Conditions: Ulcerative Colitis
Keywords: Colitis, Ulcerative Gastrointestinal Diseases Inflammatory Bowel Disease Immunomodulator Therapy Glucocorticoids Anti-Inflammatory Agents Therapeutic uses Kappaproct IDX0150 DIMS0150
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 213
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate efficacy of cobitolimod treatment at different dose levels and frequencies compared to placebo in patients with moderate to severe left-sided ulcerative colitis.

Detailed description:
This was a Phase IIb study in patients with moderate to severe left-sided ulcerative colitis. Patients either received cobitolimod 31 mg, 125 mg or 250 mg at two occasions or 125 mg or placebo at four occasions during a 3-weeks period. To ensure blindness, patients received active treatment at two occasions and placebo at the other two occasions. Blood, stool, and tissue samples was collected at various time points throughout the study to evaluate safety and efficacy. Primary endpoint was evaluated at week 6.

Duration of participation for patients was approximately 12 weeks (from screening to final follow-up visit).

Arms:
arm 1: Dose 31 mg of cobitolimod at 2 occasions, placebo at 2 occasions arm 2: Dose 125 mg of cobitolimod at 2 occasions, placebo at 2 occasions arm 3: Dose 250 mg of cobitolimod at 2 occasions, placebo at 2 occasions arm 4: Dose 125 mg of cobitolimod, at 4 occasions arm 5: Placebo at four occasions

Interventions: intervention 1: cobitolimod intervention 2: Placebo
Intervention descriptions: intervention 1: Rectal administration intervention 2: Solution manufactured to mimic cobitolimod

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
CONFIDENTIAL 
 
Clinical Study Protocol CSUC-01/16       
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CLINICAL STUDY PROTOCOL 
(including synopsis) 
 
 
 
Protocol Title: 
A Randomised Dose-Optimisation Study to Evaluate the Efficacy 
and Safety of Cobitolimod in Moderate to Severe Active Ulcerative 
Colitis Patients 
Protocol Number: 
CSUC-01/16 
EudraCT Number: 
2016-004217-26 
Phase: 
IIb 
Study Sponsor: 
InDex Pharmaceuticals AB 
Protocol Version: 
1.1  
Version Date: 
19JAN2017 
 
–CONFIDENTIAL– 
The information in this CLINICAL STUDY PROTOCOL is property of InDex Pharmaceuticals AB. 
It is provided confidentially and should only be disclosed to those persons responsible for execution 
and organisation of the trial and on condition that all such persons agree upon no further dissemination 
 
 
NCT 03178669 
Dataprotection 


 
 
 
 
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STATEMENT OF COMPLIANCE 
 
This study will be conducted in accordance with this Clinical Study Protocol, CSUC-01/16 
version 1.1, dated 19JAN2017 and also in accordance with the following; 
• Declaration of Helsinki (Fortaleza, Brazil, October 2013). 
• Good Clinical Practice of the European Community/International Conference on 
Harmonization (CPMP/ICH/135/95). 
• European Clinical Trial and Food and Drug Administration Directives  
• Respective local laws and regulations. 
• Regulatory requirements for reporting of serious adverse events  
 
  
 
DATE:  
 
Karin Arnesson 
Clinical Trial Manager 
InDex Pharmaceuticals AB, Sweden 
 
 
 
  
 
DATE:  
 
Raja Atreya 
Coordinating Investigator 
 
 


 
 
 
 
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SIGNATURE PAGE 
The signature below constitutes that I have read and agreed to protocol. CSUC-01/16  
version 1.1, dated 19JAN2017. I am aware of my responsibilities as an investigator under 
Good Clinical Practice (GCP), Helsinki Declaration, European Clinical Trials Directives, 
Food Drug Administration (FDA) and local regulations (as applicable) and the study protocol. 
I agree to conduct the study according to these guidelines and to appropriately direct and 
assist the staff who will be involved in the study. 
 
 
Investigator´s Signature: 
 
 
Date: 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 


 
 
 
 
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KEY ROLES AND CONTACT INFORMATION 
 
COORDINATING 
INVESTIGATOR  
 
Professor Raja Atreya 
Universitätsklinikum Erlangen 
Medizinische Klinik 1 
Ulmenweg 18 
91054 Erlangen, Germany 
 
 
PROJECT MANAGER 
 
Kerstin Wagner 
PAREXEL International GmbH 
Waldecker Strasse 10-12 
64546 Moerfelden, Germany 
Phone:+49 6105 9430 115 
Mobil:+49 151 544 161 94 
Email: kerstin.wagner@PAREXEL.com 
 
 
STUDY SPONSOR 
 
InDex Pharmaceuticals AB  
Tomtebodavägen 23a 
171 77 Stockholm, Sweden 
Phone: +46 (0) 8 508 847 30   
 
 
SPONSORS CLINICAL TRIAL 
MANAGER 
 
Karin Arnesson 
Phone: +46 (0) 70 6365061  
Email: karin.arnesson@indexpharma.com 
 
STUDY MEDICAL 
MONITOR 
 
PAREXEL MEDICAL MONITOR 
 
 
STUDY MEDICAL ADVISOR 
 
Professor Walter Reinisch 
Medical University of Vienna 
Div. Gastroenterology & Hepatology 
Working Party Inflammatory Bowel Disease (IBD) 
Waehringer Guertel 18-20,  
A-1090 Vienna, Austria 
 
Dataprotection 


 
 
 
 
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STATISTICIAN 
 
Jan Kowalski  
InDex Pharmaceuticals AB 
 
PAREXEL statistician 
 
 
DATA MANAGEMENT 
 
 
PAREXEL  
 
SAFETY HANDLING 
 
 
PAREXEL  
 
CLINICAL LABORATORY 
 
PAREXEL  
 
 
 
 
 


 
 
 
 
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TABLE OF CONTENTS 
 
 
STATEMENT OF COMPLIANCE ................................................................................ 2 
SIGNATURE PAGE .................................................................................................... 3 
KEY ROLES AND CONTACT INFORMATION .......................................................... 4 
TABLE OF CONTENTS .............................................................................................. 6 
LIST OF ABBREVIATIONS ...................................................................................... 10 
SYNOPSIS ................................................................................................................ 13 
CLINICAL STUDY PROTOCOL ............................................................................... 24 
1. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE .............................................................................................................. 25 
1.1. 
The Disease .............................................................................................................. 25 
1.2. 
Cobitolimod .............................................................................................................. 26 
1.3. 
Non-Clinical Experience .......................................................................................... 27 
1.4. 
Clinical Experience .................................................................................................. 27 
1.4.1. 
Pilot Study, HICS-9801.................................................................................... 28 
1.4.2. 
Phase II Dose Finding Study, CSUC-01/02 ..................................................... 28 
1.4.3. 
Phase II Proof of Concept Study, CSUC-01/06 ............................................... 28 
1.4.4. 
Named Patient Basis Use of Cobitolimod, CU-UC-01/11 ............................... 29 
1.4.5. 
Phase III Study, CSUC-01/10 .......................................................................... 29 
1.5. 
Study Rationale ........................................................................................................ 29 
1.6. 
Potential Risks and Benefits ..................................................................................... 30 
2. STUDY OBJECTIVES .......................................................................................... 31 
2.1. 
Primary Objective .................................................................................................... 31 
2.2. 
Secondary Objective ................................................................................................ 31 
3. STUDY DESIGN AND ENDPOINTS ..................................................................... 31 
3.1. 
Overview .................................................................................................................. 31 
3.2. 
Study Evaluation Criteria ......................................................................................... 31 
3.2.1. 
Primary Efficacy Endpoint ............................................................................... 32 
3.2.2. 
Secondary Exploratory Endpoints .................................................................... 32 
3.2.3. 
Safety Endpoints .............................................................................................. 33 
4. STUDY POPULATION .......................................................................................... 33 
4.1. 
Inclusion Criteria ...................................................................................................... 33 
4.2. 
Exclusion Criteria ..................................................................................................... 35 
4.3. 
Randomisation and Stratification ............................................................................. 36 


 
 
 
 
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4.4. 
Patient participation .................................................................................................. 36 
4.4.1. 
Patient Replacement ......................................................................................... 37 
4.4.2. 
Follow-up of early discontinued patients ......................................................... 37 
5. STUDY TREATMENT ........................................................................................... 37 
5.1. 
Study Drug ............................................................................................................... 37 
5.2. 
Study Drug Administration ...................................................................................... 37 
5.3. 
Study Drug Packaging, Labelling, Shipment and Storage ....................................... 38 
5.3.1. 
Study Drug Packaging ...................................................................................... 38 
5.3.2. 
Study Drug Labelling ....................................................................................... 38 
5.3.3. 
Shipment of Study Drug ................................................................................... 38 
5.3.4. 
Storage of Study Drug ...................................................................................... 38 
5.4. 
Study Drug Compliance ........................................................................................... 38 
5.5. 
Blinding and Unblinding .......................................................................................... 38 
5.6. 
Overdose ................................................................................................................... 39 
5.7. 
Concomitant Medications ........................................................................................ 39 
5.8. 
Prohibited Medications ............................................................................................ 39 
5.9. 
Oral Corticosteroid Tapering Regimen .................................................................... 40 
5.10. Rescue Medications .................................................................................................. 40 
6. STUDY SCHEDULE ............................................................................................. 40 
6.1. 
Visit 1a (Day -14) and 1b (Day -7 to -10) – Screening Visits ................................. 40 
6.2. 
Visit 2a (Day -4 to-7) and 2b (Week 0) – Randomisation Visits ............................. 41 
6.3. 
Visit 3 - (Week 1) ..................................................................................................... 42 
6.4. 
Visit 4 - (Week 2) ..................................................................................................... 43 
6.5. 
Visit 5 - (Week 3) ..................................................................................................... 43 
6.6. 
Visit 6 - (Week 6) Primary Endpoint or Discontinuation visit ................................ 43 
6.7. 
Visit 7 – (Week 10) .................................................................................................. 44 
6.8. 
Unscheduled Visit .................................................................................................... 44 
7. STUDY PROCEDURES ........................................................................................ 44 
7.1. 
Central reading ......................................................................................................... 44 
7.2. 
Concomitant Medication .......................................................................................... 44 
7.3. 
Collection of Adverse Event and Serious Adverse Event ........................................ 44 
7.4. 
Demographics ........................................................................................................... 44 
7.5. 
Electrocardiogram .................................................................................................... 44 
7.6. 
Eligibility and Evaluation ......................................................................................... 45 
7.7. 
Endoscopy, Biopsy and Histology ........................................................................... 45 
7.8. 
Extraintestinal Manifestation Assessment ............................................................... 45 
7.9. 
Inflammatory Bowel Disease Questionnaire ............................................................ 45 
7.10. Informed Consent ..................................................................................................... 45 
7.11. Laboratory Procedures ............................................................................................. 46 
7.12. Leakage Measure ...................................................................................................... 47 
7.13. Medical History ........................................................................................................ 47 
7.14. Mayo Score .............................................................................................................. 47 
7.15. Patient eDiary completion and Review .................................................................... 47 
7.16. Physical Examination ............................................................................................... 48 
7.17. Pregnancy Test ......................................................................................................... 48 


 
 
 
 
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7.18. Prior Therapies ......................................................................................................... 48 
7.19. Study Drug Administration ...................................................................................... 48 
7.20. Tobacco Use ............................................................................................................. 48 
7.21. Ulcerative Colitis History and Assessment .............................................................. 48 
7.22. Urgency of Defecation ............................................................................................. 49 
7.23. Vital Signs ................................................................................................................ 49 
8. ADVERSE EVENT ................................................................................................ 49 
8.1. 
Adverse Event Definition ......................................................................................... 49 
8.2. 
Adverse Drug Reaction Definition ........................................................................... 49 
8.3. 
Serious Adverse Event Definition ............................................................................ 49 
8.4. 
Adverse Events by Intensity ..................................................................................... 50 
8.5. 
Classification of Adverse Events by Relationship to Study Drug ........................... 50 
8.6. 
Reporting of Adverse Events ................................................................................... 50 
8.7. 
Reporting of Serious Adverse Events ...................................................................... 51 
8.8. 
Follow-up Period after an Adverse Event ................................................................ 52 
8.9. 
Coding of Adverse Events ........................................................................................ 52 
9. STATISTICAL CONSIDERATIONS ...................................................................... 52 
9.1. 
Statistical Analysis Plan ........................................................................................... 52 
9.2. 
Determination of Trial Size ...................................................................................... 52 
9.3. 
Study Population ...................................................................................................... 53 
9.3.1. 
Full Analysis Set .............................................................................................. 53 
9.3.2. 
Per Protocol Set ................................................................................................ 53 
9.3.3. 
Safety Analysis Set ........................................................................................... 53 
9.4. 
Patient Demographic and Baseline Characteristics .................................................. 53 
9.5. 
Primary Efficacy Endpoint Analysis ........................................................................ 53 
9.6. 
Exploratory Efficacy Endpoints Analyses ............................................................... 54 
9.7. 
Safety Analysis ......................................................................................................... 54 
9.7.1. 
Analysis of Adverse Events ............................................................................. 54 
9.7.2. 
Other Safety Assessments ................................................................................ 54 
9.8. 
Adjustment of Covariates ......................................................................................... 55 
9.9. 
Handling of Dropouts and Missing Data .................................................................. 55 
9.10. Rules for Excluding Patients from Analysis ............................................................ 55 
9.11. Procedures for Reporting Deviations from Original Statistical Plan ....................... 55 
9.12. Interim Analysis ....................................................................................................... 55 
10. 
DATA HANDLING .......................................................................................... 55 
10.1. Data Handling .......................................................................................................... 55 
10.2. Data Management .................................................................................................... 56 
10.2.1. 
Electronic Case Report Form ........................................................................... 56 
10.2.2. 
Entry of Data .................................................................................................... 56 
10.2.3. 
Query Process ................................................................................................... 56 
10.2.4. 
Source Documents ............................................................................................ 57 
10.2.5. 
User Identification ............................................................................................ 57 
10.2.6. 
Audit Trail ........................................................................................................ 57 
10.2.7. 
Medical Review of Safety Data ....................................................................... 57 
10.3. Study Monitoring and Auditing ............................................................................... 57 


 
 
 
 
