subject becomes pregnant. 
• Upon the decision of relevant Regulatory Authorities and/or the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). 
Subjects who progress and/or relapse will be withdrawn from the study at the Investigator’s 
discretion and will be able to receive local standard-of-care. 
4.5.1 Handling of Early Discontinuation 
If a subject is withdrawn from the study, either at his or her request or at the Investigator’s 
discretion, or fails to return, every effort should be made to determine the reason. This 
information will be recorded on the subject’s case report form (CRF). All subjects who 
withdraw from the study prematurely, regardless of cause, should undergo Early 
Discontinuation Study Visit (see Section 5.4). It is important to obtain follow-up data for any 
subject withdrawn due to an AE or abnormal laboratory test finding.  In any case, every effort 
must be made to undertake safety follow-up procedures. 
4.5.2 Adverse Events 
Any serious AE (SAE) must be reported to the Sponsor or Sponsor's designee (by telephone/ 
fax/text/email) as well as by inputting to the EDC within 24 hours; the IRB/IEC must be 
notified as required, according to site’s regulations (for SAE notification procedures, refer to 
7.4).  
In the event of any AEs considered to be clinically significant by the Investigator, subjects 
will be followed up with appropriate medical management until the outcome is determined or 
stabilized, according to the Investigator’s clinical judgment. All follow-up information will 
be recorded in the subject's CRF until resolution of the AE. Subsequent follow-up will be 
documented in the subject's personal file. 
4.6 SPONSOR'S TERMINATION OF STUDY  
The Sponsor reserves the right to discontinue the study at any time at the participating centers 
for any reason.  Regulatory Authorities also have the right to terminate the study for any 
reason. 
5. STUDY PROCEDURES AND ASSESSMENTS 
The schedule of events for this study is shown in Appendix A.  No protocol related 
procedures, including cessation of prohibited concomitant medications should be performed 
before subjects provide written informed consent. Study related events and activities 
including specific instructions, procedures, concomitant medications, dispensing of study 
medication and descriptions of AEs should be recorded in the appropriate source documents 
and CRF. The total amount of blood drawn during this study and by study visit is detailed in 
the Laboratory Manual. 
5.1 SCREENING PERIOD (VISIT 1, DAY -28 TO DAY -1) 
The purpose and procedures of the study will be fully explained to participating subjects.  
Those wishing to enroll in the study will sign a written informed consent prior to initiating 
any study related evaluations or procedures.  
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The following assessments will be done at the screening visit, up to 28 days before initiation 
of treatment (Day 0): 
• Review and sign Informed Consent 
• Assign screening number 
• Inclusion and Exclusion Criteria 
• Medical history and demographic data 
• Prior and concomitant medications 
• Physical examination (including vital signs, height and weight measurements) 
• ECG 
• Screen for active/latent tuberculosis (Interferon Gamma Release Assay)  
• Screen for C. Difficile toxin in stool sample 
• Flexible sigmoidoscopy with biopsies. At least 3 tissue samples are required from 
area of active inflammation. Additional biopsy samples may be obtained at the 
Investigator’s discretion for histological assessment.  
• Mayo score  
• UCEIS 
• Eotaxin-1 in tissue will be measured using two of the biopsy samples  
• Eosinophil count in tissue will be measured histologically using the remaining biopsy 
sample 
• Calprotectin in fecal sample  
• Laboratory evaluations: hematology, biochemistry, serology and serum pregnancy 
test for females of childbearing potential. 
• Eligible subjects will be randomized in a 2:1 ratio to one of two treatment arms, 
bertilimumab 10 mg/kg or matching placebo. 
The screening visit may be conducted over multiple days. Screening visit data (Mayo score, 
UCEIS, eotaxin-1 and eosinophil count in tissue sample) will be considered baseline data for 
statistical analysis purposes. 
5.2 TREATMENT PERIODi: VISIT 2 (DAY 0), VISIT 3 (DAY 14) AND VISIT 4 
(DAY 28)  
At Visit 2 (Day 0), inclusion exclusion criteria will be reviewed.   
The following assessments will be performed at each treatment visit (Day 0, Day 14 and Day 
28) pre-dose:  
• Physical examination  
• Vital signs  
• ECG  
• Partial Mayo score  
• Safety laboratory evaluations: hematology, biochemistry, antibodies to bertilimumab.  
• Blood samples for eosinophil countj, serum eotaxin-1, hs-CRPk and ECP  
                                                 
i Visits 3 and 4 during the Treatment Period have a ±2 day window. 
j Done using the hematology blood sample. 
k Done using the biochemistry blood sample. 
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• Blood samples for bertilimumab (PK analysis)  
• Calprotectin in fecal samples  
• Urine pregnancy test (for females of childbearing potential) 
Subjects will receive a pretreatment regimen for infusion reaction prophylaxis.  The regimen 
is as follows: 
• Dexamethasone 10 mg PO 24-18 hours prior to administration of study drug. 
• Acetaminophen 1000 mg PO 1 hour prior to administration of study drug. 
• Either loratadine 10 mg PO or cetirizine 10 mg PO one hour prior to the 
administration of study drug. 
In the event that dexamethasone was not administered previously, then 10 mg dexamethasone 
IV may be administered 1-3 hours prior to study drug administration. 
Following completion of pre-dose assessments and administration of pretreatment regimen 
according to the appropriate timelines above, study drug will be administered by IV infusion 
over 30 minutes.  
Subjects will remain in the clinic for up to 4 hours following completion of the 30 minutes IV 
infusion for PK assessment and safety follow-up.  The following procedures will be 
conducted post-dose: 
• Vital signs: 15 minutes (during infusion), 30 (+ 15) minutes (immediately post-
infusion), 2 hr (±20 minutes) and 4 hr (±20 minutes) following initiation of study 
drug infusion.  
• ECG at 30 (+15) minutes after initiation of study drug infusion.  
• Blood samples for bertilimumab (PK analysis) at 30 (+15) minutes (immediately 
post-infusion) and 4 hours (±20 minutes) following initiation of study drug infusion.  
• Recording of AEs (including post-infusion reactions, if applicable) and concomitant 
medications.  
5.3 FOLLOW-UP PERIODl: VISIT 5 (DAY 35), VISIT 6 (DAY 42), VISIT 7 (DAY 
56) AND VISIT 8 (DAY 90) 
Subjects will be followed for 3 months post first study drug administration. The following 
assessments will be performed at the follow-up visits:  
• Physical exam  
• Vital signs  
• ECG  
• AE and concomitant medication recording  
• Partial Mayo score (at Visits 5, 6 and 8)  
• Safety laboratory evaluations: hematology, biochemistry, antibodies to bertilimumab  
• Blood samples for eosinophil count, serum eotaxin-1i, hs-CRPj and ECP 
• Blood samples for bertilimumab (PK analysis) 
• Calprotectin in fecal samples  
• Flexible sigmoidoscopy with biopsies. On Day 56 (or early discontinuation visit), at 
least 3 tissue samples are required from the same region where the Screening 
                                                 