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10.4. Retention of Records ................................................................................................ 58 
10.5. Use of Study Findings .............................................................................................. 58 
11. 
ETHICAL REQUIREMENTS .......................................................................... 58 
11.1. Ethical Conduct of the Study ................................................................................... 58 
11.2. Indemnification ........................................................................................................ 58 
11.3. Sponsor Discontinuation Criteria ............................................................................. 59 
12. 
STUDY COMMITTEES ................................................................................... 59 
12.1. Data Safety Monitoring Board ................................................................................. 59 
13. 
PUBLICATION/DATA SHARING POLICY ..................................................... 59 
14. 
REFERENCES ............................................................................................... 60 
15. 
APPENDICES ................................................................................................ 62 
15.1. Mayo Scoring System for Assessment of Ulcerative Colitis Activitya .................... 62 
15.2. Definitions of stool frequency and rectal bleeding .................................................. 63 
15.3. Nancy Histological Index ......................................................................................... 64 
15.4. Extraintestinal Manifestations of Inflammatory Bowel Disease .............................. 65 
15.5. Urgency of defecation index .................................................................................... 66 
 
Tables in Text 
Table 1. Schedule of Activities ............................................................................................................................ 21 
Table 2. Schedule of Steroid Dose Reduction given in Mg/Day.......................................................................... 40 
Table 3. Clinical Laboratory Analysis. ................................................................................................................ 46 
 
Figures in Text 
Figure 1. Study Design ......................................................................................................................................... 23 
 
 
 
 


 
 
 
 
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LIST OF ABBREVIATIONS 
5-ASA 
5-Aminosalicylic Acid 
6-MP 
6-Mercaptopurine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AZA 
Azathiopurine 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CAI 
Clinical Activity Index 
CPK 
Creatine Phosphokinase 
CRO 
Contract Research Organisation 
CRP 
C-reactive Protein 
CSUC 
Clinical Study Ulcerative Colitis 
CU-UC 
Compassionate Use Ulcerative Colitis 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
ECCO 
European Crohn´s and Colitis Organisation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
EU 
European Union 
FAS 
Full Analysis Set 
GCS 
Glucocorticosteroids 
GGT 
Gamma-Glutamyl Transpeptidase 
HR 
Heart Rate 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL-10 
Interleukin 10 
ITT 
Intention-to-Treat 
IV 
Intravenous 
 
 


 
 
 
 
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IVRS 
Interactive Voice Response System 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-Steroidal Anti-inflammatory Drugs 
NRI 
Non Responder Imputation 
PI 
Principal Investigator 
PGA 
Physicians Global Assessment 
PPS 
Per Protocol Analysis Set 
PRO 
Patient Reported Outcome 
PT 
Prothrombin Time 
QOL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOP 
Standard Operating Procedures 
SP 
Sulphasalazine 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TPMT 
Thiopurine Methyltransferase 
TNFα 
Tumour Necrosis Factor Alpha 
UC 
Ulcerative Colitis 
US 
United States 
WBC 
White Blood Cells 


 
 
 
 
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Clinical Study Synopsis 
CSUC-01/16 


 
 
 
 
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SYNOPSIS 
Name of the Sponsor/Company: 
InDex Pharmaceuticals AB 
Name of Active Ingredient/Product: 
Cobitolimod (earlier named Kappaproct®) and/or DIMS0150, (deoxyribonucleic acid-based 
immunomodulatory sequence 0150) 
 
STUDY CODE: CSUC-01/16 
A Randomised Dose Optimisation Study to Evaluate the Efficacy and Safety of Cobitolimod 
in Moderate to Severe Active Ulcerative Colitis Patients 
INVESTIGATOR(S): TBD 
STUDY CENTRE(S):  
Approximately 90 European sites will participate in the study. 
PHASE OF DEVELOPMENT: Phase IIb 
STUDY OBJECTIVES: 
Primary Objective  
To evaluate the efficacy of cobitolimod treatment at different dose levels and frequencies 
compared to placebo with regard to clinical remission 6 weeks after first treatment, in patients 
with moderate to severe active ulcerative colitis (UC). 
Secondary Objectives 
• To evaluate the safety and tolerability of cobitolimod. 
• To evaluate the efficacy of cobitolimod treatment compared to placebo in clinical 
remission, clinical response and clinical symptoms. 
• To evaluate the efficacy of cobitolimod treatment compared to placebo in endoscopic 
and histological remission and response. 
• To evaluate the effect of cobitolimod on quality of life (QOL). 
STUDY DESIGN: 
This phase IIb study is a randomised, double-blind, dose-optimisation study, of cobitolimod 
compared to placebo. The study population will be patients with moderate to severe active UC 
who are no longer responding adequately, to conventional therapies. 
Active left sided UC patients with a Modified Mayo score (excluding the friability at grade 1 


 
 
 
 
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for the endoscopic sub score) of 6-12, with an endoscopic sub score ≥2 and no other 
individual sub score <1, who are at least 18 years of age will be eligible for enrolment. 
In total, 215 eligible patients will be randomly assigned in a 1:1:1:1:1 allocation to receive 
rectal doses of cobitolimod 31 mg, cobitolimod 125 mg, cobitolimod 250 mg, at Week 0 and 
3 (in total two doses of active drug) and placebo at Week 1 and 2, cobitolimod 125 mg at 
Week 0, 1, 2, 3 (in total four doses of active drug) or placebo at Week 0, 1, 2, 3. 
Randomisation will be stratified for the following categories of patients: concomitant use of 
glucocorticoidsteroid (GCS) treatment (Yes/No) and previously treated with tumour necrosis 
factor alpha (TNF-α) inhibitors (Yes/No). 
Study treatment will be administered rectally using an enema. 
The screening period will have two screening visits. At the first screening visit 1a 
a written informed consent will be obtained before any other study procedure is done. Patients 
will be assigned a patient identification number and enrolment procedures will commence.  
At the second screening visit 1b, a full colonoscopy will be performed.  
Visits will be performed at Day -14, Day-7, Day -4, Week 0 and Week 1, 2, 3, 6, 10. 
Evaluation and follow-up of patients will be performed at all visits. If the patient’s disease 
deteriorates or does not improve, it is the investigator´s responsibility to judge if an alternative 
treatment is needed. 
SELECTION OF PATIENTS: 
Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be randomised in the 
study: 
1. Male or female ≥ 18 years of age  
2. Established diagnosis of UC, with minimum time from diagnosis of ≥3 
months  
3. Moderately to severely active left sided UC (disease should extend 15 cm or 
more above the anal verge and not beyond the splenic flexure) determined by 
a Modified Mayo score (excluding the friability at grade 1 for the endoscopic 
sub score) of 6 to 12 with an endoscopic sub score ≥2 assessed by central 
reading of endoscopy performed at screening visit 1b, and no other individual 
sub score <1 
4. Current oral 5-ASA/SP use or a history of oral 5-ASA/SP use  
5. Current GCS use or history of GCS dependency, refractory, or intolerance, 
including no GCS treatment due to earlier side-effects (only one of the GCS 
criteria have to be fulfilled, see definition in European Crohn´s and Colitis 
organisation (ECCO) guidelines) 
6. Demonstrated an inadequate response, loss of response, or intolerance to at 
least one of the following agents: 


 
 
 
 
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• Immunomodulators, e.g. cyclosporine, methotrexate, AZA/6-MP, 
tacrolimus  
o For example,signs and symptoms of persistently active disease despite 
previous treatment with at least one 8 week regimen of oral AZA (≥1.5 mg/kg) 
or 6-MP (≥0.75 mg/kg) or lower doses prompted by intolerance or thiopurine 
methyltransferase (TPMT) deficiency or 
o For example, previous intolerance (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, liver function test 
(LFT) abnormalities, lymphopenia, TPMT genetic mutation, 
infection) to at least one immunomodulator  
• TNF-α inhibitors and/or anti-integrins: 
o Signs and symptoms of persistently active disease despite previous 
treatment with at least one induction regimen with 2 doses at least 2 
weeks apart (or doses as recommended according to the current 
labels) of for e.g.: 
▪ Infliximab 5 mg/kg (intravenous (IV)) or 
▪ Golimumab 200/100 mg (subcutaneous (SC)) or 
▪ Adalimumab 160/80 mg (SC) or 
▪ Vedolizumab 300 mg (IV) or 
o History of intolerance (including but not limited to infusion-related 
reaction, demyelination, congestive heart failure, infection) 
Recurrence of symptoms during maintenance dosing with any of the above medications 
following prior clinical benefit, (secondary failure) [discontinuation despite clinical benefit 
does not qualify] 
7. Allowed to receive a therapeutic dose of following UC drugs during the 
study: 
a) Oral GCS therapy (≤20 mg prednisone or equivalent/daily) providing that 
the dose has been stable for 2 weeks prior to visit 1a 
b) Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks 
before visit 1 a. 
c) Oral 5-ASA/SP compounds, providing that the dose has been stable for 2 
weeks prior to visit 1a and initiated at least 8 weeks before visit 1a 
d) AZA/6-MP providing that the dose has been stable for 8 weeks prior to 
visit 1b and been initiated at least 3 months before visit 1a 
8. Ability to understand the treatment, willingness to comply with all study 
requirements and ability to provide informed consent 
Exclusion Criteria  
Patients presenting with any of the following will not be included in the study: 
1. Suspicion of differential diagnosis such as; Crohn’s enterocolitis, ischaemic 
colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular 
disease, associated colitis, microscopic colitis, massive pseudopolyposis or 
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2. Acute fulminant UC and/or signs of systemic toxicity 
3. UC limited to the rectum (disease which extend <15 cm above the anal 
verge) 
4. History of malignancy, except for: 
• Treated (cured) basal cell or squamous cell in situ carcinoma 
• Treated (cured) cervical intraepithelial neoplasia or carcinoma in situ 
of the cervix with no evidence of recurrence within the previous 5 
years prior to the screening visit 1a 
5. History or presence of any clinically significant disorder that, in opinion of 
the investigator, could impact on patient’s possibility to adhere to the 
protocol and protocol procedures or would confound the study result or 
compromise patient safety 
6. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, TNF-α 
inhibitors, anti-integrins or similar immunosuppressants and 
immunomodulators at enrolment. Any prior treatment with such drugs must 
have been discontinued at least 8 weeks prior to visit 1a or have non-
measurable serum concentration levels 
7. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 Weeks before 
visit 1b 
8. Long term treatment with antibiotics or non-steroidal anti-inflammatory 
drugs (NSAIDs) within two weeks prior to visit 1a (one short treatment 
regime for antibiotics and occasional use of NSAIDS are allowed) 
9. Serious active infection 
10. Gastrointestinal infections including positive Clostridium difficile stool assay 
11. Currently receiving parenteral nutrition or blood transfusions 
12. Females who are lactating or have a positive serum pregnancy test during the 
screening period 
13. Women of childbearing potential not using reliable contraceptive methods 
(reliable methods are barrier protection, hormonal contraception, intra-
uterine device or abstinence) throughout the duration of the study 
14. Concurrent participation in another clinical study with investigational therapy 
or previous use of investigational therapy within 5 half-lives and within at 
least 30 days after last treatment of the experimental product prior to 
enrolment 
15. Previous exposure to cobitolimod 
PLANNED TRIAL SIZE: 
Given that the purpose of this trial is to determine whether cobitolimod is efficient and 
therefore whether to proceed with further development, there is only one outcome of interest, 
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a one-sided testing framework is appropriate. 
Further phase III trials will be required to confirm the efficacy, and thus the standard type I 
error rate control at the 0.05 level is not strictly necessary. The assumption is that a one-sided 
test of the null hypothesis, that there is no difference in the primary endpoint between each 
active treatment arm and control (placebo), with a false-positive (type I error) rate of 0.10 is 
appropriate. The use of this higher type I error and of a low type II error of 0.10 gives to the 
trial high statistical power to detect a clinically meaningful effect while maintaining an 
acceptable sample size. 
Assuming 
• a 10 % remission rate for the placebo 
• a type I error of 0.10 
• a 35 % remission rate for the active cobitolimod treatment 
• a power of 90 % 
• a one-tailed test for differences between proportions 
Thirty-five (35) patients per group are needed. 
To allow for 10-20 % dropout rate the sample size is decided to 43 patient per treatment group 
and 215 patients in total. 
Allocating 43 patients per treatment arm will also satisfy a power goal of 80 % using a two-
sided test at the 0.05 type I error rate. 
Power calculation was performed using the Chi-square test for independent groups. Nquery 
7.0 was used for power calculation. 
INVESTIGATIONAL THERAPY AND TREATMENT DURATION: 
During the treatment period of the study, cobitolimod 31 mg, 125 mg or 250 mg or placebo 
will be given in two doses, at Week 0 and Week 3 and placebo will be given at Week 1 and 
Week 2 or cobitolimod 125 mg every week (Week 0, 1, 2, and 3). To ensure the study 
remains blinded, all patients will be treated Week 0, 1, 2, and 3 with either cobitolimod or 
placebo. The drug will be administered by study personnel using an enema. 
The primary endpoint will be assessed after 6 weeks. Safety evaluation and disease 
monitoring will be performed at each visit after the first dose. 
REFERENCE THERAPY:  
Placebo is a rectal solution where the ingredient is water, identically packed and administered 
as cobitolimod. 
CONCOMITANT THERAPY: 
The patients may be receiving a therapeutic dose of the following concomitant therapies:  
oral GCS (≤ 20 mg prednisone or equivalent/day), if stable dose for at least 2 weeks prior to 
screening visit 1a, and/or oral MMX Budesonide (9mg/day) if stable dose for at least 8 weeks 
prior screening visit 1a, and/or oral 5-ASA and/or SP, if stable dose for at least 2 weeks prior 


 
 
 
 
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screening visit 1a. The 5-ASA/SP treatment should have been initiated at least 8 weeks before 
screening  
visit 1a. 
The patient may also receive AZA/6-MP, if stable dose for at least 8 weeks prior to screening 
visit 1b. The treatment should have been initiated at least 3 months before visit 1a. 
The patient shall stay on same dose of allowed UC treatment up to end of study (Week 10) 
except for the GCS that can start to be tapered off at Week 6, if the patient is in remission. 
  
During the study, concomitant treatment with biologics (such as TNF-α inhibitors and  
anti-integrins), cyclosporine, methorexate, tacrolimus, or similar immunomodulatory/ 
immunosuppressant drugs is not allowed, and should have been stopped (due to documented 
lack of efficacy, side effects or other reasons,) at least 8 weeks prior to visit 1a or have non-
measurable serum concentration levels. 
OUTCOME MEASUREMENTS: 
Primary Efficacy Endpoint 
Proportion of patients with clinical remission at Week 6, defined by Modified Mayo sub 
scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease 
from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding friability). 
Secondary Exploratory Endpoints  
• Proportion of patients with symptomatic remission at Week 6, defined by the Mayo 
sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease  from Baseline, Week 0), (patient reported outcome) [PRO2] 
• Proportion of patients with absence of rectal bleeding at Week 6, defined by the Mayo 
sub score rectal bleeding of 0 
• Proportion of patients with normal or enhanced stool frequency at Week 6, defined by 
the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from 
Baseline, Week 0) 
• Proportion of patients with endoscopic remission at Week 6, defined by the Modified 
Mayo endoscopic sub score of 0 or 1 (excluding friability) 
• Proportion of patients with histological remission at Week 6, defined by the Nancy 
histological index of grade 0 or 1 
• Proportion of patients with complete histological remission at Week 6, defined by the 
Nancy histological index grade of 0 
• Proportion of patients with histological response at Week 6, defined by the Nancy 
histological index score of ≤2 (if 2 then with at least one point decrease from Baseline,  
Week 0)  
• Proportion of patients with endoscopic and histological remission at Week 6  


 
 
 
 
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• Proportion of patients with symptomatic remission at Week 4, defined by the Mayo 
sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease  from Baseline, Week 0), (patient reported outcome) [PRO2] 
• Proportion of patients with absence of rectal bleeding at Week 4, defined by the Mayo 
sub score rectal bleeding of 0 
• Proportion of patients with normal or enhanced stool frequency at Week 4, defined by 
the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from 
Baseline, Week 0) 
• Proportion of patients with modified clinical remission at Week 6, defined by the 
Modified Mayo score ≤ 2 and sub scores, i) rectal bleeding of 0, ii) stool frequency of 
0 or 1 (with at least one point decrease from Baseline, Week 0), iii) endoscopy score 
of 0 or 1 (excluding friability ) and iiii) physician´s global assessment (PGA) of 0 or 1 
• Proportion of patients with durable symptomatic remission, defined by the Mayo sub 
scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease from Baseline, Week 0) [PRO2] at both Week 6 and Week 10 
• Proportion of patients with clinical response at Week 6, defined as clinical remission 
or a three point and ≥30 % decrease from Baseline, Week 0 in the sum of the Modified 
Mayo score, i) rectal bleeding, ii) stool frequency and iii) endoscopy score (excluding 
friability), iiii) physicians global assessment (PGA) 
• Proportion of patients with a defecation urgency score of 0 or a decrease of at least 
one point in defecation urgency at Week 6 compared to Baseline, Week 0 
• Mean change in faecal calprotectin at Week 1, 2, 3, and 6 compared to Baseline,  
Week 0 
• Mean change in steroid dosage for patients in remission at Week 6 to Week 10 
• Mean change in each of the inflammatory bowel disease questionnaire (IBDQ) sub 
domains at Week 6 compared to Baseline, Week 0 
Safety Endpoints 
• Incidence of adverse events (AEs) 
• Incidence of serious adverse events (SAEs) 
• Vital signs 
• Electrocardiogram (ECG) 
• Physical Examination 
• Laboratory Findings 
STATISTICAL METHODS: 
Planned Interim Analysis: 
No formal statistically based interim analysis will be performed. However, the safety data will 


 
 
 
 
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be reviewed periodically during the conduct of the study by the independent data safety 
monitoring board (DSMB). The objective of the DSMB data review is safety.  
Study Population: 
The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which 
consists of all randomised patients who meet the inclusion criteria (as assessed by the 
investigator on the inclusion/exclusion criteria form), and receive at least one dose of the 
study drug (active or placebo). 
The per protocol set (PPS) is defined as FAS patients who do not have important protocol 
deviations considered to have a major effect on the primary efficacy endpoint, and have 
completed the Modified Mayo sub scores assessment at Week 0 and Week 6. 
Safety population: all patients included in the study and treated with at least one dose of study 
drug. 
Planned Analysis: 
The analysis of the primary endpoint is conducted on the FAS and PPS. 
The primary analysis of the primary endpoint will be performed using the Cochran Mantel 
Haenzel test adjusting for randomisation strata GCS use/non use and TNF-α prior use/non use 
at Baseline, Week 0. 
The primary endpoint will be proportion of patients with clinical remission at Week 6 tested 
using an overall type I error rate of 0.10 using a one-sided test.  
The p-value for testing the null hypotheses must be less than 0.10 to be considered to have 
met the primary objective.  
The primary efficacy endpoint will also be tested using the same approach as described above 
but with the use of an overall type I error rate of 0.05 using a two-sided test.  
There will be no adjustment for multiplicity as all results will be regarded as exploratory. If a 
statistically significant difference among cobitolimod groups compared to placebo will exist, 
an analysis in terms of fractional polynomial for analysis of binary data will be applied to 
explore the dose-response relationship. 
SAFETY: 
Safety data will be evaluated using descriptive statistics. 
• AEs: Number, frequency and severity. 
• Change in safety variables, such as laboratory measurements and vital signs are 
measured at every clinic visit. 
• Change in concomitant medication: recorded at each visit 
Data Safety Monitoring Board  
DSMB will monitor the study for patient safety data. 
 


 
 
 
 
 
 
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Table 1. Schedule of Activities 
Study Procedures 
Screening 
Randomisation 
Treatment Period 
Primary 
Endpoint/ 
Early  
discontinuatio
n 
Follow Up 
 
Visit 1a 
Visit 1b 
Visit 2a (Phone) 
Visit 2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Day -14  
Day-7 to -10 
Day -4 to -7 
Week 0 
Week 1 
Week 2 
Week 3 
Week 6 
Week 10 
 
 
 
Day 0 
Day 7 
+/- 3 days 
Day 14 
+/- 3 days 
Day 21 
+/- 3 days 
Day 42 
+/- 3 days 
Day 70 
+/- 7 days 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
Review incl/excl criteria 
X 
X 
X 
 
 
 
 
 
 
Tobacco Use 
X 
 
 
 
 
 
 
X 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
Ulcerative Colitis History2 
X 
 
 
 
 
 
 
 
 
Prior Therapies19 
X 
 
 
 
 
 
 
 
 
Vital Signs 3 
X 
 
 
X 
X 
X 
X 
X 
X 
Physical Examination4 
X 
 
 
X 
X 
X 
X 
X 
X 
Laboratory: 
 
 
 
 
 
 
 
 
 
  Haematology5 
X 
 
 
X 
X 
X 
X 
X 
X 
  Blood Chemistry6 
X 
 
 
X 
X 
X 
X 
X 
X 
  Lipid profile7 
X 
 
 
 
 
 
 
X 
 
  Urinanalysis8 
X 
 
 
X 
 
 
 
X 
 
  Stool Culture/microscopy9 
X 
 
 
 
 
 
 
 
 
  Pregnancy Test10 
X 
 
 
X 
X 
X 
X 
X 
 
  Biomarkers11  
X 
 
 
X 
X 
X 
X 
X 
X 
Future Biomedical Research 
X 
 
 
X 
X 
X 
X 
X 
X 
ECG12 
X 
 
 
X 
 
 
 
X 
 
Endoscopy: 
 
 
 
 
 
 
 
 
 
-Full colonoscopy+biopsy13 
 
X 
 
 
 
 
 
 
 
-Flex sigmoidoscopy+ biopsy13 
 
 
 
 
 
 
 
X 
 
eDiary instructions14 
X 
 
 
 
 
 
 
 
 
Assessments: 
 
 
 
 
 
 
 
 
 
  eDiary compliance14 
 
X 
 
X 
X 
X 
X 
X 
X 
  PGA15 
 
X 
(X) 
 
 
 
 
X 
X 
  IBDQ16 
 
 
 
X 
 
 
X 
X 
 
  Urgency of defecation  
 
 
 
X 
X 
X 
X 
X 
X 
Adverse Event (AE)17 
 
X 
X 
X 
X 
X 
X 
X 
X 
Extraintestinal Manifestation18 
 
 
 
X 
 
 
 
X 
X 
Concomitant Medication19 
 
 
 
X 
X 
X 
X 
X 
X 
Randomisation20 
 
 
X 
 
 
 
 
 
 
Study Drug administration21 
 
 
 
X 
X 
X 
X 
 
 
Leakage Measure22 
 
 
 
X 
X 
X 
X 
 
 


 
 
 
 
 
 
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1. 
Date of birth, gender, race, height (cm), weight (kg). 
2. 
Medical History (including UC history) is to include the entire screening period, until just prior to the first dose of study drug with exception of AEs related to study 
procedures. 
3. 
Blood pressure and heart rate at every visit (except visit 1b and 2a), body temperature, height and weight only at Visit 2b. 
4. 
The following system organ classes will be reviewed for any relevant findings and appropriate physical examinations should be performed: general appearance, 
skin, musculoskeletal, eyes, ears, nose, throat, thyroid, cardiovascular, chest, abdomen, lymph nodes and neurological examination. Clinically significant findings 
will be reported as medical history prior to first dose of study drug and thereafter as an AE.  
5. 
Haemoglobin, haematocrit, platelet count, RBC, WBC, platelets, neutrophil, eosinophil, basophil, lymphocyte, and monocytes count. Fibrinogen, APTT and PT 
(including INR) in non-fasting samples. 
6. 
Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), amylase, blood urea nitrogen (BUN), calcium, chloride, 
creatine phosphokinase (CPK), creatinine, gamma glutamyl transferase (GGT), glucose, phosphorus, potassium, sodium,total bilirubin, total protein, uric acid, in 
non-fasting samples. 
7. 
Total cholesterol and triglyceride, in non-fasting samples. 
8. 
Blood, glucose, ketones, leucocytes, nitrite, protein, pH. 
9. 
Stool culture of Clostridium difficile Toxin B, Shigella, Campylobacter, Yersinia and Salmonella, as well as ova and parasites. 
10. 
Only for females of childbearing potential; Serum pregnancy test at screening visit 1a and then dip-stick tests at all other occasions. 
11. 
Serum CRP and faecal calprotectin.  
12. 
A 12 lead ECG will be done at screening visit 1a and visit 6. On visit 2b, ECG will be taken before study drug administration and 30 minutes after treatment. 
13. 
A full colonoscopy will be required at visit 1b, and flexible sigmoidoscopy at primary endpoint, visit 6. Videos will be sent for central reading and biopsies 
collected for histopathological grading according the Nancy score and future biomedical research (if consented). 3 biopsies should be taken from each bowel 
segment investigated (see protocol section 7.7; separate instructions are provided). 
14. 
Patient will be prompted to fill in the e-dairy on a daily basis. Patient should be instructed how to use the eDiary at visit 1a and if needed on all visits. 
15. 
PGA will be assessed at visit 1b (if not eDiary data are available then at visit 2a) and at visit 6 and 7 
16. 
IBDQ should be filled in before administration of study drug. 
17. 
The patients will be questioned about AEs at each clinic visit. Only AEs related to study specific procedures at screening visit will be recorded at  
Visit 1a, 1b and 2b.  
18. 
There will be questions regarding Extra Intestinal Manifestation disease/symptoms at visit 2b, visit 6 and visit 7. 
19. 
All concomitant medication taken should be reported at each visit. UC treatment should be reported up to 3 years before screening visit. For UC treatment dose and 
start and stop date will be reported for the last treatment period. 
20. 
Inclusion/exclusion criteria will be reviewed at several occasions during the screening period up to randomisation e g when the results of the safety laboratory and 
stool culture analyses have been obtained. When central reading result has been obtained a telephone contact visit will be done to ensure patient is still willing to 
participate and that all inclusion and exclusion criteria still are fulfilled. Randomisation procedure will then commence and patient will be scheduled for the first 
treatment visit. 
21. 
The study drug solution will be administered by the physician using a rectal enema. The exact time for start of the administration will be recorded in the eCRF.  
22. 
Any leakage of study drug should be recorded in the eCRF. 
 
 


 
 
 
 
 
 
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Figure 1. Study Design 
 
 
 


 
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Clinical Study Protocol 
 
 
 