l Visits during the Follow-Up Period have a ±3 day window. 
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biopsies were obtained. Additional biopsy samples may be obtained at the 
Investigator’s discretion for histological assessment.   
• Eotaxin-1 in tissue will be measured using 2 of the biopsy samples (Visit 7 only) 
• Eosinophil count in tissue will be measured histologically using the remaining biopsy 
sample (Visit 7 only). 
• Mayo score (Visit 7 only) 
• UCEIS (Visit 7 only) 
5.4 EARLY DISCONTINUATION STUDY VISIT 
An early discontinuation study visit will be performed for subjects who withdraw from the 
study for the reasons specified in Section 4.5. 
All reasons for treatment discontinuation will be documented in the source documents as well 
as the CRF. Only one reason (the most severe) for early discontinuation should be recorded in 
the CRF. If one of the reasons for discontinuation is an AE – this should be chosen as the 
reason. Every effort should be made to follow-up these subjects for resolution of AE. 
At this visit, flexible sigmoidoscopy with biopsies will be done in addition to the activities 
relating to the study period at which time the subject discontinuation visit will be performed. 
That is, if the subject discontinues during the Treatment period, the visit activities will be 
similar to those described in Section 5.2; likewise, if the subject discontinues during the 
Follow-up Period, the visit activities will be similar to those described in Section 5.3. 
Activities may include (but not limited to): AEs, concomitant medications, laboratory tests, 
vital signs, and physical examination. Appropriate procedures and evaluations will be 
completed as deemed necessary by the Investigator. 
This visit may be performed on the same day as an originally scheduled visit or could be 
conducted separately. Data collection at these visits should primarily be guided according to 
principles to protect subject safety and well-being. 
5.5 UNSCHEDULED VISIT  
An unscheduled visit may be performed at any time during the study at the subject's request 
or as deemed necessary by the Investigator. The date and reason for the unscheduled visit will 
be recorded. AE monitoring and concomitant medication recording will be performed by the 
Investigator. Appropriate procedures and evaluations will be completed as deemed necessary 
by the Investigator and may include (but not limited to) laboratory tests, vital signs and 
physical examination. 
5.6 SAFETY ASSESSMENTS 
Safety assessments will be based on changes from Baseline of AEs (either reported by the 
subject or observed by the Investigator), concomitant medication use, treatment compliance 
(e.g., dropouts due to AEs), vital signs, ECG, physical examination and laboratory 
assessments (hematology, blood chemistry, anti-bertilimumab antibodies).   
5.6.1 Adverse Events (AEs) 
Adverse events will be assessed throughout the study. Any AE that occurs will be recorded.  
Any new AE that occurs between scheduled visits should be brought to the attention of the 
Investigator and recorded in the subject’s medical file and on the appropriate CRF page. 
AEs will be coded by Data Management using Medical Dictionary for Regulatory Activities 
(MedDRA®) version 14.0 or higher (see section 10.4 for more details). 
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5.6.2 Concomitant Medications 
Recording of concomitant medication use will be conducted at all study visits.  
5.6.3 Vital Signs 
Vital signs will be measured at all study visits. On dosing days, vital signs will be measured 
pre-dose and at 15 minutes (during infusion), 30 (+ 15) minutes (immediately post infusion), 
2 hr (± 20 minutes) and 4 hr (± 20 minutes) following initiation of study drug administration. 
Vital signs will include blood pressure, pulse rate, oral temperature and respiration rate after 
at least 5 minutes rest as per standard practice at the investigational site. Significant findings 
noticed after the start of study drug, which meet the definition of an AE must be recorded on 
the AE CRF module.  
5.6.4 Electrocardiogram 
ECG will be performed at all study visits. On dosing days, ECG will be performed pre-dose, 
and at 30 minutes (+ 15 minutes) following initiation of study drug administration 
(immediately post-infusion). The subject should rest for at least 10 minutes before 
measurement is taken. 
The ECG will be evaluated by the Investigator (signed and dated) and the printout should be 
kept in the source documentation file. When potentially clinically significant findings are 
detected by the site Investigator, a cardiologist should be consulted for a definitive 
interpretation and treatment administered based on medical need. All communications and 
diagnoses should be filed in the source documentation file. The Investigator/local cardiologist 
is responsible to determine whether the ECG findings are of clinical significance. All 
abnormalities will be closely monitored until stabilized or resolved. 
5.6.5 Physical Examination 
Physical examination will be conducted at all study visits. On dosing days, physical 
examination will be performed pre-dose.  Height will be recorded at Visit 1 (screening). 
Physical examination will include weight measurements, assessment of head, lungs, 
cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, central nervous 
system and, where appropriate, other body systems as indicated in the study schedule.  
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions CRF. Significant 
findings made after the start of study drug, which meet the definition of an AE must be 
recorded on the AE CRF.  
5.6.6 Infusion Reactions 
Infusion reactions to monoclonal antibody administration are not uncommon and are 
typically mild to moderate in intensity.  They can develop during the infusion or several 
hours thereafter, and, are most commonly associated with a complex of chills, fever, nausea, 
asthenia, headache, skin rash or pruritus.  However, infusion reactions in a small percentage 
of patients, may also present with a variety of signs and symptoms of severe hypersensitivity 
characterized by the acute onset of bronchospasm, hypotension, urticaria and/or cardiac 
arrest.  Therefore, all subjects in the study will be pre-medicated with a prophylactic regimen 
prior to study treatment on each of the dosing days (Days 0, 14 and 28) to prevent potential 
infusion reactions and will be closely monitored for up to 4 hours post-infusion.   
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5.6.7 Safety Laboratory Assessments  
Clinical laboratory assessments will be performed by a central laboratory. Investigators at 
each site will review these laboratory data for safety considerations. Hematology and 
biochemistry will be conducted at all study visits. Screen for active/latent mycobacterium 
tuberculosis (TB) infection and Clostridium difficile toxin stool assay will be conducted at 
screening only. Anti-bertilimumab antibodies will be evaluated from Day 0 until the end of 
the study. Pregnancy test for women of childbearing potential will be conducted at Screening 
(serum) and before each study drug infusion (urine). 
Safety laboratory sampling will be performed as follows by a central laboratory: 
Evaluations 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelet count, red blood cell count, reticulocytes, 
white blood cell count with differential count 
Biochemistry  
Alanine aminotransferase, alkaline phosphatase, α-amylase, aspartate 
aminotransferase, calcium, cholesterol, creatinine, gamma-glutamyl 
transferase, glucose, potassium, sodium, total bilirubin, triglycerides, 
urea/BUN 
Immunology* 
Anti-bertilimumab antibodies 
Pregnancy test  
Serum β-hCG pregnancy test at Screening  
Urine β-hCG on dosing days (pre-dose) 
 