 
CSUC-01/16 


 
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1. 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
1.1. 
The Disease 
Ulcerative colitis (UC) is a disease characterized by chronic inflammation of the rectal and 
colonic mucosa, affecting the innermost lining in the first stage. The disease is recurrent, with 
both active and inactive stages that differ in pathology, symptoms and treatment. The 
underlying cause of UC is not understood, nor is it known what triggers the disease to recur 
between its inactive and active forms [1]. Symptoms of active UC include progressive loose 
stools with blood and increased frequency of bowel movements. Active mucosal 
inflammation is diagnosed by endoscopy.  
The stools contain pus, mucous and blood and are often associated with abdominal cramping 
with urgency to evacuate (tenesmi). Diarrhoea may have an insidious onset or, more rarely, 
start quite suddenly. In severe cases the symptoms may include fever and general malaise. In 
severe stages, deep inflammation of the bowel wall may develop with abdominal tenderness, 
tachycardia, fever and risk of bowel perforation. Furthermore, patients with UC may suffer 
extra intestinal manifestations such as arthralgia and arthritis, erythema nodosum, pyoderma 
gangrenosum and inflammation in the eyes. In the case of remission or inactive UC, patients 
are usually free of bowel symptoms. The extent of inflamed and damaged mucosa differs 
among patients with UC. UC that affects only the rectum is termed ulcerative proctitis. The 
condition is referred as distal colitis when inflammatory changes are present in the left side of 
the colon up to the splenic flexure. In extensive UC the transverse colon is also affected, and 
pancolitis designates a disease involving the entire colon. 
Active mucosal inflammation is diagnosed by endoscopy and is characterized by a loss of 
vascular patterning, oedema, petechia, spontaneous bleeding and fibrinous exudates. The 
endoscopic picture is that of continuous inflammation, starting in the rectum and extending 
proximally to a variable extent into the colon. Biopsies obtained at endoscopy and subjected 
to histological examination help to diagnose the condition. Infectious causes, including 
Clostridium difficile, Campylobacter, Salmonella and Shigella, may mimic UC and should be 
excluded by stool cultures. 
The medical management of UC is divided into treatment of active disease and maintenance 
of remission. The treatment of patients with active UC aims to reduce inflammation and 
promote colon healing and mucosal recovery. In the majority of cases the disease may be 
controlled with conventional drugs including sulphasalazine (SP), 5-aminosalicylic acid (5-
ASA) [2] and glucocorticosteroids (GCS) [3]. Distal disease, limited to the rectum and the 
recto-sigmoid area, is usually brought into remission using rectal formulations. When the 
extent is more proximal and/or the symptoms more severe, oral GCS is also needed. GCS are 
generally used to treat disease flare-ups and are not recommended for maintenance of 
remission since there are significant side effects in long-term use (immunodeficiency, adrenal 
insufficiency, hyperglycemia, hypothalamic pituitary adrenal axis suppression, steroid-
induced osteoporosis: reduced bone density, weight gain, muscle break down) and the 
possible development of steroid dependent disease. Glucocorticoid drugs act non-selectively, 
so in the long run they may impair many healthy anabolic processes. As a result, maintenance 
treatment with systemic GCS is not advised [4]. New formulations of GCS have been 
developed with the aim of limiting systemic activity and reducing GCS adverse events (AEs) 
for patients who become refractory to GCS and suffer from severe or moderately severe 
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cyclosporine are sometimes used as rescue therapies and last resort before surgery. However, 
immunomodulators are slow-acting and the induction of remission in these patients is often 
temporary [5]. 
Treatment options for UC have rapidly expanded over the past 10 years and now include 
multiple biologic agents in addition to prior medication options [6]. Three tumour necrosis 
factor alpha (TNF-α) inhibitors currently approved for the treatment of moderate to severe UC 
are infliximab, adalimumab, and golimumab. These agents bind TNF-α, neutralize its activity, 
and prevent it from binding to its receptor. Infliximab and adalimumab have also been shown 
to induce apoptosis of activated T cells and macrophages. All three TNF-α inhibitors carry 
potential risks associated with their use, and should be avoided in patients with uncontrolled 
infections, advanced heart failure, neurologic conditions and in patients with a history of 
malignancy, due to a potential risk of accelerating the growth of a tumour. Other potential 
adverse effects of TNF-α inhibitor therapy include acute infusion reactions and serious 
infusion reactions, including anaphylaxis, convulsions, and hypotension. Injection site 
reactions and rare anaphylactic reactions can also occur with subcutaneously (SC) 
administered TNF-α inhibitor agents. Other possible adverse effects include neutropenia, 
hepatotoxicity, serum sickness, leukocytoclastic vasculitis, rash including psoriasiform rash, 
and induction of autoimmunity. Approximately 50% of patients receiving infliximab develop 
antinuclear antibodies after 2 years. Serious infections occur in 2–4% of patients treated with 
TNF-α inhibitors [6]. 
All three TNF-α inhibitor agent have been shown to be effective in inducing and maintaining 
clinical response and remission in patients with UC, with fairly comparable safety profiles. 
Regardless of the TNF-α inhibitor agent chosen, combination therapy with azathioprine is 
likely more effective for inducing remission than TNF-α inhibitor monotherapy. However, 
there are still up to 50% of patients receiving TNF-α inhibitor agent who fail to respond to 
induction dosing, and even more patients who lose response to the TNF-α inhibitor agent over 
time [6]. Vedolizumab, an α4β7 integrin inhibitor was recently approved for the treatment of 
UC. In the GEMINI 1 trial, vedolizumab was found to be more effective than placebo for 
inducing and maintaining clinical response, clinical remission, and mucosal healing [7]. In 
theory, because of the unique location of the α4β7 integrin on lymphocytes homing to the gut, 
it may be expected that vedolizumab will have a reduced risk of systemic infections and 
malignancy compared with systemically acting agents. In the GEMINI 1 trial, there was no 
increased risk of infection, serious adverse reaction, or malignancy in patients receiving 
vedolizumab. 
UC patients who are chronically active and treatment refractory poses a serious medical 
challenge and often the only remaining course of action is colectomy. A total colectomy is a 
potentially curative option in severe UC, but is a life-changing operation that entails risks as 
complications, such as pouch failure, pelvic sepsis, infertility in women, and nocturnal faecal 
soiling, may follow. Therefore, surgery is usually reserved for patients with severe refractory 
disease, surgical emergencies, or patients with colorectal dysplasia or cancer. 
1.2. Cobitolimod 
Cobitolimod is a modified single strand deoxyribonucleic acid (DNA)-based synthetic 
oligodeoxyribonucleotide of 19 bases in length. The drug functions as an immunomodulatory 
agent by targeting the Toll-like receptor 9 (TLR9) present in immune cells. These immune 
cells (i.e., B-cells and plasmacytoid dendritic cell reside in high abundance on mucosal 
surfaces, such as colonic and nasal mucosa). The immune system is the key mediator of the 


 
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changes of UC. The mucosa of the colon and rectum of patients with UC contains active 
immune cells, which produce damage to the tissue. Cobitolimod will be administered in the 
region of inflammation, which places the drug in close contact with a high number of 
intended target cells, ensuring that the drug will reach an area rich in TLR9 expressing cells. 
The activation of these cells by cobitolimod induces various cytokines, such as type I 
interferons and interleukin 10 (IL-10) which are believed to be important factors for the 
clinical effect of cobitolimod. 
1.3. Non-Clinical Experience 
A range of non-clinical safety studies have been conducted with cobitolimod according to 
good laboratory practice. 
A 13-week, repeat dose toxicity study in rats examining the effects of repeated intravenous 
(IV), and subcutaneous (SC) administration of cobitolimod showed that the drug was well 
tolerated with no mortality and no treatment related clinical signs observed. Increases in white 
blood cell counts (WBC) and spleen weights were observed at doses of 100 mg/kg. However, 
recovery was seen in both parameters. Subcutaneous administration was associated with 
minimal or mild subcutaneous inflammation and reddening at the injection site at necropsy. 
No clinical adverse effects were recorded [8]. 
A 13-week, repeat dose toxicity study in rats of repeated rectal administration of cobitolimod 
showed equally low toxicity. Pathology examinations revealed no necropsy or histology 
findings related to repeated administration of cobitolimod. The no observed adverse effect 
level (NOAEL) in this study was determined to be 33 mg/kg/day. [9]. 
A 19 day, repeat dose toxicity study in cynomolgus monkey, with a 4-week recovery period 
after repeated IV infusion or SC administration of 100 mg/kg cobitolimod showed no 
treatment related adverse effects on any of the parameters analyzed. The animals were dosed 
on 6 occasions during the test period. Studies investigating the toxicokinetics showed no 
evidence of drug accumulation after dosing. There was a transient presence of cobitolimod in 
plasma shortly after administration, with higher levels shown after intravenous infusion 
compared to subcutaneous administration. The NOAEL was considered to be 100 mg/kg/day. 
[10]. 
A fertility and early embryonic development study as well as an embryo-foetal development 
study in the rat, dosed by subcutaneous and rectal routes, showed no adverse effect of 
cobitolimod on mating behaviour, fertility, early embryonic development, pregnancy or on 
conseptus development from implantation to the closure of the hard palate, following 
exposure during the period of organogenesis (Day 6 to 16 of gestation). 
The in vivo genotoxic potential of cobitolimod has been evaluated in a micronucleus test 
(GLP) in bone marrow erythrocytes of young male and female CD-1 mice (after 0 h and 24 h 
intravenous dosing followed by sampling at 48 h). No micronucleus induction was detected. 
1.4. Clinical Experience 
Four clinical trials have been performed with, cobitolimod. Along with the named patient use 
programme a total of 249 Inflammatory Bowel Disease patients have received at least one 
dose of cobitolimod to date. The most evaluated dose is 31.2 mg (15,6 mg/mL, in a 2 mL 
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1.4.1. 
Pilot Study, HICS-9801 
Cobitolimod was first assessed for clinical efficacy and safety in an explorative placebo- 
controlled, double-blind study in steroid resistant or steroid dependent patients with active 
distal UC or distal Crohn´s disease and concomitant steroid treatment.  
Eleven patients were randomised to receive either a single rectal dose of cobitolimod (3 mg or 
30 mg) or placebo.  
Clinical and endoscopic evaluation at Week 1 showed a response rate of >70% in the 
treatment group and of 25% in the placebo group [11]. 
1.4.2. 
Phase II Dose Finding Study, CSUC-01/02 
This was a double-blind, randomised, placebo-controlled, single-dose, multicentre, dose 
finding study of cobitolimod in 151 mild to moderately active UC patients. 
Patients were treated with either a single rectal dose of cobitolimod (at 0.3, 3, 30 or 100 mg) 
or placebo.  
The primary endpoint was defined as clinical remission at any time during the 12 Week study 
period.  
The primary endpoint, induction of clinical remission, was defined as a Mayo score equal to 
zero at any time point. At Week 4 a numerically higher proportion of patients in the 30 mg 
and 100 mg groups had achieved clinical remission than patients in the lower dose active 
treatment groups and the placebo group. At Week 4, 16.7% and 20.7% were in clinical 
remission in the 30 mg and 100 mg groups, respectively, compared to 10.3% in the placebo 
group, 9.7% in the 0.3 mg group and 3.4% in the 3 mg group. At Week 12, clinical remission 
was achieved in 9.7%, 13.8%, 30.0%, and 27.6% in the 0.3 mg, 3 mg, 30 mg, and 100 mg 
group, respectively, as compared to 24.1% in the placebo group. Thus, there was a tendency 
towards earlier response in the 30 mg and 100 mg groups compared to the other groups, 
including placebo. There was also a trend, however not statistically significant, of a dose-
response relationship for achieving clinical remission among the active treatment groups, but 
at Week 12 the incidence of clinical remission in the placebo group was nearly equal to that 
found in the 30 mg and 100 mg groups. 
Treatment with cobitolimod was safe and well tolerated.  
Adverse drug reactions (ADRs) reported in more than one patients per treatment group were 
headache in the 0.3 mg, 3 mg and placebo groups, worsening of UC in the 3 mg and placebo 
groups, and haematuria, proteinuria and pyrexia in the 100 mg group. In the 30 mg group, 
only single cases of ADRs occurred [12]. 
1.4.3. 
Phase II Proof of Concept Study, CSUC-01/06 
This study was a multicentre, randomised, placebo-controlled, double-blind, proof of concept 
study, evaluating clinical response and safety after a single rectal dose of 30 mg cobitolimod 
or placebo in 34 UC patients with moderate to severe active disease.  
Clinical response rates did not show statistically significant differences between cobitolimod 
and placebo treated patients.  
The clinical response at Week 1 was 41.2% in the cobitolimod treated group and 9.1% in the 
placebo group. Six of the seven patients (85.7%) in the cobitolimod group that showed 
response at Week 1 were still responders at Week 4, whereas the placebo group patient that 


 
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showed response at Week 1 had relapsed by Week 4. In the cobitolimod treated group clinical 
remission was 11.8 % at Week 1 and 17.7% at Week 4. 
None of the patients receiving placebo were in clinical remission at Week 1 or 4. Among the 
9 clinical responders at Week 4, four (44.4%) showed concomitant histopathological 
remission, whereas none of the 4 clinical responders in the placebo group showed 
histopathological improvement [13]. 
1.4.4. 
Named Patient Basis Use of Cobitolimod, CU-UC-01/11 
A total of 14 chronic active UC patients who were total treatment failures were treated on a 
named patient basis with cobitolimod. All patients had a marked reduction in clinical activity 
index (CAI) scores (Rachemilewitz [14]) within the first week following a single treatment 
with cobitolimod. Only four patients had a colectomy.  
No AEs related to cobitolimod were recorded [15]. 
1.4.5. 
Phase III Study, CSUC-01/10 
This was a placebo-controlled, double-blind, randomised multi-centre study to assess the 
efficacy and safety of two doses of cobitolimod as an add-on to current practice in 131 
chronic active treatment refractory UC patients with a CAI score ≥9 and an endoscopic score 
≥2. 
Patients were on a stable tolerable dose of concomitant steroid treatment at inclusion and for 
the first 12 weeks of treatment.  
Patients were treated with 2 rectal doses of cobitolimod (30 mg), or placebo; at Week 0 and at 
Week 4. 
The primary efficacy endpoint of clinical remission at Week 12, defined as a CAI score of ≤4 
showed no statistically significant difference between the two treatment groups. 
Secondary endpoints showed statistically significant effects in symptomatic remission, (sub 
scores of blood in stools and number of weekly stools not exceeding 0 or 1, at Week 4 and 8, 
and in registration remission (CAI score of ≤4 and an endoscopic score of 0 or 1, at Week 4).  
The dosing regime was well tolerated. 59.2 % of the patients reported at least one AE (59.8 % 
in the cobitolimod group and 58.1 % in the placebo group). 
Treatment related AEs were reported in 10 (11.5%) patients in the cobitolimod group 
compared to 4 (9.3%) in the placebo group. A total of 18 (13.8%) patients reported serious 
adverse events (SAE) across both treatment groups with a greater proportion of patients in the 
placebo group reporting SAEs than patients in the cobitolimod group: 8 (18.6%) patients and 
10 (11.5%) patients, respectively [16]. 
Overall, data on cobitolimod support a positive benefit- risk assessment for patients with 
chronic active treatment refractory UC. Cobitolimod is safe and well tolerated and has been 
shown to be effective at clinical response and remission in patient with chronic active UC, as 
well as in symptomatic and endoscopic remission in patients with moderate to severe chronic 
active treatment refractory UC. 
1.5. Study Rationale 
The doses used in the first clinical testing of cobitolimod in UC patients were extrapolated 
from previous pre-clinical work and during the study it was demonstrated that both doses (3 


 
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mg and 30 mg) were effective. However, due to the limited number of included patients, no 
certain assessment of which of the two doses was more effective could be made. 
The dose finding phase II study considered doses of 0.3 mg, 3 mg, 30 mg and 100 mg and at 
all dose levels, no statistical significant benefit was noted when compared to placebo. 
However signs of efficacy were observed at the high dose levels compared to the low dose 
levels. The study did demonstrate that cobitolimod was well tolerated with no SAEs recorded. 
The phase II proof of concept study in UC patients, as well as the named patient basis use 
patients, again addressed the dose of 30 mg that showed efficacy in the pilot study. This dose 
has shown beneficial clinical effects and as such, there was no reason to alter this dose level 
for the treatment of chronic active treatment refractory UC patients in the study to follow.  
Thus in the fourth trial patients were treated with two doses of cobitolimod 4 weeks apart. 
Such patients demonstrated significant improvements in symptomatic remission rates and 
endoscopic improvement in particular at Week 4 compared to patients receiving placebo. 
Non-clinical data suggest that higher doses of cobitolimod could increase its efficacy. Given 
the good safety profile higher doses will be evaluated. The non-clinical data limits the total 
dose exposure to 500 mg during one month, and therefore the posology studied will be 31, 
125 or 250 mg given twice (at Week 0 and 3) and 125 mg given 4 times (Week 0, 1, 2 and 3), 
giving a maximum total exposure of 500 mg. 
In the clinical studies performed so far a low and infrequent or even just a single dose of 
cobitolimod has provided remission rates as good as or better than the marketed biologics in 
moderate to severe UC with a delta of 15-20%. A signal has been seen in all our clinical 
studies performed demonstrating clinical proof of concept in a meta-analysis. 
Cobitolimod will be administered in the left-sided colon, which places the drug in close 
contact with a high number of intended target cells. 
1.6. Potential Risks and Benefits 
Cobitolimod has been studied in steroid and treatment refractory UC patients administered as 
a controlled rectal infusion. The target groups for treatment are patients with chronic active 
UC in whom previous treatments with conventional drugs, including GCS, have not resulted 
in adequate response. Results from prior studies indicate a high likelihood of efficacy with 
cobitolimod in such patients. 
Non-clinical safety studies in rodents and cynomolgus monkey have indicated that 
cobitolimod is well tolerated and no evidence of systemic or local toxicity has been found. 
Safety assessments from the four placebo-controlled trials with cobitolimod have not 
indicated any significant toxicity. Administration of cobitolimod is straightforward and drug 
compliance has been reported as excellent. Overall, cobitolimod has been well tolerated.  
The overall data on cobitolimod, as well as extensive clinical experience from similar 
oligonucleotides, would therefore support a positive benefit risk assessment when 
administered according to the proposed protocol to chronic active moderate to severe UC 
patients. For further information, please see the Investigator’s brochure. 


 
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2. 
STUDY OBJECTIVES  
2.1. Primary Objective 
To evaluate the efficacy of cobitolimod treatment at different dose levels and frequencies 
compared to placebo with regard to clinical remission 6 weeks after first treatment, in patients 
with moderate to severe active UC. 
2.2. Secondary Objective 
• To evaluate the safety and tolerability of cobitolimod. 
• To evaluate the efficacy of cobitolimod treatment compared to placebo in clinical 
remission, clinical response and clinical symptoms. 
• To evaluate the efficacy of cobitolimod treatment compared to placebo in endoscopic 
and histological remission and response. 
• To evaluate the effect of cobitolimod on quality of life (QOL). 
3. 
STUDY DESIGN AND ENDPOINTS 
3.1. Overview 
This is a randomised, double blind, placebo-controlled, dose-optimisation, phase IIb study in 
patients with moderate to severe active left sided UC determined by a Modified Mayo score 
(excluding the friability at grade 1 for the endoscopic sub score) of 6 to 12 with an endoscopic 
sub score ≥2 and no other individual sub score <1. Patients who meet all the inclusion criteria 
and none of the exclusion criteria will be randomised into one of the five treatment arms on a 
1:1:1:1:1 ratio and followed for 10 weeks; 
• Cobitolimod 31 mg at Week 0 and Week 3, Placebo at Week 1 and 2 
• Cobitolimod 125 mg at Week 0 and week 3, Placebo at Week 1 and 2 
• Cobitolimod 250 mg at Week 0 and week 3, Placebo at Week 1 and 2 
• Cobitolimod 125 mg at Week 0, 1, 2 and 3 
• Placebo at Week 0, 1, 2 and 3  
Approximately 90 sites in Europe are planned to be enrolled and 215 patients are planned to 
be randomised. Patient must provide written consent to participate in the study. 
A patient will be considered to have completed the study when the assessment at Week 10 has 
been completed. 
A detailed Schedule of Activities is provided in Table 1. A schematic of the study design is 
provided in Figure 1. 
3.2. Study Evaluation Criteria 
Endpoints including the Mayo sub scores of blood in stool and stool frequency (patient 
reported outcome [PRO2]) will be derived using eDiary data. The derivation rules for the 
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3.2.1. Primary Efficacy Endpoint 
• Proportion of patients with clinical remission at Week 6, defined by Modified Mayo 
sub scores; i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding 
friability). 
3.2.2. Secondary Exploratory Endpoints 
• Proportion of patients with symptomatic remission at Week 6, defined by the Mayo 
sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease  from Baseline, Week 0), (patient reported outcome) [PRO2] 
• Proportion of patients with absence of rectal bleeding at Week 6, defined by the Mayo 
sub score rectal bleeding of 0 
• Proportion of patients with normal or enhanced stool frequency at Week 6, defined by 
the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from 
Baseline, Week 0) 
• Proportion of patients with endoscopic remission at Week 6, defined by the Modified 
Mayo endoscopic sub score of 0 or 1 (excluding friability) 
• Proportion of patients with histological remission at Week 6, defined by the Nancy 
histological index of grade 0 or 1 
• Proportion of patients with complete histological remission at Week 6, defined by the 
Nancy histological index [17,18] grade of 0 
• Proportion of patients with histological response at Week 6, defined by the Nancy 
histological index score of ≤2 (if 2 then with at least one point decrease from Baseline,  
Week 0)  
• Proportion of patients with endoscopic and histological remission at Week 6  
• Proportion of patients with symptomatic remission at Week 4, defined by the Mayo 
sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease  from Baseline, Week 0), (patient reported outcome) [PRO2] 
• Proportion of patients with absence of rectal bleeding at Week 4, defined by the Mayo 
sub score rectal bleeding of 0 
• Proportion of patients with normal or enhanced stool frequency at Week 4, defined by 
the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from 
Baseline, Week 0) 
• Proportion of patients with modified clinical remission at Week 6, defined by the 
Modified Mayo score ≤ 2 and sub scores, i) rectal bleeding of 0, ii) stool frequency of 
0 or 1 (with at least one point decrease from Baseline, Week 0), iii) endoscopy score 
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• Proportion of patients with durable symptomatic remission, defined by the Mayo sub 
scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point 
decrease from Baseline, Week 0) [PRO2] at both Week 6 and Week 10 
• Proportion of patients with clinical response at Week 6, defined as clinical remission 
or a three point and ≥30 % decrease from Baseline, Week 0 in the sum of the Modified 
Mayo score, i) rectal bleeding, ii) stool frequency and iii) endoscopy score (excluding 
friability), iiii) physicians global assessment (PGA) 
• Proportion of patients with a defecation urgency score of 0 or a decrease of at least 
one point in defecation urgency at Week 6 compared to Baseline, Week 0 
• Mean change in faecal calprotectin at Week 1, 2, 3, and 6 compared to Baseline,  
Week 0 
• Mean change in steroid dosage for patients in remission at Week 6 to Week 10 
• Mean change in each of the inflammatory bowel disease questionnaire (IBDQ) sub 
domains at Week 6 compared to Baseline, Week 0 
3.2.3. Safety Endpoints 
• 
Incidence of AEs  
• 
Incidence of SAEs 
• 
Vital signs 
• 
Electrocardiogram (ECG) 
• 
Physical Examination 
• 
Laboratory Findings 
4. 
STUDY POPULATION 
All relevant medical and non-medical conditions should be taken into consideration when 
deciding whether a particular patient is suitable to participate in this study. Patient eligibility 
should be reviewed and documented by an appropriately qualified member of the 
investigator´s study team prior to inclusion in the study. If patient fails to fulfil the 
inclusion/exclusion criteria, patient can be considered to be re-screened at a later time if 
eligible. 
4.1. Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be randomised in the 
study: 
1. Male or female ≥ 18 years of age  
2. Established diagnosis of UC, with minimum time from diagnosis of ≥3 
months  
3. Moderately to severely active left sided UC (disease should extend 15 cm or 
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a Modified Mayo score (excluding the friability at grade 1 for the endoscopic 
sub score) of 6 to 12 with an endoscopic sub score ≥2 assessed by central 
reading of endoscopy performed at screening visit 1b, and no other individual 
sub score <1 
4. Current oral 5-ASA/SP use or a history of oral 5-ASA/SP use  
5. Current GCS use or history of GCS dependency, refractory, or intolerance, 
including no GCS treatment due to earlier side-effects (only one of the GCS 
criteria have to be fulfilled, see definition in European Crohn´s and Colitis 
organisation (ECCO) guidelines) 
6. Demonstrated an inadequate response, loss of response, or intolerance to at 
least one of the following agents: 
• Immunomodulators, e.g. cyclosporine, methotrexate, AZA/6-MP, 
tacrolimus  
o For example,signs and symptoms of persistently active disease despite 
previous treatment with at least one 8 week regimen of oral AZA (≥1.5 mg/kg) 
or 6-MP (≥0.75 mg/kg) or lower doses prompted by intolerance or thiopurine 
methyltransferase (TPMT) deficiency or 
o For example, previous intolerance (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, liver function test 
(LFT) abnormalities, lymphopenia, TPMT genetic mutation, 
infection) to at least one immunomodulator  
• TNF-α inhibitors and/or anti-integrins: 
o Signs and symptoms of persistently active disease despite previous 
treatment with at least one induction regimen with 2 doses at least 2 
weeks apart (or doses as recommended according to the current 
labels) of for e.g.: 
▪ Infliximab 5 mg/kg (intravenous (IV)) or 
▪ Golimumab 200/100 mg (subcutaneous (SC)) or 
▪ Adalimumab 160/80 mg (SC) or 
▪ Vedolizumab 300 mg (IV) or 
o History of intolerance (including but not limited to infusion-related 
reaction, demyelination, congestive heart failure, infection) 
 
Recurrence of symptoms during maintenance dosing with any of the above medications 
following prior clinical benefit, (secondary failure) [discontinuation despite clinical benefit 
does not qualify] 
 