The volume of blood to be drawn for each subject and processing and storage of samples are 
detailed in the Laboratory Manual.  
All laboratory tests with values that became abnormal and are considered clinically 
significant after drug administration will be repeated as clinically indicated until the values 
return to normal, or until the etiology has been determined and the condition considered 
stable. Abnormal laboratory test results that are considered to be clinically important by the 
Investigator will be reported as an AE in the AE CRF. A laboratory abnormality will not be 
considered an AE unless: 
• Intervention is required 
• Changes in dose are required (decrease, discontinued, interrupted) 
• Other treatment/therapy is required 
• It is associated with other diagnoses. 
Laboratory results will be reported to the Investigator who will review abnormal laboratory 
findings for clinical significance. The Investigator will note any laboratory test results of 
clinical concern, or values that were outside normal ranges and provide details of the 
relationship to investigational product and the action taken. If a change in a laboratory value 
represents a medical condition, the medical condition will be listed in the AE CRF page. If no 
correlation is possible, the direction of change (increase or decrease) in addition to the actual 
value will be recorded. 
5.7 EFFICACY ASSESSMENTS 
5.7.1 Sigmoidoscopy 
Flexible sigmoidoscopy with biopsies will be performed at Screening (Visit 1) and Day 56 
(Visit 7) or early discontinuation visit. At least 3 tissue samples are required from an area of 
active inflammation at Screening. On Day 56 (or early discontinuation visit), at least 3 tissue 
samples are required from the same region where Screening biopsies were obtained. 
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Additional biopsy samples may be collected at the Investigator’s discretion for histological 
assessment.  
The Endoscopic Finding Sub-score grading is provided in Appendix B. The UCEIS grading 
is provided in Appendix C. Each site will perform sigmoidoscopy at Screening (Visit 1) to 
evaluate eligibility (see Inclusion/Exclusion criteria). For efficacy evaluation, all endoscopic 
images (Visits 1 and 7 [or early discontuation visit]) will be reviewed centrally according to 
the procedure provided by the Institution conducting the central reading. 
5.7.2 Mayo score 
The Mayo Scoring System (Appendix B) for assessment of UC activity will be used for 
efficacy evaluation. The score will be determined at Screening (Visit 1) and Day 56 (Visit 7).  
The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 
(severe disease) and is a composite of 4 sub-scores: Stool Frequency Sub-score, Rectal 
Bleeding Sub-score, Endoscopic Finding Sub-score and Physician's Global Assessment Sub-
score, each of which ranges from 0 (normal) to 3 (severe disease) [18]. The sub-scores are 
summed to give a total score that ranges from 0–12. 
The partial Mayo Score is a 9-point scale that excludes the Endoscopic Finding Sub-score. It 
will be used for assessment of disease activity on Day 0 (Visit 2), Day 14 (Visit 3), Day 28 
(Visit 4), Day 35 (Visit 5), Day 42 (Visit 6) and Day 90 (Visit 8). 
5.8 PD ASSESSMENTS 
5.8.1 Fecal calprotectin 
Calprotectin is a cytosolic protein in neutrophilic granulocytes that correlates with 
neutrophilic infiltration of the intestinal mucosa [19, 20]. Fecal calprotectin is a marker of 
intestinal inflammation in UC. Fecal samples for analysis of calprotectin level will be 
collected at every study visit.  On treatment days, samples will be collected pre-dose. 
Analysis will be conducted by a central laboratory. 
5.8.2 Eosinophil count, serum eotaxin-1, hs-CRP and ECP 
Blood samples for eosinophil counti, eotaxin-1, hs-CRP and ECP j will be collected at every 
study visit (excluding screening visit). On treatment days, samples will be collected pre-dose. 
Processing and storage of the samples are detailed in the Laboratory Manual. Analysis will be 
conducted by a central laboratory. 
5.8.3 Eosinophil count and eotaxin-1 concentrations in biopsy tissue 
Biopsy tissue samples for analysis of eotaxin-1 concentrations and eosinophil count will be 
collected at screening (Visit 1) and on Day 56 (Visit 7) or early discontinuation.  
Analysis of eotaxin-1 and eosinophil count in biopsy tissue will be conducted by a central 
laboratory and the handling, storage, processing and analysis procedures will be described in 
the Laboratory Manual. 
5.9 PK ASSESSMENTS 
PK outcome is study drug (bertilimumab) concentration in the serum. PK parameters will 
include: 
Cmax  
Maximum bertilimumab serum concentration 
Tmax 
Time to Cmax (peak exposure) 
Cavg 
Average bertilimumab serum concentration 
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Cmin 
Minimum bertilimumab serum concentration 
λz 
Elimination rate constant 
t1/2  
Elimination half-life, calculated as 0.693/λz. 
Additional PK parameters may be calculated if deemed necessary.  
PK blood samples will be collected at every study visit (excluding screening).  On dosing 
days, blood samples will be collected pre-dose and at 30 (+15) minutes (immediately post-
infusion) and 4 hours (±20 minutes) following the initiation of study drug administration. The 
actual sampling times will be recorded. 
Processing and storage of the samples are detailed in the Laboratory Manual. PK analysis 
will be conducted by a central laboratory using a validated method. 
6. INVESTIGATIONAL PRODUCT 
6.1 IDENTITY OF INVESTIGATIONAL PRODUCT 
Bertilimumab is a recombinant human IgG4 monoclonal antibody that neutralizes human 
eotaxin-1 (eotaxin). The drug product consists of bertilimumab formulated in phosphate 
buffered saline (PBS) at pH 7.2 and at a concentration of 10 mg/mL, presented as a sterile, 
clear, colorless solution in 10 mL clear glass vials. 
The formula for the PBS is sodium chloride 77 mM, monosodium phosphate 17 mM and 
disodium phosphate 50 mM. 
Matched placebo glass vials will contain PBS. 
Polysorbate 20, a non-ionic surfactant to prevent protein aggregation, is added to the 
bertilimumab or placebo formulationat the time of vialing or to the saline infusion bag prior 
to dosing. The Pharmacy Manual will indicate whether polysorbate 20 is to be added prior to 
dosing. 
6.2 STUDY DRUG ADMINISTRATION AND DOSAGE 
Bertilimumab (10 mg/kg) or placebo will be administered by intravenous infusion over 30 
minutes. A pretreatment prophylactic regimen (as detailed in section 5.2) will be administered 
prior to dosing on each treatment dosing day (Days 0, 14 and 28) to reduce the likelihood of an 
infusion reaction. 
6.3 MANUFACTURING OF STUDY MEDICATION 
A cGMP vendor will perform the drug product and placebo manufacturing and release.  
6.4 PACKAGING AND LABELLING OF STUDY MEDICATION 
Bertilimumab vials or matching placebo will be packaged and labeled in compliance with 
GCP and local health authority guidelines. Each study center’s hospital pharmacy facility will 
be responsible for handling and preparation of the study drug. 
6.5 DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION 
Study drug will be packed and shipped in appropriate boxes. If, upon arrival at the clinical 
investigation site, the study drug appears to be damaged, the study monitor should be 
contacted immediately.  
Each shipment of study drug supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, acknowledgement of receipt and other appropriate 
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documentation. The shipment form will assist in maintaining current and accurate inventory 
records. The study staff will confirm the receipt of clinical supply to the study monitor.  
All study supplies should arrive at the Pharmacy/Investigational site in sufficient quantity and 
in time to enable dosing as scheduled. The Sponsor or its representative must notify the 
principal Investigator prior to dispatch of drug supplies with the anticipated date of their 
arrival.   
6.6 STORAGE AND INSTRUCTIONS FOR PREPARATION AND INFUSION OF THE 
INVESTIGATIONAL PRODUCT 
The study medication will be stored in each study center’s hospital pharmacy facility. The 
study drug (bertilimumab or placebo) will be stored in glass vials under refrigeration at 2-
8°C.  The polysorbate 20, if not included during vialing and necessary for inclusion to the 
saline infusion bags prior to subject dosing, will be provided to the center's hospital pharmacy 
facility where it is to be stored, under frozen (-20°C) conditions.   
Records should be kept by the pharmacist as to how much study drug was used by each 
subject. The study monitors must periodically check the study drug supplied to ensure expiry 
date and sufficient amount of study drug, and be sure that drug accountability is being 
performed at each visit, and the drug accountability logs (for study drug/placebo and 
polysorbate) are maintained.  
All investigational products must be kept in a locked area with access to the study drug 
limited to designated study personnel.  
Preparation of the study drug dose for administration must be carried out by a trained medical 
professional at the study center’s hospital pharmacy using aseptic technique according to the 
Pharmacy Manual. The number of vials used as well as the study drug volume dispensed per 
dose will be recorded in the study logbook.   
Only trained personnel under the supervision of either the Investigator or the local pharmacist 
are authorized to administer study drug to participating subjects.  
6.7 ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT 
Each delivery must be acknowledged by the hospital pharmacist (or authorized study team 
member responsible for the investigational medicinal product) by filling in the receipt record 
form and returning it by fax to delegated CRO. Accurate, complete, and timely 
documentation for all distribution to the study staff and subjects will be maintained by the 
pharmacy and the study staff of the investigational site which may include confirmation of 
receipts of clinical supply, drug accountability logs, and other forms.  
The hospital pharmacist (or authorized study team member responsible for the investigational 
medicinal product) is responsible for ensuring the supervision of the storage and allocation of 
these supplies, which will be forwarded to the Investigator at the appropriate time before 
administration. The Investigator may dispense investigational drug only to subjects enrolled 
in the study.  
Drug accountability records must be maintained by the clinical investigation site at all times. 
At the last study visit, all used and unused investigational drug will be collected and drug 
accountability performed by the study staff.  The study monitor will check these regularly 
during monitoring visits.  
Unused drug supplies will be returned to the Sponsor. At the end of the study, all the clinical 
supply and the corresponding accountability forms must be returned to the Sponsor, the study 
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monitor or designee for reconciliation and destruction. A photocopy of these records must be 
kept at the clinical investigation site. 
The inventory will be made available to the study monitor who will verify accountability and 
verify dose during the course of the study. 
Study drug orders, records of study drug receipts, dispensing records, and inventory forms 
located at the site will be examined and reconciled by the study monitor periodically during 
and at the end of the study.   
6.8 BLINDING AND RANDOMIZATION 
Subjects will be block randomized centrally (i.e., not within each center), stratified by 
previous anti-TNF treatment to ensure that approximately equal proportions of subjects who 
received previous anti-TNF treatment will be in each of the two treatment arms. 
A CRO will be responsible to assign and track the treatment randomization for each enrolled 
subject and to provide the randomization number to the sites. The randomization assignment 
for a subject will be made available to the pharmacist at the study site but not to any other 
person on the study staff nor to any of the Sponsor’s personnel or blinded monitors.  
However, if the identity of the test medication administered needs to be known in order to 
manage the subject’s condition, the Principal Investigator may be allowed access to the 
database treatment emergency code for that subject and the test medication identified. All 
such occurrences should be documented in the study file. Treatment emergency codes should 
not be broken except in emergency situations and, if possible, the Sponsor should be 
contacted before the emergency code is accessed.    
Whenever disclosure of the identity of the test medication is necessary, adequate procedures 
will be in place to ensure integrity of the data. Any unblinding will be documented in the 
study report with date, reason for identifying the drug and the name of all the person(s) who 
had to be unblinded.  
6.9 CONCOMITANT THERAPY 
At the screening visit, relevant treatments currently received by the subject will be recorded 
on the subject’s CRF including treatment's name, indication, dose, total daily dose and start 
and stop dates.  Any medications (including prescription, over-the-counter, herbal 
supplements and other health store-type products) to be taken during the study must be 
approved by the Investigator and recorded in the CRF.  
6.9.1 Allowed Medications 
The following concomitant medications/therapies will be allowed during the treatment 
period: 
• Occasional use of NSAID and acetaminophen for headache, arthritis, myalgia, 
menstrual cramps etc., and daily use of low-dose (81-162 mg) aspirin for 
cardiovascular prophylaxis is permitted  
• Mesalazine ≤ 4.8 g is allowed if the dose during the 2 weeks prior to the screening 
visit was stable; subject is to remain on stable dose through Visit 6 (Study Day 42). 
• Systemic corticosteroids not exceeding the equivalent of 20 mg/day of prednisone 
(see Corticosteroid Comparison Chart below) are allowed if the dose during the 4 
weeks prior to the screening visit was stable; subject is to remain on stable dose 
through Visit 6 (Study Day 42), excluding corticosteroid used in pretreatment 
prophylaxis.   
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• Cortiment (budesonide) up to a daily dose of 9 mg is allowed during the screening 
period and throughout the study owing to limited systemic absorption.   
Table 1:  Corticosteroid Comparison Chart 
 
Approximate Equivalent Dose, mg Relative Potency 
Hydrocortisone  
20 
1.0 
Cortisone Acetate 
25 
0.8 
Prednisone 
5 
4.0 
Prednisolone 
5 
4.0 
Methylprednisolone 
4 
5.0 
Dexamethasone 
0.75 
30-150 
Reference: Welsh GA, Manzullo EF and Nieman LK. The surgical patient taking glucocorticoids.  
2007 UpToDate® www.uptodate.com. 
 