7. Allowed to receive a therapeutic dose of following UC drugs during the 
study: 
a) Oral GCS therapy (≤20 mg prednisone or equivalent/daily) providing that 
the dose has been stable for 2 weeks prior to visit 1a 
b) Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks 
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c) Oral 5-ASA/SP compounds, providing that the dose has been stable for 2 
weeks prior to visit 1a and initiated at least 8 weeks before visit 1a 
d) AZA/6-MP providing that the dose has been stable for 8 weeks prior to 
visit 1b and been initiated at least 3 months before visit 1a 
8. Ability to understand the treatment, willingness to comply with all study 
requirements and ability to provide informed consent 
4.2. Exclusion Criteria  
Patients presenting with any of the following will not be included in the study: 
1. Suspicion of differential diagnosis such as; Crohn’s enterocolitis, ischaemic 
colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular 
disease, associated colitis, microscopic colitis, massive pseudopolyposis or 
non-passable stenosis 
2. Acute fulminant UC and/or signs of systemic toxicity 
3. UC limited to the rectum (disease which extend <15 cm above the anal 
verge) 
4. History of malignancy, except for: 
• Treated (cured) basal cell or squamous cell in situ carcinoma 
• Treated (cured) cervical intraepithelial neoplasia or carcinoma in situ 
of the cervix with no evidence of recurrence within the previous 5 
years prior to the screening visit 1a 
5. History or presence of any clinically significant disorder that, in opinion of 
the investigator, could impact on patient’s possibility to adhere to the 
protocol and protocol procedures or would confound the study result or 
compromise patient safety 
6. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, TNF-α 
inhibitors, anti-integrins or similar immunosuppressants and 
immunomodulators at enrolment. Any prior treatment with such drugs must 
have been discontinued at least 8 weeks prior to visit 1a or have non-
measurable serum concentration levels 
7. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 Weeks before 
visit 1b 
8. Long term treatment with antibiotics or non-steroidal anti-inflammatory 
drugs (NSAIDs) within two weeks prior to visit 1a (one short treatment 
regime for antibiotics and occasional use of NSAIDS are allowed) 
9. Serious active infection 
10. Gastrointestinal infections including positive Clostridium difficile stool assay 
11. Currently receiving parenteral nutrition or blood transfusions 
12. Females who are lactating or have a positive serum pregnancy test during the 
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13. Women of childbearing potential not using reliable contraceptive methods 
(reliable methods are barrier protection, hormonal contraception, intra-
uterine device or abstinence) throughout the duration of the study 
14. Concurrent participation in another clinical study with investigational therapy 
or previous use of investigational therapy within 5 half-lives and within at 
least 30 days after last treatment of the experimental product prior to 
enrolment 
15. Previous exposure to cobitolimod 
4.3. Randomisation and Stratification 
Patients will be randomised to one of five treatment arms (see section 3.1) on a 1:1:1:1:1 
ratio. Randomisation to treatment will be performed at the Randomisation Visit (2a, Phone 
Call). Randomisation will be stratified for the following factors: concomitant use of GCS 
treatment (Yes/No) and previous treatment with TNF-α inhibitors (Yes/No). A computer 
generated randomisation schedule will be used to assign patients to treatment sequences. 
Treatment assignments will be obtained through the interactive voice response system 
(IVRS). Information regarding the treatment assignments will be kept securely by PAREXEL 
per its standard operating procedure (SOP). 
4.4. Patient participation 
A patient will be considered to have completed the study when he or she completes the 
assessment at Week 10. Patients should be encouraged to complete the study but have the 
right to make decision regarding the study participation e.g. to discontinue the study drug, but 
still come on visits or discontinue study drug and not come on further study visits. The patient 
has no obligation to explain why he/she does not want to continue. The investigator also has 
the right to stop the patient’s treatment in the event of AE, protocol deviations, administrative 
reasons or other reasons. It is understood by all concerned that an excessive rate of 
discontinues can render the study un-interpretable. Therefore, unnecessary discontinuation 
should be avoided.  
If a patient decides to not continue with study drug at any time during the study, every effort 
to complete the early discontinuation examinations (Week 6) should be taken. Irrespective of 
the reason for not continuing in the study and whenever possible, the patient should be 
examined. Relevant laboratory test samples should be obtained and all relevant assessments 
should be completed if applicable.  
All SAEs should be followed up until they have returned to baseline status or stabilised. 
A final visit in the electronic case report form (eCRF) should be completed for every 
randomised patient whether the patient completed the study or not. The reason for any early 
discontinuation should be indicated on this form.  
The primary reason for a patient discontinue prematurely should be selected from the following: 
AE: Clinical or laboratory events that in the judgment of the investigator, Data Safety 
Monitoring Board (DSMB) or the Sponsor and in the best interest of the patient constitute 
grounds for discontinuation. This includes serious and non-serious AE regardless of relation 
to study drug.  
Withdrawal of Consent: If a patient withdraws consent for disclosure of future information 
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should be performed and no additional data should be collected. The Sponsor may retain and 
continue to use data collected before patient withdrew his/her consent. The Withdraw Consent 
reason is only applicable if the patient denies any further contact with site and no further data 
collection. 
Lack of Efficacy/Treatment Failure: Patients experiencing deterioration or no improvement 
of disease as judged by the investigator, may be discontinued from the study at any time 
during the study, offered alternative treatment and scored as treatment failures. Treatment 
failures includes disease worsening, requirement for rescue medication for treatment of UC, 
requirement for surgical intervention and study drug related AE. Patients may be discontinued 
for sustained non-response at the discretion of investigator. 
Protocol Violation: The patient´s findings, or conduct, fails to meet protocol entry criteria or 
fails to adhere to the protocol requirements. 
Lost to Follow-Up: The patient does not show up for further visits and study personnel can´t 
reach the patient. 
Other: Termination of other reason 
4.4.1. Patient Replacement 
Randomised patients who discontinued from the study will not be replaced. 
4.4.2. Follow-up of early discontinued patients 
Patients treated with at least one dose of study treatment should be followed for safety for up 
to 10 weeks after the first dose. 
5. 
STUDY TREATMENT 
5.1. Study Drug 
Cobitolimod is a fully synthetic DNA based 19 mer oligodeoxyribonucleotide of the 
following sequence: 5’G*G*A*ACA GTT CGT CCA T*G*G*C3’ where each asterisk * 
indicates phosphorothioate (PS) linkages. 
Active Ingredient:  
cobitolimod  
Empirical Formula:  
C185H213N73O106P18S6Na18 
Molecular Weight:   
Free acid 5925 Daltons; Na salt: 6321 Dalton 
Placebo is a rectal solution where the ingredient is water. It is tested for microbiological 
quality and compliant with European Pharmacopoeia (Ph Eur) requirements. 
5.2. Study Drug Administration 
Cobitolimod and matching placebo will be provided to the study sites by InDex 
Pharmaceuticals AB or its representative. Cobitolimod is a solution of 0.62 mg/mL (31 mg) 
and 2.5 mg/mL (125 mg) and 5 mg/mL (250 mg) drug in 50 mL water for injection in single-
use siliconised glass vials with rubber stopper and aluminium cap. 
The study drug will be administered only to eligible patients under the supervision of the 
investigator or identified designee(s). Female patients must have a negative urine pregnancy 
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The study drug will be administered via a rectal enema while patients are in a lying left-sided 
position. All patients and study personnel will be blinded to study drug assignment for the 
entire study. 
The time for start of the administration will be recorded in the eCRF. After administration the 
patient will be asked to remain recumbent for 30 minutes and it is allowed to move over to a 
bed. Any leakage (weight) of study drug will be recorded in the eCRF. The study drug will be 
administered at visit 2b, 3, 4 and 5. The visit schedule allows for a +/- 3 day deviation from 
the planned date of visit, and is always calculated from the day of visit 2b. At least three days 
must pass between visits and thus between the administration of study drug. 
5.3. Study Drug Packaging, Labelling, Shipment and Storage 
5.3.1. Study Drug Packaging  
Apoteket AB Production Laboratories (APL) will pack the study drug. Each vial is labelled 
with content, vial number and study number.  
Apoteket AB Production Laboratories will prepare individual patient supplies according to a 
computer generated randomisation code. The supplies will be packaged in accordance with 
good manufacturing practice (GMP). 
5.3.2. Study Drug Labelling 
Each vial will be labelled according to the GMP/good clinical practice (GCP) and the 
regulatory requirements for the countries participating in the study.  
5.3.3. Shipment of Study Drug 
Study drug will be delivered to the investigational sites by InDex Pharmaceuticals AB or its 
representative. The drug will be shipped at room temperature, under controlled conditions. 
5.3.4. Storage of Study Drug 
The study drug should be stored under controlled conditions at site at 2º - 8ºC. All partially 
used or unused vials will be retrieved by the sponsor. The investigator should not destroy 
unused study drug unless the sponsor has provided a written authorisation to do so. The shelf 
life of the study drug is 36 months at 2º - 8ºC.  
5.4. Study Drug Compliance 
In accordance with International Conference on Harmonisation (ICH), the investigator and the 
pharmacy must keep an inventory of all study drug received and administered during the 
study in the drug accountability log (e.g., drug dispensing and return forms). Prior to site 
closure, the investigator and pharmacy (if involved) will provide 100% accountability for all 
vials received and dispensed.  
After completion of the study, all unused and returned study drug packs (whether empty or 
full) should have been destroyed according to approved procedure, the destruction will be 
documented.  
5.5. Blinding and Unblinding 
The study is double-blind to study treatments. Blinding is accomplished by giving all study 
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to the treatment arms which are only given active doses at Week 0 and Week 3. The study 
will remain blinded until clean file has been declared. 
If the treatment assignment must be revealed for the safety of the patient or to treat an AE the 
investigator may break the blind through IVRS. The IVRS will allow automated emergency 
unblinding via telephone at any time. Further details of this procedure are described in the 
separate IVRS manual. Any unblinding must be fully documented. The required information 
includes date and reason for unblinding as well as the name and the signature of the person 
who performed the unblinding. If the reason for unblinding is an AE it should be reported on 
the AE form.  
IVRS will retain an audit trail of all unblinding that has occurred during the study. All 
relevant parties per the IVRS specification will be notified. 
Whenever possible, the study Medical Monitor should be contacted before breaking the code 
or of any intended unblinding.  
If a need of unblinding arises when the investigator is unavailable further contact information 
is provided at the emergency card handed out to the patient at randomisation. 
5.6. Overdose  
Deliberate or accidental study drug overdose should be treated symptomatically and should be 
reported as an AE. Definition of overdose is treatment with more than one vial at 
administration or at other visits than visit 2b, 3, 4 and 5. 
5.7. Concomitant Medications 
All medications that the patient is prescribed and has taken during the study must be recorded 
in the eCRF. Any changes need to be reported. 
The following concomitant UC medications are allowed: 
• Oral GCS therapy (≤20 mg prednisone or equivalent/daily) providing that the 
dose has been stable for 2 weeks prior to visit 1a, and need to be kept stable 
up to primary endpoint (Week 6). Tapering can start at Week 6 if patients are 
in remission, see suggested tapering scheme below. 
• Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before 
screening visit 1 a and need to be kept stable up to primary endpoint  
(Week 6). Tapering can start at Week 6 if patients are in remission. Tapering 
per local practice. 
• Oral 5-ASA and/or SP compounds, providing that the dose has been stable 
for 2 weeks prior to visit 1a, and initiated at least 8 weeks before visit 1a. 
Stable dose up to end of study (Week 10). 
• AZA/6-MP providing that the dose has been stable for 8 weeks prior to visit 
1b, and been initiated at least 3 months before visit 1a. Stable dose up to end 
of study (Week 10). 
5.8. Prohibited Medications 
The following concomitant medications are prohibited throughout the duration of study: 
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• methotrexate 
• tacrolimus or similar immunosuppressants/ immunomodulators. 
• TNF-α inhibitors 
• anti-integrins  
Any prior treatment with these drugs must be discontinued at least 8 weeks prior to visit 1a or 
have non-measurable serum concentration levels. 
5.9. Oral Corticosteroid Tapering Regimen 
Steroid tapering is recommended to start when the patient has reached clinical remission, but 
earliest at Week 6. Once the decision to initiate steroid tapering is taken based on the 
investigator’s assessment, reduction of the oral steroid dosage following the schedule outlined 
in the table below is recommended (Table 2). Consideration of the risk of adrenal gland 
insufficiency is cautioned, especially when the daily dose is lowered to less than 10 mg. For 
patient who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms 
the dose may be increased up to original dose. For oral MMX budesonide the tapering 
schedule should follow the local practice. 
 
Table 2. Schedule of Oral Steroid Dose Reduction given in Mg/Day. 
Week 
 
Starting steroid dose 
20 mg/day 
15 mg/day 
10 mg/day 
6-7 
15 
10 
7.5 
7-8 
10 
7.5 
5 
8-9 
7.5 
5 
2.5 
9-10 
5 
2.5 
0 
10-11 
2.5 
0 
0 
11-12 
0 
0 
0 
Final visit in the study is Week 10, table show titration after study completion as a guide 
5.10. Rescue Medications 
If a patient requires rescue therapy or dose increase of prior UC treatment, the patient will be 
discontinued from study drug. Administration of rescue medications constitutes treatment 
failure. Rescue medications should not be withheld if, in the opinion of the investigator, 
failure to prescribe them would compromise patient safety. It is on the investigators discretion 
to decide what treatment is best for the patient. 
6. 
STUDY SCHEDULE 
6.1. Visit 1a (Day -14) and 1b (Day -7 to -10) – Screening Visits 
The Screening period, will be divided in two separate visits, Visit 1a and 1b.  
At the first Screening Visit, 1a the patient will in detail be informed about the study and if 
agreement to participate, an informed consent form (ICF) will be signed off before any study 
specific procedures occur (it is accepted that patient sign the ICF before first screening visit, 
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the Screening Visit 1a, procedures to assure the patient´s eligibility for the study participation 
will be performed. Demographics, (date of birth, gender and race), Vital Signs (blood pressure 
[BP], heart rate [HR], height, weight, smoking habits), medical history and UC history 
(including patient´s normal number of stools/day when in remission) will be obtained. A 
physical examination will also be performed and a 12-lead ECG will be taken. 
Non-fasting blood samples will be collected for haematology, blood chemistry including CRP 
(biomarker), lipid profile analysis and future biomedical research (if consented to). Urine 
sample will be collected for dipstick analysis (Blood, Glucose, Ketones, Leucocytes, Nitrite, 
Protein and pH) and if clinically significant microscopy and/or culture. Stool sample for 
culture, microbiology and biomarker´s will also be collected. Females of childbearing 
potential will have a serum pregnancy test taken. Concomitant medications will be recorded. 
Prior UC treatment should be reported up to 3 years before screening visit and will be 
recorded with used dose; start/stop date and reason why not re-started to ensure inclusion 
criteria are fulfilled. The last treatment period of each UC drug will be collected. Allowed UC 
medications will be recorded with start date and dose to ensure stable dose is used during the 
entire study (GCS up to Week 6). Treatment with cyclosporine, methotrexate, TNF-α 
inhibitors, anti-integrins, tacrolimus or similar immunomodulatory/immunosuppressant drugs 
should have been stopped (at least 8 weeks before visit, 1a). These drugs should only have 
been stopped due to lack of efficacy or intolerable side effects. When laboratory results are 
available and the patient still is suitable for the study, patient will be informed about 
preparation for colonoscopy (separate instructions will be provided to the patient) which will 
be performed at screening visit 1b. 
The patient will before leaving the clinic also receive training and instructions how to use an 
electronic diary (eDiary) for daily entry of data up to the day before the randomisation Visit 
2b.  
At the second screening visit 1b a full colonoscopy will be performed in order to determine 
the extent of inflammation. The colonoscopy will be video recorded and send for central 
reading. During the endoscopy, three biopsy samples will be taken from each bowel segment 
investigated (ascending colon, transverse colon, descending colon, sigmoid colon, and 
rectum). These biopsies will be used for central read histopathological evaluation and for 
future biomedical research (if consented to, if not consented only two biopsies from each 
segment will be taken). 
All inclusion and exclusion criteria will be reviewed at several time points before 
randomisation.  
The interpretation from central reading of colonoscopy videos must be reviewed by the 
investigator to ensure eligibility prior to randomisation.  
Any AEs related to study specific procedures will be recorded at the Randomisation Visit 2b. 
PGA assessment should be done at visit 1b after the endoscopy. In case eDiary data are not 
available (3 days consecutive) the PGA can be done before visit 2a when randomisation 
occurs. 
All obtained information will be reported in the eCRF. 
6.2. Visit 2a (Day -4 to-7) and 2b (Week 0) – Randomisation Visits  
When the Central reading assessment is available and UC disease is qualifying for the study, 
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the study. If the patient is found to be eligible for study participation, the investigator will 
follow a central randomisation procedure and obtain a unique number (Patient Identification 
number) for the patient. If the patient fails to fulfil the inclusion/exclusion criteria, the patient 
can be re-screened at a later time point. If the re-screening will take place more than 1 month 
after the first screening visit all procedures need to be re-done, otherwise the s Sponsor/CRO 
will confirm to site which screening procedures have to be repeated at re-screening in order to 
ensure that the patient fulfils the criteria for entering the study. If the re-screening is 
performed more than 1 month after the first screening, patient will receive a new Patient 
Identification number. 
The patient must be scheduled for the Visit 2b/Week 0 visit within 10 days from the 
performed endoscopy (including the day of endoscopy and first treatment).  
At the visit 2b; before study drug administration vital signs (HR, BP and temperature) and 
physical examination will be performed. Females of childbearing potential will take a dip 
stick urinary pregnancy test. An ECG will be taken before study drug administration and 
approximately 30 minutes after treatment, before leaving the clinic.  
The patient will be asked to complete an IBDQ questionnaire and extra intestinal 
manifestations and defecation urgency assessment will be obtained. Non-fasting blood 
samples will be collected for haematology, blood chemistry including CRP (biomarker) and 
future biomedical research (if consented to).  Urine sample will be collected for dipstick 
analysis (Blood, Glucose, Ketones, Leucocytes, Nitrite, Protein and pH) and if clinically 
significant microscopy and/or culture will be send to central laboratory. Stool sample for 
faecal calprotectin (biomarker) will also be collected. Repeated training and instructions for 
the patient eDiary handling will be given. It is important to ensure the patient understands that 
eDiary data are necessary to evaluate the study. Information on concomitant medication will 
be collected. Any AEs related to study specific procedures, will be recorded. 
The patient will thereafter receive the study drug they were allocated to during the 
randomisation procedure. The study drug will be administered with a rectal enema. Following 
study drug administration the patient will be asked to remain recumbent for at least 30 
minutes. Any leakage will be measured. 
All obtained information will be reported in the eCRF. 
6.3. Visit 3 - (Week 1) 
This visit should occur on Day 7 (± 3 days). Vital signs (BP and HR) and physical exam will 
be measured. Non-fasting blood samples will be collected for haematology, blood chemistry 
including CRP (biomarker) and future biomedical research (if consented to). Stool sample for 
faecal calprotectin (biomarker) will also be collected. A dipstick urine pregnancy test should 
be checked. Defecation urgency assessment will be obtained. Repeated instructions for the 
eDiary handling will be given if necessary. It is important to ensure the patient understands 
that eDiary data are necessary to evaluate the study. Changes in concomitant medication or 
new medications should be reported. The patient will be treated with cobitolimod/placebo 
with a rectal enema. Following drug administration the patient will be asked to remain 
recumbent for at least 30 minutes. Any leakage will be measured. Patient will be asked if any 
AE has occurred since last visit. 
All obtained information will be reported in the eCRF. 


 
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6.4. Visit 4 - (Week 2) 
The visit should occur on Day 14 (± 3 days). Vital signs (BP and HR) and physical exam will 
be measured. Non-fasting blood samples will be collected for haematology, blood chemistry, 
including CRP (biomarker) and future biomedical research (if consented to). Stool sample for 
faecal calprotectin (biomarker) will also be collected. A dipstick urine pregnancy test should 
be checked. Defecation urgency assessment will be obtained. Repeated instructions for the 
eDiary handling will be given if necessary. It is important to ensure the patient understands 
that eDiary data are necessary to evaluate the study. Changes in concomitant medication or 
new medications should be reported. The patient will be treated with cobitolimod/placebo 
with a rectal enema. Following drug administration the patient will be asked to remain 
recumbent for at least 30 minutes. Any leakage will be measured. Patient will be asked if any 
AE has occurred since last visit. 
All obtained information will be reported in the eCRF. 
6.5. Visit 5 - (Week 3) 
The visit should occur on Day 21 (± 3 days). Vital signs (BP and HR) and physical exam will 
be measured. Non-fasting blood samples will be collected for haematology, blood chemistry 
including CRP (biomarker) and future biomedical research (if consented to). Stool sample for 
faecal calprotectin (biomarker) will also be collected. The patient will be asked to complete 
IBDQ questionnaire and extra intestinal manifestations and defecation urgency assessment 
will be obtained. Repeated instructions for the eDiary handling will be given if necessary. It is 
important to ensure the patient understands that eDiary data are necessary to evaluate the 
study. Changes in concomitant medication or new medications should be reported. The 
patient will be treated with cobitolimod/placebo with a rectal enema. Following drug 
administration the patient will be asked to remain recumbent for at least 30 minutes. Any 
leakage will be measured. Patient will be asked if any AE has occurred since last visit.  
All obtained information will be reported in the eCRF. 
6.6. Visit 6 - (Week 6) Primary Endpoint or Discontinuation visit 
The visit should occur on Day 42 ± 3 days from planned visit schedule (calculated from visit 
2b) or if patient decides to not come on further visits perform Week 6 procedures as final 
visit. Vital signs (BP and HR), tobacco use and physical exam will be measured. Non-fasting 
blood samples will be collected for haematology, blood chemistry including CRP 
(biomarker), lipid profile and future biomedical research (if consented to). Urine sample will 
be collected for dipstick analysis and if clinically significant microscopy and/or culture will 
be send to central laboratory.  Stool sample for faecal calprotectin (biomarker) will also be 
collected. The patient will be asked to complete IBDQ questionnaire and extra intestinal 
manifestations and defecation urgency assessment will be obtained. A dip stick urine 
pregnancy test should be checked. Changes in concomitant medication or new medications 
should be reported. A flex sigmoidoscopy will be performed and three biopsy samples will be 
taken from descending colon, sigmoid colon, and rectum (if not consent for future biomedical 
research only two biopsies from each segment will be taken). The investigator should fill in a 
PGA. An ECG will be taken. Repeated instructions for the eDiary handling will be given if 
necessary. It is important to ensure the patient understands that eDiary data are necessary to 
evaluate the study. Patient will be asked if any AE has occurred since last visit. 
All obtained information will be reported in the eCRF. 


 
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6.7. Visit 7 – (Week 10) 
 
The visit should occur on Day 70 ± 7 days from planned visit schedule (calculated from  
visit 2b). Vital signs (BP and HR) and physical exam will be measured. Non-fasting blood 
samples will be collected for haematology, blood chemistry including CRP (biomarker) and 
future biomedical research (if consented to). Stool sample for faecal calprotectin (biomarker) 
will also be collected. The patient will be asked questions regarding extraintestinal 
manifestations and defecation urgency. The investigator should fill in a PGA. Changes in 
concomitant medication or new medications should be reported. Patient will be asked if any 
AE has occurred since last visit.  
All obtained information will be reported in the eCRF.  
6.8. Unscheduled Visit 
An extra visit can be performed at any time when there is a need for it, as judged by the 
Investigator. In case of values outside the normal range, the DSMB can request an extra visit 
where additional examinations should be conducted and blood sample(s) drawn as agreed 
with the DSMB. 
7. 
STUDY PROCEDURES 
The schedule of activities is provided in Table 1. Study assessments will be performed by the 
investigator, delegated study personnel or central reader. Patient related events and activities, 
including specific instructions, procedures, concomitant medications, administration of the 
study drug; steroid tapering and descriptions of AEs should be recorded in eCRF. 
7.1. Central reading 
During the endoscopy a video will be recorded (separate instruction will be provided). These 
videos will be sent to trained central readers for assessment.  
7.2. Concomitant Medication 
All changes to the prior treatment need to be recorded during the study e. g. stop date or entry 
of a new treatment. 
7.3. Collection of Adverse Event and Serious Adverse Event 
Collection of AE will start directly after an Informed Consent is signed. During the screening 
period only AEs related to study procedure will be reported. Definitions, documentation and 
reporting of AEs are described in detail in Section 8. 
7.4. Demographics 
Patient demographics, including sex, age, and race will be collected at the screening visit 1a. 
7.5. Electrocardiogram 
A 12-lead ECG will be performed and assessed at visit 1a, 2b and 6. At visit 2b the ECG 
should be taken before study drug administration (after 5 minutes rest) and another ECG 
approximately 30 minutes after study drug administration. The ECG will be reviewed by the 
investigator. If abnormalities before first dose of study drug the findings should be reported as 
medical history. Findings during study should be reported as AEs. 


 
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7.6. Eligibility and Evaluation 
At visit 1a, the investigator should estimate the patient´s eligibility to the study based on 
Medical History, UC History and Concomitant therapy. Patient should also be asked about 
number of daily stool and presence of rectal bleeding. The combined information gives 
information to decide if patient is eligible for endoscopy.  
For assessing eligibility to the study (Mayo score of 6-12) the Modified Mayo score at visit 
2a, will be calculated by summarising the visit 1b endoscopy sub score, the PGA assessment 
and the Mayo sub scores assessed from eDiary at visit 2a.  
All components for the assessment of Mayo score have to be collected within 10 days before 
visit 2b. 
7.7. Endoscopy, Biopsy and Histology 
A full colonoscopy will be performed with a video endoscope, at the Screening Visit (1b). 
The endoscope should inspect the whole bowel, up to the Cecum. Three biopsies should be 
taken from each bowel segment investigated (ascending colon, transverse colon, descending 
colon, sigmoid colon, and rectum). These biopsies will be used for central read 
histopathological evaluation (in end of the study) (appendix 15.3) and future biomedical 
research (if consented to, if not consented only two biopsies from each segment will be 
taken). There is a centralised assessment and processing of the endoscope videos.  
A flexible sigmoidoscopy, performed with a video endoscope will be performed at visit 6. 
The endoscope should inspect the left-sided colon, up to splenic flexure. Three biopsies 
should be taken from each bowel segment investigated (descending colon, sigmoid colon, and 
rectum). The biopsies will be used for central read histopathological evaluation (in end of the 
study) and future biomedical research (if consented to, if not consented only two biopsies 
from each segment will be taken). There will be a centralized assessment and processing of 
the endoscope videos. 
Separate instructions for procedure preparations will be provided to the patients. 
7.8. Extraintestinal Manifestation Assessment 
Patient will be asked questions (appendix 15.4) about specific diseases at visit 2b, visit 6 and 
visit 7. [20] 
7.9. Inflammatory Bowel Disease Questionnaire 
IBDQ is a patient questionnaire with 32 questions grouped into four dimensions: bowel, 
systemic, social, and emotional. The IBDQ will be completed at visit 2b before study drug 
administration, visit 5 and visit 6 or early termination visit. 
7.10. Informed Consent  
All patients will receive written and verbal information concerning the study prior to any 
study related procedures. The given information emphasises that participation in the study 
will be voluntary and that the patient might discontinue and/or withdraw consent from the 
study at any time and for any reason. All patients will be given the opportunity to ask 
questions about the study and will be given sufficient time to decide whether to participate in 
the study or not. Patient’s consent will be sought regarding data that will be recorded, 
collected, processed and might be transferred to the European Union (EU) and non-EU 


 
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countries. The data will not identify any person taking part in the study, in accordance with 
the EU Data Protection Directive (95/46/EU).  
A copy of the patient information, including the signed ICF, will be given to the patient. 
7.11. Laboratory Procedures 
Blood, urine and stool samples will be collected at the time point identified in schedule of 
activities (Table 1). All samples will be collected in a non-fasting state. The clinical analyses 
to be performed are listed in Table 3. Unscheduled clinical labs may be obtained at any time 
during the study to assess any perceived safety concerns.  
All females will have a serum pregnancy test at visit 1a and urine dip stick test at visit 2b, 3, 
4, 5 and 6; it should be completed prior to each dosing of study drug. 
A central laboratory will be used to perform safety tests for haematology and blood chemistry. 
Central laboratory will also analyse urine (microscopy and/or culture) if the urine dipstick 
analysis are clinically significant. Safety laboratory reports will show the reference range for 
each variable and will be reviewed at each visit. In the event of an unexplained clinically 
noteworthy abnormal laboratory test value, the test should be immediately repeated and 
followed-up until it has returned to the normal range and/or an adequate explanation of the 
abnormality is found. Clinically significant abnormal findings should be recorded as AEs. 
For the purpose of Future Biomedical Research (if consented to), serum and biopsy 
specimen’s may be collected (if not consented no extra samples will be collected) during this 
clinical trial. The collected specimens may be used for future assay development and to 
explore and identify biomarkers that enhance the scientific understanding of ulcerative colitis 
and/or the therapeutic treatment. Such research is for mode of action biomarker testing to 
address emergent questions not described elsewhere in the protocol (as part of the main trial) 
or development of UC evaluation score and will only be conducted on specimens from 
appropriately consented subjects. 
The signed and interpreted laboratory results will be kept together with the patient’s source 
data as supplemental pages.  
Table 3. Clinical Laboratory Analysis.  
Haematology 
Clinical Chemistry 
Urine 
Other 
Hemoglobin1 
Hematocrit1 
Platelet count1 
RBC s1 
WBCs1 
Platelets1 
Neutrophils1 
Eosinophils1 
Monocytes1 
Basophils1 
Lymphocytes 1  
1 
 
 
Albumin1 
ALP1 
ALT1 
AST1 
Amylase1 
BUN1 
Calcium1 
Chloride1 
CPK1 
Creatinin1 
CRP1,4 
GGT1 
Glucose1 
Phosphorus1 
Potassium1 
Blood2 
Glucose2 
Ketones2 
Leucocytes2 
Nitrite2 
Protein2 
pH2 
 
 
 
 
 
 
 
 
Faecal Calprotectin4 
Stool culture for; 
• Clostriudium DifficileToxin B 
• Shigella 
• Campylobacter 
• Yersinia 
• Salmonella 
• Faecal Ova and Parasites 
Urine pregnancy test3 
Pregnancy test3 
Triglycerides1 
Cholesterol1 
Fibrinogen1 
APTT1 
PT (including INR)1 


 
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1 non-fasting state  
2 dip stick in all cases; microscopy and or/culture if clinically indicated. 
3 for women of childbearing potential 
4 for biomarker assessment 
5 Central read histopathological evaluation. 
 
7.12. Leakage Measure 
Weigh the under pad/surface protection sheet before the patient gets on the bed. After the 
drug has been administered and patient has been lying for 30 minutes weigh the under 
pad/surface protection again. The outcome will be registered in the eCRF. 
7.13. Medical History 
A complete medical history will be collected covering information up to the first dose of 
study drug. Diagnosis/symptoms/signs and the start year will be collected. Findings and/or 
abnormalities detected by physical exam and ECG interpretation at Visit 1a should be 
reported on medical history, preferably as a diagnosis. Information regarding postmenopausal 
status will be collected as medical history. 
7.14. Mayo Score  
• 
Full Mayo Score 
A full Mayo score includes the sub scores; stool frequency, rectal bleeding, endoscopy and 
PGA. 
• 
Modified Mayo Score 
The Modified Mayo Score excludes the friability at grade 1 for the endoscopic sub score. 
The Modified Mayo Score excluding friability at grade 1 (appendix 15.1), [21] will be used at 
visit 2b, to evaluate eligibility to the study. 
The sub scores stool frequency and blood in stool will be evaluated during screening period, 
using eDiary data for the sub scores. The endoscopy sub score will be assessed by using 
centrally read result from a full colonoscopy (performed within 10 days prior Visit 2b) or 
sigmoidoscopy (at Visit 6). 
• 
Patient Reported Outcome  
PRO2 includes the sub score; stool frequency and rectal bleeding reported daily by the patient 
and via an eDiary. 
7.15. Patient eDiary completion and Review 
A Patient eDiary will be used for data collection with regard to patients daily symptoms. The 
following symptoms will be assessed daily from visit 1a to visit 7. 
• 
Absolute number of stools 
Sodium1 
Total Bilirubin 1 
Total Protein1 
Uric Acid1 
 
Future Biomedical Research1 
Colon biopsies5 


 
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• 
Stool frequency according to the Mayo sub score  
• 
Blood in stool scoring according to the Mayo sub score 
eDiary data will be used to calculate the sub scores stool frequency and rectal bleeding 
(PRO2). 
7.16. Physical Examination 
A complete physical examination should be performed at each visit and should include the 
following body system evaluations: general appearance, skin, musculoskeletal, eyes, ears, 
nose, throat, thyroid, cardiovascular, chest, abdomen, lymph nodes and neurological 
examination. If clinical significant abnormalities, it should be reported either as medical 
history (during screening) or as an AE (after first dose).  
7.17. Pregnancy Test 
Pregnancy tests will be performed on all females of childbearing potential at all visits up to 
Week 6. Serum pregnancy tests will be carried out at Visit 1a. Pregnancy tests done at Visit 
2b, 3, 4, 5 and 6 will be performed with urine dipsticks. If the pregnancy test is positive this is 
considered as an AE, contact the CRA for further guidance. 
7.18. Prior Therapies 
The use of any concomitant therapy will be recorded with preferably generic name and start 
and stop date. For all non-UC therapy the last 8 weeks treatment prior to Screening visit 1a 
needs to be recorded. For UC treatment such as: GCS, MMX Budesonide, 5-ASA/SP, 
AZA/6-MP, TNF-α inhibitor, anti-integrins, cyclosporine, tacrolimus or other 
immunomodulatory/immunosuppressant drugs, generic name, start date and stop date (if 
applicable) and dose should be recorded unless when treated. Only need to record the last 
treatment period for each. The reason why these drugs were not restarted when patient 
relapsed has also to be reported. 
7.19. Study Drug Administration 
Study drug will be administered via a rectal enema (see separate instructions). 
7.20. Tobacco Use 
The patient’s tobacco history/use will be collected at Visit 1a and Visit 6. 
7.21. Ulcerative Colitis History and Assessment 
A detailed history of UC, including month and year of diagnosis, and disease severity will be 
collected. Information of what is the patients normal stool frequency when in remission 
duration of flare and number of flares per year will also be collected, as well as the patient´s 
stool frequency prior to the initial onset of signs and symptoms of UC. 
 
Definition of stool 
Patients should be instructed that a stool is defined as a trip to the toilet when the patient has 
either a bowel movement, or passes blood alone, blood and mucus, or mucus only. 
 