Additional medications/therapies may be allowed at the discretion of the Investigator in 
consultation with the Sponsor. All concomitant medications used to treat AEs will be 
recorded in the subject’s medical file and on the appropriate CRF page. 
6.9.2 Prohibited Prior and Concomitant Medication 
Medications having the potential to interfere with the study assessments are excluded 
throughout the trial and include:   
• Use of vaccines or other immunostimulator within 4 weeks prior to screening or any 
time during the study.  
• Use of >4.8 g mesalazine or equivalent within 2 weeks prior to the screening visit.   
• Use of systemic corticosteroids exceeding the equivalent of 20 mg/day of prednisone 
within four weeks prior to the screening visit.  
• Change in dose of immunosuppressive drugs (e.g., corticosteroids, 6-mercaptopurine 
[6-MP], azathioprine) within four weeks prior to the screening visit. 
• Use of TNF-blockers (e.g., infliximab or adalimumab) within 60 days of the 
screening visit. 
• Use of oral or parenteral antibiotics within two weeks prior to the screening visit. 
• Use of chronic non-steroidal anti-inflammatory (NSAID) therapy.  
In the interests of patient safety, and acceptable standards of medical care, the Investigator 
may prescribe treatment(s) at his/her discretion, which will be recorded on the subject’s CRF. 
7. SAFETY AND PHARMACOVIGILANCE 
7.1 ADVERSE EVENT 
An adverse event (AE) is any adverse change from the subject’s baseline condition, whether 
or not considered investigational product related. This includes any subjective signs, 
symptoms or diagnosis, clinical significant deviation from baseline laboratory values or vital 
signs, or worsening (more severe, more frequent or increased in duration during the 
investigational product treatment) of the concomitant disease present at baseline visit (after 
initiation of investigational product treatment). Stable chronic conditions that are present 
prior to study entry and do not worsen during the study will not be considered AEs. Disease-
related adverse events will not be considered AEs only if they worsen beyond what would be 
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expected in the normal progression of the disease. In all cases, the etiology should, as much 
as possible, be identified and the Sponsor notified. 
An abnormal result of diagnostic procedures including abnormal laboratory or vital sign 
findings will be considered an AE if it: 
• Results in subject’s withdrawal by the Investigator 
• Is associated with clinical signs or symptoms 
• Is considered by the physician to be of clinical significance. 
Adverse events reported by the subject or observed by the Investigator will be individually 
listed on an AE form in the CRF as follows: the specific event or condition, whether the event 
was present pre-study, the dates and times of occurrence, duration, severity, relationship to 
study medication, specific countermeasures and outcome.  
The intensity or severity of the AE will be characterized as: 
• 
Mild:  
Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
• 
Moderate:  
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
• 
Severe:   
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required; hospitalization possible. 
The Investigator will document in his/her opinion the relationship of the AE to the 
investigational product (study medication) using the following criteria: 
Category 
Definition 
Unrelated 
Clearly due only to extraneous causes, and does not meet criteria listed under 
possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration. May have 
been produced by the subject’s clinical state or by environmental factors or 
other therapies administered. 
Possible 
Follows a reasonable temporal sequence from administration, but may have 
been also produced by the subject’s clinical state, environmental factors or other 
therapies administered. 
Probable 
Clear-cut temporal association with administration with improvement on 
cessation of investigational medicinal product or reduction in dose. Reappears 
upon rechallenge. Follows a known pattern of response to the investigational 
medicinal product. 
7.2 SERIOUS ADVERSE EVENT 
A serious adverse event (SAE) is any adverse event occurring at any dose that suggest a 
significant hazard or side effect, regardless of the Investigator or Sponsor's opinion on the 
relationship to the investigational product and that results in, but may not be limited to, any of 
the following outcomes: 
• death (regardless of the cause) 
• a life-threatening adverse drug experience 
• inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care 
facility) 
• a persistent or significant disability/incapacity 
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• a congenital anomaly or birth defect. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Hospitalization for elective treatment of a pre-study condition that did not worsen while on 
study and hospitalizations for treatment of non-adverse events (e.g., cosmetic surgery) are not 
considered serious adverse events. 
Significant medical events are those, which may not be immediately life-threatening, but 
may jeopardize the subject and may require intervention to prevent one of the other serious 
outcomes listed above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization; resulting in an adverse event will normally be considered serious by this 
criterion. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or 
that they occurred as a consequence of the event. Hospitalization for elective treatment of a 
pre-study condition that did not worsen while on study and hospitalizations for treatment of 
non-adverse events (e.g., cosmetic surgery or diagnostic procedure) are not considered 
serious adverse events. 
Any new SAE that occurs after the study period and is considered to be related 
(possibly/probably) to the investigational product or study participation should be recorded 
and reported immediately. 
A life-threatening adverse drug experience is any adverse event that places the subject, in 
the view of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
7.3 DEFINITION OF AN UNEXPECTED ADVERSE EVENT 
An unexpected adverse drug experience (event) is any adverse event, the specificity or 
severity of which is not reported in the current Investigator’s brochure. 
7.4 NOTIFICATION ABOUT SERIOUS OR UNEXPECTED ADVERSE EVENTS 
All SAEs must be reported immediately to the Immune Pharmaceuticals representative as 
soon as it becomes known to the Investigator and not later than within 24 hours of their 
knowledge of the occurrence of an SAE.   The notification will occur via data entry to the 
EDC with phone/fax/text/email notification to the Sponsor.   
Immune Pharmaceuticals Representative: 
  
Phone: 
 
, ext: 
 
Mobile: 
 
 
Fax:  
 
 
E-mail: 
 
 
These preliminary reports will be followed within 24 hours by detailed descriptions that will 
include a completed SAE form, copies of hospital case reports, autopsy reports and other 
documents, when requested and applicable. 
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In addition, all AEs / SAEs / Suspected Unexpected Serious Adverse Reaction (SUSARs) 
will be reported to the local EC and regulatory authorities as required by local regulations and 
ICH-GCP guidelines.  
Minimal information should include: 
• An identifiable subject (e.g., Subject randomization number) 
• An identifiable reporting source 
• All related adverse events 
• The suspect medicinal product 
• Follow-up of SAEs / SUSARs 
• Follow-up of SAEs / SUSARs that occur during the study will continue until their 
satisfactory resolution or stabilization. 
If, when supplementary information is available, a follow-up SAE Report Form must be 
completed by the site and data entry inputted to the EDC with follow-up phone/fax/text/email 
to Sponsor within 24 hours. 
The contact information for follow up SAE reporting is the same as for initial SAE reports 
(see above section).  
The paper copy of the SAE form and accompanying documentation should be placed in the 
SAE section of the Investigator’s file. If supplementary information on a SAE has to be sent, 
the SAE form has to be used marked as “follow-up report.”   
Follow-Up Reports on non-serious AEs 
All AEs must be followed until resolution or stabilization. In outstanding cases, it may be 
defined as “ongoing without further follow-up” by the Investigator and Sponsor’s decision. 
8. PLANNED STATISTICAL ANALYSES AND METHODS  
A statistical analysis plan (SAP) will be written and finalized before the study closure, i.e., 
database closure and unblinding of the randomization code. The SAP will provide full details 
of the analyses, the data displays and the algorithms to be used for data derivations. The SAP 
will include the definition of major and minor protocol deviations and the link of major protocol 
deviations to the analysis sets. 
8.1 DESIGN CONSIDERATIONS  
This is a two-arm, parallel control, double-blind, multi-center trial comparing three doses of 
bertilimumab 10 mg/kg to placebo in subjects with active moderate to severe UC. Subjects 
will be block randomized centrally (over all centers) in a 2:1 ratio (bertilimumab to placebo) 
and stratified by previous anti-TNF treatment, with approximately equal proportion of 
subjects with previous anti-TNF history included in each arm. Additionally, to reduce bias, 
the Mayo score and UCEIS will be evaluated by a central reader blind to subject identifier.  
8.2 DETERMINATION OF SAMPLE SIZE 
This is the first study investigating clinical outcome of treatment with bertilimumab in UC 
patients, and is therefore exploratory. Consequently, this trial’s analyses are descriptive in 
nature and whose sample size has been chosen, in consultation with physicians in the field 
and based on studies with similar objectives in the literaturem, to provide reasonable precision 
                                                 
m Parikh, A. et al. Vedolizumab for the treatment of ulcerative colitis: a randomized controlled phase II dose-
ranging study. Inflammatory Bowel Disease, 2012; 18:1470-1479. 
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in initial estimation of the drug’s clinical effect at one dose level. Specifically, up to 42 
subjects will participate in this trial. 
8.3 STATISTICAL METHODS 
All measured variables and derived parameters will be listed individually. Outcomes will be 
summarized by treatment group, depending on their nature, as follows: 
• For dichotomous variables: Categorization into success/failure-like categories; then 
incidence of failure and relative risk of failure in the active group compared to 
placebo with 95% confidence interval.   
• For numeric continuous endpoints: Descriptive statistics and summary tables will 
include sample size, arithmetic mean, standard deviation, median, minimum and 
maximum, and 95% Confidence Interval (CI) for mean at the relevant time points by 
treatment. 
• For ordered categories endpoints: incidences in the different categories and, after 
dichotomization into success/failure-like categories, incidence of failure and relative 
risk of failure by treatment with 95% confidence intervals.  
All tests applied will be two-tailed, and p value of 0.1 or less will be considered statistically 
significant. Since this is an exploratory trial, there will be no Alpha-correction for multiple 
testing. The data will be analyzed using the SAS® 9.1 software package or higher (SAS 
Institute, Cary, North Carolina). 
8.3.1 Analysis Sets 
8.3.1.1 Safety Analysis Set 
The Safety Analysis Set will include all subjects who were exposed to any of the study 
treatments. 
8.3.1.2 Modified Intent to Treat Analysis Set 
The modified intent to treat (mITT) analysis set will include all randomized subjects who 
received at least one dose of study treatment (placebo or bertilimumab), and had at least a full 
Mayo score at screening and at least one post-baseline partial Mayo score from visit 3 
onward. Excluded from mITT will be subjects with major entry violations as determined by 
blind review.  
Missing primary efficacy data in mITT will be imputed as follows: 
Full Mayo Score at Visit 7:  
• Subjects with a Full Mayo Score post-screening prior to Visit 7 (and none at Visit 7) 
will have their Visit 7 score imputed by last observation carried forward (LOCF). 
• Subjects with a Full Mayo Score after Visit 7 (and none at Visit 7) will have their 
Visit 7 score imputed by last observation carried backward (LOCB). 
• Subjects with only partial Mayo score(s) from Visit 3 onward will have their Full 
Mayo Score at Visit 7 imputed by multiple imputation (MI), using a model that 
includes screening data, treatment and partial Mayo Score.n 
UCEIS (a secondary endpoint that will be analyzed in mITT as well) 
                                                 
n a) The continuous Full Mayo Score will be imputed using MI, after which clinical response will be computed 
and b) Should there be variables causing the MI model not to converge, these will be excluded from the model. 
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• Subjects with UCEIS post-screening prior to Visit 7 (and none at Visit 7) will have 
their Visit 7 score imputed by last observation carried forward (LOCF). 
• Subjects with UCEIS after Visit 7 (and none at Visit 7) will have their Visit 7 score 
imputed by last observation carried backward (LOCB). 
• Subjects with no post-screening endoscopy will have their UCEIS at Visit 7 imputed 
by MI using screening data, treatment and partial Mayo Score (from Visit 3 
onward).o 
8.3.1.3 Per Protocol Analysis Set 
The per protocol (PP) analysis set will be a subset of mITT subjects who had no major protocol 
violations likely to affect outcome as determined by blind review and who received at least 2 
of 3 study treatments (placebo or bertilimumab) and who had a full Mayo score at screening 
and at visit 7. Only observed data will be used in PP; primary data will not be imputed. 
8.3.2 Subject Disposition 
Major and minor protocol deviations will be identified by medically trained staff before the 
study closure. All screened subjects will be accounted for; enrolled subjects will be followed 
to completion. Protocol violations determining the belonging of subjects to the different 
analysis sets will be summarized. A full disposition tree will be generated displaying the 
number of subjects reaching the different phases of the study (screening, 
randomization/treatment, end of treatment, end of study) and the main reasons for exclusion. 
8.3.3 Demographics and Baseline Characteristics 
Baseline demographics and disease characteristics will be summarized for the safety analysis. 
Continuous demographic variables and baseline/screening disease characteristics will be 
summarized by mean, median, standard deviation, minimum and maximum. Qualitative 
demographic characteristics and baseline/screening disease characteristics will be 
summarized by counts and percentages.  Other subject characteristics (medical history, 
clinical findings, inclusion/exclusion checklist, etc.) will be listed only. 
These variables will be compared between the treatment groups in a descriptive fashion; no 
formal statistical testing will be performed. 
Previous and concomitant medications will be coded according to the WHO drug code and 
the ATC class code. They will be summarized by type (e.g., previous, concomitant, for AE) 
by tabulating the number and percentages of subjects having received each treatment. 
8.3.4 Efficacy Endpoints Analysis 
Analysis of all efficacy endpoints will be performed on the mITT set. The PP set will be used 
as supplementary analyses to test the robustness of the results. If deemed appropriate, 
supportive analyses using multiple imputations for missing data will be performed on the 
primary and secondary endpoints. Additional exploratory data-driven analyses could be 
performed with the caveat that any statistical inference will not have any confirmatory value. 
Because this is an exploratory study, alpha will be set at 0.1 for comparisons between groups. 
8.3.4.1 Primary Endpoint Analysis 
This study’s primary endpoint analyses will be descriptive, providing proportion of Mayo 
Score Clinical Response separately by treatment group, including two-sided 95% Exact 
                                                 
o a) The continuous UCEIS will be imputed using MI, after which clinical response will be computed and b) 
Should there be variables causing the MI model not to converge, these will be excluded from the model. 
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Binomial confidence intervals. Exploratory statistical testing will be done by comparing 
Bertilimumab treatment arm to placebo. 
8.3.4.2 Secondary Endpoint Analyses 
a. Primary endpoint analysis described in the preceding section will be repeated in PP. 
b. Secondary endpoints will be analysed in both mITT and PP analysis sets. 
8.3.5 
Pharmacokinetic Analysis 
To the degree possible given the limited number of sampling timepoints, PK parameters will 
include AUC, Tmax, Cmax, Cavg, Cmin, and t1/2. The PK parameters will be summarized by 
descriptive statistics (i.e., mean, standard deviation, standard error, geometric mean, median, 
minimum and maximum) by treatment group and by timepoint. Additional analyses may be 
performed if deemed necessary. 
8.3.6 
Pharmacodynamic Analysis 
Descriptive statistics will be provided by change from baseline and percentage change from 
baseline as appropriate for: 
• Fecal calprotection 
• Eosinophil count, serum eotaxin-1,hs-CRP and ECP 
• Change in eotaxin-1 concentration and eosinophil count in biopsy tissue from 
Screening to Day 56. 
8.3.7 
Safety Analysis  
The evaluation of safety endpoints will be carried out on the Safety set. Safety will be 
assessed by evaluation of adverse events and changes from baseline in vital signs, physical 
examination, infusion reactionand clinical laboratory safety test results. Individual subject 
listing will be provided. The observation period for all the safety endpoints spans from start 
of study medication up to study day 90. 
8.3.7.1 Adverse Events 
Adverse events will be coded to system organ class and preferred term using the latest 
version of Medical Dictionary for Regulatory Activities (MedDRA) and are graded by the 
Investigator in terms of severity and relation to study treatment. All data will be listed by 
subject. Only treatment emergent AEs (TEAEs) will be presented in summary tables. 
TEAEs are the adverse events that occur during the observation period, and the pre-treatment 
adverse events or pre-existing medical conditions that worsen in intensity after start of study 
medication and within the observation period.  
TEAEs will be summarized by treatment arm in terms of crude incidence rates. For each 
event the crude incidence rate is defined as the number of subjects experiencing the event 
divided by the number of subjects initially exposed to study drug, regardless of duration of 
exposure to study drug. In addition, for each event the worst severity grade and the "worst" 
Investigator's judgment on study drug relationship is considered for each subject and 
frequency tables by worst severity grade and by worst study drug relation are provided. In 
this analysis, a subject having experienced more than once events classified under the same 
preferred term (body system) will be counted only once in the number of subjects with that 
preferred term (body system).   
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Summaries of TEAEs will be presented by body system and by preferred term within each 
body system (MedDRA Terminology). The percentage of subjects who experienced AEs 
coded with the same term will be tabulated by treatment group in descending order according 
to the incidence of AEs in the active treatment groups. 
All reported adverse events will be listed independently of their onset date. Serious Adverse 
Events, causes of death and AEs leading to premature discontinuation of study drug will be 
summarized similarly and listed. Reasons for premature discontinuation of study drug will be 
listed and summarized by frequency tables on all analysis sets. 
8.3.7.2 Clinical Laboratory 
All laboratory data will be listed in original and standardized units; abnormal results will be 
flagged, depending on the direction of the change with respect to below or above the normal 
ranges, as high or low.   
Treatment-emergent laboratory abnormalities (those that newly emerge during the 
observation period) will be summarized by treatment arm in terms of crude incidence rates. 
Algorithms for the standardization of numeric values obtained from different laboratories 
and/or using different normal ranges will be defined in the SAP. In the evaluation of 
laboratory abnormalities, missing baseline values for subjects who had other assessments will 
be imputed by the mean of the normal range boundaries. 
Numeric laboratory variables, transformed to standard units, as assessed at baseline, at each 
scheduled time point during the observation period and at the last available timepoint during 
the observation period will be summarized by descriptive statistics (i.e., mean, median, 
standard deviation, standard error, quartiles, minimum and maximum) by treatment group 
both for observed values and for changes from baseline. In this evaluation, subjects will be 
included who had the baseline and the relevant assessment. 
8.3.7.3 Evaluation of Anti-Bertilimumab Antibodies 
Occurrence of anti-bertilimumab antibodies above the predefined threshold will be 
summarized by treatment arm in terms of crude incidence rate. 
8.3.7.4 ECG 
ECG parameters as assessed at baseline (i.e., pre-dosing, Day 0), at each scheduled time point 
during the observation period and at the last available timepoint during the observation period 
will be summarized by descriptive statistics (i.e., mean, median, standard deviation, standard 
error, quartiles, minimum and maximum) by treatment group both for observed values and 
for changes from baseline. In this evaluation, subjects will be included who had the baseline 
and the relevant assessment. Treatment-emergent ECG abnormalities (those that newly 
emerge during the observation period) will be summarized by treatment arm in terms of crude 
incidence rates. 
8.3.7.5 Vital Signs 
Vital signs as assessed at baseline (i.e., pre-dosing, Day 0), at each scheduled time point 
during the observation period and at the last available time point during the observation 
period will be summarized by descriptive statistics (i.e., mean, median, standard deviation, 
standard error, quartiles, minimum and maximum) by treatment group both for observed 
values and for changes from baseline. Subjects who had the baseline and the relevant 
assessment will be included in this evaluation.   
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8.3.7.6 Physical Examination 
The data collected on the physical examination form at baseline (i.e., pre-dosing, Day 0) and 
each study visit will be tabulated by frequency count and percentage for each organ system. 
8.3.8 Interim Analysis 
No interim analysis is planned in this trial. 
9. ETHICS 
9.1 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE 
Prior to initiation of the study, the Principal Investigator will submit the study protocol and 
amendments, sample Informed Consent Form (ICF), and any other documents that may be 
requested to the IRB/IEC for review and approval.  The Investigator will request that the 
IRB/IEC provide written approval of the study and will keep on file records of approval of all 
documents pertaining to this study. The Investigator will not begin the study until the 
protocol and ICF have been approved by the IRB/IEC. The Investigator must agree to make 
any required progress reports to the IRB, as well as reports of SAEs, life-threatening 
conditions or death. 
9.2 ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to GCP guidelines. This includes an 
inspection by Sponsor or its designee, health authority or IRB/IEC representatives at any 
time.  The Investigator must agree to the inspection of study-related records by health 
authority representatives and/or Sponsor or its designee.  
The study will be conducted in accordance with the following guidelines: 
• GCP: Consolidated Guideline (International Conference on Harmonization of 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, 
May 1996). 
• Declaration of Helsinki: Fortaleza, Brazil, October 2013. 
• Israeli MOH guidelines (February 2016). 
• Guidelines from the country-specific National Competent Authority as appropriate. 
9.3 PROTOCOL REVISIONS AND/OR DEVIATIONS 
Changes to the protocol may be made only by the Sponsor. All protocol modifications must 
be submitted to the IRB/IEC in accordance with local requirements and, if required, to 
Regulatory Agencies, either as an amendment or a notification. Approval for amendments 
must be awaited before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial study subjects, or when the changes involve only 
logistical or administrative aspects of the trial. No approval will be required for notifications. 
9.4 STUDY SUBJECT INFORMATION AND CONSENT 
Prior to screening for the study, each potential subject will be informed in detail about the 
study drugs to be administered, and the nature of the clinical investigation with its risks and 
discomforts to be expected. The basic elements of informed consent as specified by the FDA 
(21 CFR 50.25) and ICH-GCP will be followed.  Written consent will be obtained from each 
subject to be involved in the clinical trial by using the IRB/IEC-approved Informed Consent 
Form (ICF) prior to the conduct of any study-related activity.  Each subject will be given a 
copy of the written ICF.  Subjects will also be instructed that they are free to withdraw their 
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consent and discontinue their participation in the study at any time without prejudice. Each 
subject’s chart will include the signed ICF for study participation.  When the study treatment 
is completed and the CRF has been monitored, the ICF will be kept in the Investigator’s 
central study file for the required period.  Regulatory authorities may check the existence of 
the signed ICF in this central study folder if not having done so during the study.   
9.5 STUDY SUBJECT INSURANCE 
The Sponsor has an insurance policy for the total duration of the study covering the subjects 
and Investigators in respect of the risks involved in conducting this study according to this 
protocol.  The certificate of insurance will be filed in the Investigator's file or can be made 
available to the Investigator and to the IRB/IEC upon request. 
9.6 PERSONAL DATA PROTECTION 
The Sponsor complies with the principle of subject's right to protection against invasion of 
privacy.  Throughout this trial, all data will be identified only by an identification number and 
subject initials.  The data will be blinded in all data analyses.  The subject must be informed 
and consent is required that authorized personnel of the Sponsor and/or designee (Study 
Monitor, Auditor, etc.) and relevant health regulatory agency will have direct access to 
personal medical data to assure a high quality standard of the study.  
10. QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 AUDITS AND INSPECTIONS 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Sponsor or its designees or to 
regulatory authority inspectors after appropriate notification. The verification of the CRF data 
must be by direct inspection of source documents. These audits or inspections may take place 
at any time, during or after the study, and are based on the national regulations, as well as 
ICH guidelines.  
10.2 STUDY MONITORING 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO 
or a contract monitor. The study monitor will advise the Investigator regarding the practical 
conduct of the study and maintaining compliance with the protocol, GCP and all applicable 
regulatory requirements.  Throughout the course of the study, the study monitor will oversee 
the conduct and the progress of the study by frequent contacts with the Investigator.  This 
will include telephone calls and on-site visits.  During the on-site visits, the CRF will be 
reviewed for completeness with corresponding source documents.  As part of the data audit, 
source documents will be made available for review by the study monitor.  The study monitor 
will also perform drug accountability checks and may periodically request review of the 
Investigator’s study file to ensure completeness of documentation in all respects of clinical 
study conduct.  
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate period.  The Investigator or 
appointed delegate will receive the study monitor during these on-site visits, cooperate in 
providing the documents for inspection and respond to inquiries.   
10.2.1 Source Data and Records 
Source data/records contain all the information, which is necessary for the reconstruction and 
evaluation of the study.  Source data/records are 1) original records, 2) certified copies of 
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original records, 3) observations, 4) laboratory reports, 5) paper Case Report Forms (CRFs) 
and/or data sheets, 6) data entered directly into the eCRF.  Source data/records are to be kept 
within the control of the Investigator until the end of the regulatory retention period.  The 
Investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), with direct access to all the required source records. 
In this study, at the time of the office visit, study specific original data elements may be 
entered directly into a web-based system without first being transcribed on other media such 
as paper. These original electronic data will be stored with Target e*CTR® (electronic 
Clinical Trial Record) Viewer in a central server prior to being transmitted to the electronic 
data capture (EDC) database. Access to these electronic original data are controlled by the 
Investigator or designee. 
10.2.2 Original Records 
This study may use direct data entry of clinical trial data into the Target e*CRF® (EDC) 
system, using the Target e*CTR® (Target e*Clinical Trial Record) process.  This process 
allows a clinical study site to perform direct data entry of original data into Target e*CRF®, 
and to store these original data in PDF format in the Target e*CTR Viewer, an independent 
repository controlled by the clinical Investigator, prior to the data being recorded in the 
Target e*CRF® database. 
10.2.3 Target e*CRF® (Electronic Data Capture) 
Clinical trial data will be entered by the Investigator, or a designee into Target e*CRF®, a 
validated 21 CFR Part 11 compliant Internet-based EDC system.  Changes to the clinical trial 
data can only be performed by the Investigator or designee through the change management 
methodology that is subject to a full audit trail.  
The Investigator and staff will be trained on Target e*CRF® prior to enrollment of the first 
subject.  A list of the status of each user, including an audit trail of status changes will be 
maintained.  In addition, the user module of Target e*CRF® maintains the original status and 
an audit trail of any changes.   
At the end of the study, the completed online eCRF must be reviewed and signed 
electronically by the Investigator named in the study protocol or by a designated sub 
Investigator authorized to sign.  A certification must be obtained from all authorized persons 
to sign electronically indicating that their electronic signature is equivalent to their hand-
written signature.  In order to sign electronically, the signer must log in with their username 
and password and reenter their password on the page(s) requiring a signature(s). 
10.2.4 Target e*CTR® Viewer (Target e*Clinical Trial Record Viewer) 
Target e*CTR® Viewer is a validated 21 CFR Part 11 compliant Internet-based software 
system.  The original subject data PDF files are read-only.  Users’ access to the Target 
e*CTR® Viewer is granted by the Investigator, or a designee.  The Investigator can download 
a bookmarked PDF copy of original records of individual subjects or all subjects, including 
an audit trail of changes and electronic signatures. 
10.2.5 Certified Copies of Original Data 
In the event there is no access to the Internet for direct data entry at the time of the study 
visit, the site should record original data using paper records or equivalent.  Once the Internet 
is available, these original data must be entered into Target e*CRF®.  If these original data 
are then designated as Certified Copies within Target e*CRF®, the paper records may be 
discarded as long as:  
1. This process is supported by written procedures 
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2. The site is trained on these procedures, including instructions to visually check the 
transcribed data prior to certification. 
10.3 QUALITY LABORATORY STANDARDS 
Laboratory tests or evaluations described in this protocol will be conducted in accordance 
with quality laboratory standards as described in the SOPs of the local institution laboratory 
and central laboratories. 
10.4 DATA MANAGEMENT 
A Clinical Data Monitoring Plan (CDMoP) is created to specifically identify how data 
management will be performed for the study.  The following summarizes the CDMoP: 
The clinical database is held and managed by Target Health during the lifetime of the study. 
Target e*CRF® will be used for online edit checks, batch edit checks and query 
management.  In order to build the EDC application, an Application Setup Instructions (ASI) 
document is created.  The ASI document contains the specific instructions to both the EDC 
and data management (DM) programmers.   
Data validation is performed according to the specifications in the Data Validation Plan 
(DVP).  Within the DVP, there are 3 types of validation checks: 
• Online checks performed by the EDC system during data entry. Target Health is 
responsible for programming and resolving any hits based on these checks. 
• Batch edit checks. Target Health is responsible for programming and resolving any 
hits based on these checks. 
• Manual checks performed by the monitor and Target Health Clinical Data 
Management (CDM).  The data manager (DM) is responsible for providing listings to 
monitors to be used for manual checks. 
Queries are handled within the Target e*CRF® application.  The monitors and DMs are the 
only persons who can generate a query.  Under direction of the Investigator, the site 
Coordinator addresses the query.  If the query is due to a data entry error, the Coordinator can 
immediately make the corrections in the applicable eCRF pages.  If the query needs 
clarification, the Coordinator contacts the Investigator for resolution.  The Coordinator then 
enters the correct value or submits an answer to the query without modifying the data.  The 
monitor then reviews the corrected eCRF pages and/or answer.  If the data are changed 
correctly or the answer is acceptable, the monitor closes the query.  If the answer is not 
acceptable, the monitor submits an additional query for clarification.  All changes to the 
database require a “Reason for Change” and are subject to an audit trail.  The audit trails 
identifies the changed data, reason(s) for change, who changed the data and the time and date 
of the change (based on the Target e*CRF® server’s time). 
EDC management reports are also available to view the data for consistency. The basic 
reports are: 
• Overall Data Entry Status (By Site/Subject) 
• Investigator signature status (By Site/Subject) 
• Query Age Report (by Site) 
• Query Report (by Site/Subject) 
• Query Frequency By Site 
• Query Frequency By Edit Check 
• Query Frequency by Form 
• Subject Visit Status Report (by Site / Subject) 
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• AE Report (By Site/Subject) 
• Concomitant Medication Report (By Site/Subject) 
• Serious AE Report (by Site/Subject) 
• Subject Status Report (by Site) 
• Protocol Violation Report (by Site / Subject) 
• Treated (by Site / Subject) 
• Subject Tracking Report (Individual) 
Additional management reports can be specified and programmed during the course of the 
study.  
Centralized monitoring is performed daily or at an agreed-upon frequency, as defined in the 
CDMoP. The following are samples of reports that assist in the centralized monitoring 
process.  Study specific reports will be found in Target e*CRF®. 
1. System logs and reports to identify when users log in 
2. Time from subject visit to data entry 
3. Online edit checks 
4. Batch edit checks 
5. Data listings  
6. Subject profiles 
Results from the daily monitoring are discussed.  Meetings with the clinical research and DM 
teams are held to review and discuss data quality and data management issues, and minutes of 
meetings maintained.  When necessary, the Monitoring Plan and CDMoP are revised and 
corrective actions are implemented. 
11. STUDY ADMINISTRATION 
11.1 PARTICIPATING CENTERS 
Approximately 10-12 sites in Israel will participate in this study. Additional sites in Europe 
may be added in the event of slow recruitment. A list of the Principal Investigators will be 
maintained in the trial master file. 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the start of this study, all pre-investigational requirements must be met by the 
Investigator and study site. These may include: 
• Appropriate local health authority documentation properly signed and dated by the 
required Investigators (i.e., the submission package) 
• Signed copy (original) of the approved protocol 
• Completed and signed statement of Investigator 
• A signed Clinical Trial Agreement 
• Curriculum vitae for the Investigator and sub-Investigatorsp 
• IRB/IEC name and address; and membership list 
• Letter of approval from the IRB/IEC for both protocol (identified by protocol title 
and number) and informed consent form (identified by protocol title and number) 
• Copy of the IRB/IEC-approved written ICF to be used in the study (that has also 
been approved by the Sponsor) 
                                                 
p Can be collected at Site Initiation Visit 
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• Provisions for direct access to source/data documents if necessary for trial-related 
monitoring, audits, IRB/IEC review and regulatory inspection 
• Name and location of the laboratory utilized for laboratory assays and other facilities 
conducting tests, as well as a copy of the laboratory certificate and list of normal 
laboratory values (can be collected at Site Initiation Visit).  In case a laboratory 
certification is not available, a written statement as to how the laboratory complies 
with quality assurance should be provided.   
Upon satisfactory receipt of all required regulatory documents, Sponsor will arrange the 
supply of all required infusion and ancillary pharmacy supplies.  Study drug (bertilimumab or 
placebo), will be provided only on an as-needed basis, as subjects are enrolled in the study.  -  
Supply of all other study materials will be the responsibility of the Sponsor and/or designee. 
Subject entry should not begin until after the required regulatory documents are confirmed as 
received and the Investigator Meeting/Initiation Meeting has occurred. All personnel 
expected to be involved in the conduct of the study will undergo orientation to include review 
of study protocol, instructions for CRF completion, AE reporting, and overall responsibilities 
including those for drug accountability and study file maintenance. 
The Investigator and/or designee (study monitor) will prepare an Investigator's study file.  
This file should be used for all trial related documents.  The Investigator will be responsible 
for keeping the Investigator's file updated and ensuring that all required documents are filed. 
The file will be inspected during monitoring visits. 
11.3 CLINICAL TRIAL SUPPLIES 
The Investigator will be responsible for administrating, inventory and accountability of all 
clinical trial supplies and exercising accepted medical and pharmaceutical practices.  An 
accurate and timely record of the disposition of all clinical supplies must be maintained.  The 
supplies and inventory record must be made available for inspection upon request.  Upon 
completion or termination of the study, the Investigator will keep the remaining clinical 
supplies along with a copy of the inventory record and a record of the clinical supplies 
returned.  Under no circumstances will the Investigator allow the study drugs or other 
study-related supplies to be used other than as directed by this protocol. 
11.4 INVESTIGATOR SITE FILE 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory agencies. 
11.5 STUDY COMPLETION 
This study is expected to end when all required subjects have been enrolled and the last 
subject has completed the study and the query resolution has been completed. Data and 
materials that are required before the study can be considered complete and/or terminated are: 
• Laboratory findings, clinical data and all special test results from screening through 
the end of the follow-up period. 
• CRF properly completed by appropriate study personnel and signed by the 
Investigator. 
• Completed Drug Accountability Records. 
• Statement of outcome for each serious adverse event reported. 
• Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable). 
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11.6 FINAL REPORT 
A final study report will be prepared after the study has been completed and database has 
been cleaned, locked and analyzed. The report will be prepared according to the ICH E3 
guidelines. 
11.7 RETENTION OF STUDY RECORDS 
The Investigator will retain copies of the approved protocol, completed CRF, informed 
consent documents, relevant source documents, and all other supporting documentation 
related to the project for 15 years. If the Investigator is unable to retain the study documents 
for the required amount of time, Sponsor or designee must be informed of the individual who 
will be assuming this responsibility. 
These files must be made available for inspection upon reasonable request by authorized 
representatives of Sponsor and/or the relevant regulatory agencies. 
11.8 CONFIDENTIALITY AND PUBLICATION 
Subject medical information obtained by the study is confidential and disclosure to third 
parties other than those noted below is prohibited. Throughout the study, all data will be 
identified only by the subject identification number, and where applicable, the subject’s 
initials and birthdates. 
At the subject's request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare.  Personal physician 
will be notified by site personnel of subject participation in the study. 
All information supplied by Immune Pharmaceuticals, Inc. in association with this study and 
not previously published, is considered confidential information. This information includes, 
but is not limited to, the Investigator’s Brochure, the protocol, CRFs, and other scientific 
data. Any data collected during the study are also considered confidential. This confidential 
information shall remain sole property of Immune Pharmaceuticals, Inc., shall not be 
disclosed to others without the written consent of Immune Pharmaceuticals, Inc. and shall not 
be used except in the performance of this study. 
The information developed during the conduct of this study is also considered confidential, 
and will be used by Immune Pharmaceuticals, Inc. This information may be disclosed as 
deemed necessary by Immune Pharmaceuticals, Inc. To allow the use of this information 
derived from this study, the Investigator is obliged to provide Immune Pharmaceuticals, Inc. 
with complete test results and all data developed in this study.  
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12. REFERENCES 
1. 
Wedemeyer J, Vosskuhl K. Role of gastrointestinal eosinophils in inflammatory bowel 
disease and intestinal tumours. Best Pract Res Clin Gastroenterol. 2008;22(3):537-49. 
2. 
Langan RC, Gotsch PB, Krafczyk MA, Skillinge DD. Ulcerative colitis: diagnosis and 
treatment. Am Fam Physician. 2007 Nov 1;76(9):1323-30. 
3. 
Navaneethan U, Shen B. Pros and cons of medical management of ulcerative colitis. 
Clin Colon Rectal Surg. 2010 Dec;23(4):227-38. 
4. 
Fedorak RN, Wong K, Bridges R. Canadian Digestive Health Foundation Public Impact 
Series. Inflammatory bowel disease in Canada: Incidence, prevalence, and direct and 
indirect economic impact. Can J Gastroenterol. 2010 Nov;24(11):651-5. 
5. 
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011 Nov 3;365(18):1713-25. 
6. 
Centers for Disease Control (CDC). http://www.cdc.gov/ibd. 
7. 
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on 
systematic review. Gastroenterology. 2012 Jan;142(1):46-54 e42; quiz e30. 
8. 
Meier J, Sturm A. Current treatment of ulcerative colitis. World J Gastroenterol. 2011 
Jul 21;17(27):3204-12. 
9. 
Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. 
Adalimumab for induction of clinical remission in moderately to severely active 
ulcerative colitis: results of a randomised controlled trial. Gut. 2011 Jun;60(6):780-7. 
10. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al. 
Adalimumab induces and maintains clinical remission in patients with moderate-to-
severe ulcerative colitis. Gastroenterology. 2012 Feb;142(2):257-65 e1-3. 
11. Matthews AN, Friend DS, Zimmermann N, Sarafi MN, Luster AD, Pearlman E, et al. 
Eotaxin is required for the baseline level of tissue eosinophils. Proc Natl Acad Sci U S 
A. 1998 May 26;95(11):6273-8. 
12. Ding C, Li J, Zhang X. Bertilimumab Cambridge Antibody Technology Group. Curr 
Opin Investig Drugs. 2004 Nov;5(11):1213-8. 
13. Fries W, Comunale S. Ulcerative colitis: pathogenesis. Curr Drug Targets. 2011 
Sep;12(10):1373-82. 
14. Lampinen M, Backman M, Winqvist O, Rorsman F, Ronnblom A, Sangfelt P, et al. 
Different regulation of eosinophil activity in Crohn's disease compared with ulcerative 
colitis. J Leukoc Biol. 2008 Dec;84(6):1392-9. 
15. Saitoh O, Kojima K, Sugi K, Matsuse R, Uchida K, Tabata K, et al. Fecal eosinophil 
granule-derived proteins reflect disease activity in inflammatory bowel disease. Am J 
Gastroenterol. 1999 Dec;94(12):3513-20. 
16. Mir A, Minguez M, Tatay J, Pascual I, Pena A, Sanchiz V, et al. Elevated serum eotaxin 
levels in patients with inflammatory bowel disease. The American Journal of 
Gastroenterology. 2002 Jun;97(6):1452-7. 
17. Chen W, Paulus B, Shu D, Wilson, Chadwick V. Increased serum levels of eotaxin in 
patients with inflammatory bowel disease. Scandinavian Journal of Gastroenterology. 
2001 May;36(5):515-20. 
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18. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. 
Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 
2005 Dec 8;353(23):2462-76. 
19. Roseth AG, Schmidt PN, Fagerhol MK. Correlation between faecal excretion of 
indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in 
patients with inflammatory bowel disease. Scandinavian journal of gastroenterology. 
1999 Jan;34(1):50-4. 
20. Gisbert JP, McNicholl AG. Questions and answers on the role of faecal calprotectin as a 
biological marker in inflammatory bowel disease. Digestive and Liver Disease. 2009 
Jan;41(1):56-66. 
21. Dick AP, Grayson MJ, Carpenter RG, Petrie A. Controlled Trial of Sulphasalazine in 
the Treatment of Ulcerative Colitis. Gut. 1964 Oct;5:437-42. 
22.  Adar T., Shteingart S. et al.  The Importance of Intestinal Eotaxin-1 in Inflammatory 
Bowel Disease: New Insights and Possible Therapeutic Implications. Dig Dis Sci. ,2016 
Jul; 61(7): 1915-24  
 
 
 
 
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13. APPENDICES 
Appendix A 
Schedule of Activities .................................................................................... 53 
Appendix B 
Mayo Score .................................................................................................... 56 
Appendix C 
Ulcerative Colitis Endoscopic Index of Severity ........................................... 57 
Appendix D 
Grading of Infusion Reactions ....................................................................... 58 
 
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Appendix A Schedule of Activities 
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Study Procedures 
Screening 
Period 
Treatment Perioda 
Early 
Discontinuationb 
Follow-up Periodc 
Visit 
1 
2 
3 
4 
- 
5 
6 
7 
8 
Study Day  
-28 to -1 
0 
14 
28 
- 
35 
42 
56 
90 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographic & medical history  
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X* 
X* 
X* 
X 
X 
X 
X 
X 
Vital signs  
X 
Xd 
Xd 
Xd 
X 
X 
X 
X 
X 
ECG 
X 
Xe 
Xe 
Xe 
X 
X 
X 
X 
X 
Screen for active/latent tuberculosis and fecal sample for C. difficile 
toxin  
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Mayo Score 
X 
 
 
 
X 
 
 
X 
 
Partial Mayo Score 
X 
X* 
X* 
X* 
X 
X 
X 
X 
X 
Bertilimumab or Placebo infusion- (after administration of pretreatment 
regimen)j 
 
X 
X 
X 
 
 
 
 
 
Flexible sigmoidoscopy with biopsiesf 
X 
 
 
 
X 
 
 
X 
 
Ulcerative Colitis Endoscopic Index of Severity 
X 
 
 
 
X 
 
 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion reaction assessmentg 
 
X 
X 
X 
 
 
 
 
 
Urine β-hCG 
 
X* 
X* 
X* 
 
 
 
 
 
Hematology and biochemistry 
Xh 
X* 
X* 
X* 
X 
X 
X 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
PK (bertilimumab) blood sampling 
 
Xi 
Xi 
Xi 
X 
X 
X 
X 
X 
Anti-bertilimumab antibodies 
 
X* 
X* 
X* 
X 
X 
X 
X 
X 
Eotaxin-1, eosinophil count, eosinophil cationic protein (ECP)-s-CRP 
 
X* 
X* 
X* 
X 
X 
X 
X 
X 
                                                 
a Visits during the treatment period have a ±2 day window. 
b At this visit the activities relating to the study period at which time the patient discontinued will be performed.  
c Visits during the follow-up period have a ±3 day window. 
d  Vital signs will be measured pre-dose and 15 min (during), 30 minutes (+15 minutes), 2 hr (± 20 minutes), and 4 hr (± 20 minutes) following initiation of study drug administration. 
e  ECG will be performed pre-dose, and at 30 (+ 15) minutes following initiation of study drug administration. 
f At least 3 tissue samples are required from area of active inflammation at Screening. On Day 56 (or early discontinuation visit), at least 3 tissue samples are required from the same region where 
Screening biopsies were obtained. Additional biopsy samples may be collected at the Investigator’s discretion for histological assessment. 
g  Infusion reactions will be monitored for up to 4 hours following study drug administration and graded, as applicable, as appears in Appendix D 
h Biochemistry will include serum β-hCG at screening. 
i Blood samples for bertilimumab (PK analysis) will be collected pre-dose, 30 (+15) minutes (immediately post-dose) and 4 hours (± 20 minutes) following initiation of study drug infusion. 
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Study Procedures 
Screening 
Period 
Treatment Perioda 
Early 
Discontinuationb 
Follow-up Periodc 
Visit 
1 
2 
3 
4 
- 
5 
6 
7 
8 
Study Day  
-28 to -1 
0 
14 
28 
- 
35 
42 
56 
90 
Calprotectin in fecal sample  
X 
X* 
X* 
X* 
X 
X 
X 
X 
X 
Eotaxin-1 & eosinophil count in tissue samples  
X 
 
 
 
X 
 
 
X 
 
* Denotes assessment will be done pre-dose.  
j The pretreatment dosing regimen is as follows:  
Dexamethasone 10 mg PO 24-18 hours prior to administration of bertilimumab. 
Acetaminophen 1000 mg PO 1 hour prior to administration of bertilimumab 
Loratadine 10 mg PO or cetirizine 10 mg PO one hour prior to the administration of bertilimumab. 
In the event that dexamethasone was not administered previously, then 10 mg dexamethasone IV may be administered one to three hours prior to bertilimumab administration. 
 
 
 
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Appendix B Mayo Score 
The Mayo score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 
(severe disease) and is a composite of 4 sub-scores: Stool Frequency Sub-score, Rectal 
Bleeding Sub-score, Endoscopic Finding Sub-score, and Physician's Global Assessment Sub-
score, each of which ranges from 0 (normal) to 3 (severe disease). 
Mayo Scoring System* for Assessment of Ulcerative Colitis Activity 
Stool Frequency Sub-score 
 
0 
Normal number of stools for study patient 
1 
1 to 2 stools per day more than normal 
2 
3 to 4 stools more than normal 
3 
≥5 stools more than normal 
Rectal Bleeding Sub-score 
 
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 passes 
Endoscopic Finding Sub-score 
 
0 
Normal or inactive disease 
1 
Mild Disease (erythema, decreased vascular pattern, 
mild friability) 
2 
Moderate Disease (marked erythema, lack of 
vascular pattern, friability, erosions) 
3 
Severe Disease (spontaneous bleeding, ulceration) 
Physician’s Global Assessment 
Sub-score 
 
0 
Normal 
1 
Mild Disease 
2 
Moderate Disease 
3 
Severe Disease 
*Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, et al. (2005 Dec) Infliximab for induction and maintenance 
therapy for ulcerative colitis. N Engl J Med. 8;353(23):2462-76. 
 
 
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Appendix C Ulcerative Colitis Endoscopic Index of Severity 
 
 
 
 
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Appendix D Grading of Infusion Reactions 
Grade 
1 
2 
3 
4 
Signs and 
symptoms 
Transient ﬂushing or rash, 
drug fever <38o C; 
asymptomatic 
bronchospasm 
Generalized urticaria 
responsive to medication; 
drug fever >38°C; dyspnea 
or reversible 
bronchospasm  
Bronchospasm requiring 
medication; symptomatic 
urticaria persisting with 
medication; allergy-related 
edema/angioedema; 
hypotension; signs and 
symptoms not rapidly 
responsive to interruption 
of infusion 
Anaphylaxis (defined 
below); laryngeal/ 
pharyngeal edema 
requiring resuscitation; 
cardiopulmonary 
instability requiring 
ventilatory support or 
pressors 
Intervention None 
Infusion held up to 30 
minutes or until symptoms 
recede; if symptoms recur 
upon resuming infusion, 
then discontinue infusion 
Discontinue infusion; 
initiate additional 
interventions if warranted 
clinically 
Discontinue infusion; 
urgent intervention 
indicated 
Anaphylaxis criteria (adopted from the NIAAD/FAAN Clinical Criteria for Anaphylaxis, The 
Second Symposium on the Definition and Management of Anaphylaxis, Sampson et al. 2006): 
One or both of the following: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
And at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow, hypoxemia)
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g.,
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur minutes to several hours after exposure to a likely
allergen for that patient:
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow, hypoxemia)
c.
Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope,
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
58