Definition of remission reference stool frequency 
The patient should be asked to identify at the visit 1a how many stools he or she had in a 24-
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If the patient does not report that he or she has achieved remission, then the patient should be 
asked to identify the number of stools he or she had per day before initial onset of signs and 
symptoms of UC. 
7.22. Urgency of Defecation 
Patient will be asked questions (appendix 15.5) [22] about defecation urgency at visit 2b, 3, 4, 
5, 6 and 7. 
7.23. Vital Signs 
Systolic and diastolic BP (mmHg) and HR (beats/min) will be measured in sitting position 
and after 5 minutes rest at every visit. The use of automated devices for measuring BP and 
HR are acceptable. Blood pressure and HR should be measured before blood samples are 
taken. On dosing days, vital signs should be obtained prior to treatment. Body temperature 
(ºC) will be measured and weight and height will be measured or reported from patient at visit 
2b. 
8. 
Adverse Event  
Collection of AEs will start directly after the ICF has been signed. During the screening 
period only AEs related to study procedure will be reported. 
Investigators are responsible for recording all AEs observed during the study period (i.e., 
from the time patient signs the ICF and until the patient has completed the study, (only AEs 
related to study specific procedures at screening visit will be recorded at Visit 1 and 2 while 
any other medical finding will be recorded as medical history). Following study drug 
administration, the patients will be questioned about AEs at each visit to the clinic.  
8.1.  Adverse Event Definition 
An AE is any untoward medical occurrence associated with the use of a drug, whether or not 
considered drug related. An AE can be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
study drug, whether or not it is considered to be study drug related. This includes any newly 
occurring event or previous condition that has increased in severity or frequency since the 
administration of study drug.  
8.2. Adverse Drug Reaction Definition 
An ADR is an AE suspected to be causally related to a product. In clinical studies this means 
that the investigator has judged that there is at least a reasonable possibility that the event is 
related to the product.  
8.3. Serious Adverse Event Definition 
A SAE is any AE, occurring at any dose and regardless of causality defined as;  
• 
death 
• 
a life-threatening AE (means that the patient was at immediate risk of death as it 
occurred, does not include if the death may have occurred if a more severe form) 
• 
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• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
a congenital anomaly or birth defect 
• 
regarded as medically important without meeting the above mentioned criteria 
8.4. Adverse Events by Intensity 
Intensity for each AE, including any laboratory abnormality, will be defined according to the 
following criteria: 
 
MILD: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted. If the intensity category changes over a number 
of days, then those changes should be recorded separately (with distinct onset dates). 
8.5. Classification of Adverse Events by Relationship to Study Drug 
UNLIKELY RELATED: This category applies to those AEs that are judged to be 
unrelated to the test drug.  
LIKELY RELATED: This category applies to those AEs that the investigator feels are 
with high probability related to the test drug.  
 
8.6. Reporting of Adverse Events 
At each visit, the patient will be asked if any new signs or a symptom has occurred since last 
visit. For all AEs, the investigator must obtain information to determine the outcome of the 
AE and to assess whether it meets the criteria for classification as a SAE. 
All AEs, serious and non-serious, should be recorded in the eCRFs. If no AE has occurred 
during the study period, this should also be recorded in the eCRF. 
Preferably all AEs should be recorded in standard medical terminology rather than the 
patient’s own word; if possible diagnosis instead of symptoms should be recorded.  
UC is associated with certain characteristic signs and symptoms including diarrhea and rectal 
bleeding that may be present at Screening Visit and may fluctuate based on individual 
patient’s disease history during the course of the study. These signs and symptoms are 
considered medically anticipated clinical events for the condition under study and will not be 
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Exacerbations of disease activity (increase in the daily amount of rectal bleeding beyond the 
patient´s normal fluctuation, new signs or symptoms of UC) will be collected as AEs and 
reported according to regulatory reporting requirements. 
The following evaluations are to be done by the Investigator in connection with the AE: 
• 
type of event 
• 
seriousness 
• 
degree of severity 
• 
duration (start - end) 
• 
action taken 
• 
causality with study product 
• 
outcome of the AE 
8.7.  Reporting of Serious Adverse Events 
All SAEs must be reported to the PAREXEL Drug Safety Services within 24 hours by the 
Investigator or delegate, regardless of the time that may have elapsed from the time the event 
occurred to when the Investigator first learns of it. The initial report should contain as a 
minimum the following information: 
• 
patient identification 
• 
treatment specification 
• 
AE diagnosis 
• 
time specification for the medical event 
• 
name of the original reporter 
Any new information regarding the SAE report should be reported within 24 hours of 
knowledge. Apart from the information above, this follow-up report should also contain the 
following information: 
• 
assessment of severity 
• assessment of causality 
SAEs should be reported to PAREXEL Drug Safety Services even after the clinical study has 
been finished, if, in the judgment of the Investigator, there might be an association between 
the event and previous use of the study product, or as a result of the study procedures. 
Only SAEs that are both unexpected and related to the study drug, Suspected Unexpected 
Serious Adverse Reactions (SUSARs), are subject to expedited reporting. 
The Sponsor is responsible for informing all Investigators concerned of relevant information 
about SUSARs that could adversely affect the safety of patients. The appropriate ethics 
committee (EC) and regulatory authorities, as per local requirements, should be informed by 
the Sponsor about SAEs associated with the use of the product.  


 
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8.8.  Follow-up Period after an Adverse Event 
If a patient is to discontinue due to an AE, or if an SAE persists at the end of the study 
treatment period, this should be followed up until the condition has resolved or until the 
patient is under professional medical care and a potential causality between the study drug 
and the SAE has been established. An outcome assessment should be performed when an AE 
persists. 
In case of pregnancy during the study the patient and offspring must be monitored for AEs 
during the entire pregnancy. Any AE occurring to the offspring during pregnancy or at birth 
must be reported. The pregnancy should be reported in eCRF as an AE and also reported to 
PAREXEL via Pregnancy report form. 
8.9.  Coding of Adverse Events 
 
All AEs will be coded according to medical dictionary for regulatory activities (MedDRA) by 
PAREXEL after the eCRFs have been collected from the study centres. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. Statistical Analysis Plan 
The principal features of the statistical analysis of the data are described in this section. A 
more technical and detailed elaboration of the principal features will be written in a separate 
Statistical Analysis Plan (SAP). A data display plan (DDP) will also be prepared and included 
in the SAP. The DDP will describe the layout of the tables and listings to be produced. 
9.2. Determination of Trial Size 
Given that the purpose of this trial is to determine whether cobitolimod is efficient and 
therefore whether to proceed with further development, there is only one outcome of interest, 
superiority of one or more of the experimental arms to the control (placebo). In this scenario, 
a one-sided testing framework is appropriate.  
Further phase III trials will be required to confirm the efficacy, and thus the standard type I 
error rate control at the 0.05 level is not strictly necessary. The assumption is that a one-sided 
test of the null hypothesis that there is no difference in the primary endpoint between each 
active treatment arm and control (placebo) with a false-positive (type I error) rate of 0.10 is 
appropriate. The primary endpoint is, no difference between each active treatment arm and 
control (placebo) with a false-positive (type I error) rate of 0.10 is appropriate. The use of this 
higher type I error and of a low type II error of 0.10 gives to the trial high statistical power to 
detect a clinically meaningful effect while maintaining an acceptable sample size. 
Assuming 
• a 10 % remission rate for the placebo 
• a type I error of 0.10 
• a 35 % remission rate for the active cobitolimod treatment arm 
•  a power of 90 % 
• a one-tailed test for differences between proportions 


 
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Thirty-five (35) patients per group are needed. 
To allow for 10-20 % dropout rate the sample size is decided to 43 patient per treatment group 
and 215 patients in total.  
Allocating 43 patients per treatment arm will also satisfy a power goal of 80 % using a two-
sided test at the 0.05 type I error rate. 
Power calculation was performed using the Chi-square test for independent groups. Nquery 
7.0 was used for power calculation. 
9.3. Study Population 
9.3.1. Full Analysis Set  
The full analysis set (FAS), will be based on the intention-to-treat (ITT) principles, which 
consists of all randomised patients who meet the inclusion criteria (as assessed by the 
investigator on the inclusion/exclusion criteria form), and receive at least one dose of the 
study drug (active or placebo). 
9.3.2. Per Protocol Set 
The per protocol set (PPS) is defined as FAS patients who do not have important protocol 
deviations considered to have a major effect on the primary efficacy endpoint, and have 
completed the Modified Mayo score (excluding friability) assessment at Week 0 and Week 6. 
Patients in the PPS are analysed according to their randomised treatment. 
9.3.3. Safety Analysis Set 
The Safety Analysis Set is defined as all patients randomised in the study and treated with at 
least one dose of any study drug, i.e. cobitolimod in any dose or Placebo. Safety Analysis Set 
patients are analysed according to their actual treatment received. 
9.4. Patient Demographic and Baseline Characteristics 
Baseline values and patient characteristics will be presented in tables by group and in total. 
All continuous variables will be described using standard statistical measures, i.e., number of 
observations, mean and median value, standard deviation, minimum and maximum value. All 
categorical variables will be summarised in frequency tables. 
9.5. Primary Efficacy Endpoint Analysis  
Sub scores of blood in stool, stool frequency will be based on the data collected in the eDiary. 
The measure of stool frequency will be derived calculating the mean daily stool frequency. 
The measure of blood in stool will be derived calculating the maximum (worst) outcome. 
Both measures will be derived using the most recent three consecutive days prior to the Week 
0 and Week 6 visit, excluding the last two days before these visits. 
The rationale for the exclusion of the last two days before the endoscopic procedure is that the 
preparation for the endoscopy can interfere with the natural clinical course of the symptoms.  
A complete description of the derivation rules for the primary endpoint will be described in 
the SAP. 
The analysis of the primary endpoint is conducted on the FAS and PPS. 


 
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The primary analysis of the primary endpoint will be performed using the Cochran Mantel 
Haenzel test adjusting for randomisation strata GCS use/non use and TNF-α prior use/non use 
at Baseline, Week 0. 
The primary endpoint will be proportion of patients with clinical remission at Week 6 tested 
using an overall type I error rate of 0.10, using a one sided test.  
The p-value for testing the null hypotheses must be less than 0.10 to be considered to have 
met the primary objective.  
The primary efficacy endpoint will also be tested using the same approach as described above 
but with the use of an overall type I error rate of 0.05 using a two-sided test.  
There will be no adjustment for multiplicity as all results will be regarded as exploratory. If a 
statistically significant difference among cobitolimod groups compared to placebo will exist, 
an analysis in terms of fractional polynomial for analysis of binary data will be applied to 
explore the dose-response relationship [23]. 
9.6. Exploratory Efficacy Endpoints Analyses 
No multiplicity adjustments are made computing p-values of tests on exploratory variables; 
reported p-values are nominal. For overall comparison among more than two groups, the null 
hypothesis is that the proportions are the same in all groups.  
The same analysis approach used for the primary efficacy endpoint will be applied to the 
exploratory efficacy variables referred to as a “Proportion endpoints”. 
Continuous endpoints such as mean change from baseline will be evaluated using the 
ANCOVA, including treatment and stratifying factors as fixed factors and baseline as a 
covariate in the model. 
9.7. Safety Analysis 
9.7.1. Analysis of Adverse Events 
The number and percentage of patients reporting AEs, and the number of AEs reported will 
be presented. The events will be tabulated by system organ class and preferred term. In 
addition, summaries by relationship to study drug and severity will be presented. SAEs will 
also be presented in separate tabulations. 
The number of patients experiencing an AE will be compared descriptively between groups. 
All patients with AEs will be listed individually with patient number in addition to type of 
event, start and stop time, duration, seriousness, severity, action taken, relationship to study 
drug and outcome of AE. 
9.7.2. Other Safety Assessments 
All continuous safety variables, such as laboratory measurements, vital signs, ECG 
parameters, and body weight will be described using summary statistics. Changes from 
baseline will also be summarised as appropriate. 
All categorical variables, such as physical examination, will be summarised using frequencies 
and percentages.  
The safety will include laboratory safety variables and/or adverse clinical findings as 
appropriate. Laboratory data will also be presented in shift tables for selected parameters, 


 
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where the number of values within, below and above laboratory reference range will be 
displayed. 
9.8. Adjustment of Covariates 
Baseline values of the parameters to be analysed will be used as covariates in exploratory 
analyses. In addition, the prior use of TNF-α inhibitor and GCS use will be included as a 
covariate in exploratory analyses. 
9.9. Handling of Dropouts and Missing Data 
For the efficacy analyses, missing data will be replaced using the non-responder imputation 
(NRI). NRI will be used where missing data are replaced with a negative outcome, i.e. 
interpreted as a non-responder to the intervention, e.g. no clinical remission in the primary 
endpoint. The last-observation-carried-forward will be used as a sensitivity analysis for 
evaluation of study data. Additional methods for handling missing data will be used and 
described in the Statistical Analysis Plan (SAP). 
9.10. Rules for Excluding Patients from Analysis 
Patients will not be excluded from any analyses unless they fall outside a specific definition 
of the populations described earlier, or unless there is missing data for all endpoints for which 
an imputation algorithm is not described. Protocol deviations will be described in a separate 
document for the purposes of defining the Per Protocol Set prior to database lock. 
9.11. Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the original SAP will be described and justified in the final study report. 
9.12. Interim Analysis 
No formal statistically based interim analysis will be performed. However, the safety data will 
be reviewed periodically during the conduct of the study by the independent DSMB. The 
primary objective of the DSMB data review is safety. 
10. DATA HANDLING  
10.1. Data Handling 
PAREXEL will be responsible for the processing and quality control of the data. Data 
management will be carried out as described in PAREXEL’s SOPs for clinical studies. 
Handling of data, including data quality control, will comply with regulatory guidelines (e.g., 
ICH and GCP) and PAREXEL’s SOP and working instructions. The Data Management 
procedures will be detailed in a written Data Management Plan approved by InDex 
Pharmaceuticals AB. 
All source data will be identified at the start of the trial. eDiary data and laboratory data will 
be considered as source data, all other data will be entered in eCRF by Site staff based on the 
Source data. Data Management routines include procedures for handling the eCRF, database 
set up and handling, data verification and entry, data validation, database quality control and 
documentation of activities performed, including information on discrepancies in the 
procedure. 
The investigator must ensure the accuracy, completeness, legibility, and timeliness of data 
reported in the eCRF and all required reports. Any change or correction to the eCRF must be 
dated, signed and explained (if necessary) and must not obscure the original entry. This 
process applies to both written and electronic changes. 


 
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eCRF reported data that are derived from source documents should be consistent with the 
source documents, or the discrepancies must be explained. 
Within three days of completion of each patient visit, the investigator should agree to have 
completed and entered data into eCRF for inspection by the clinical monitor. 
All of the AEs (whether serious or not) described in the eCRF will be entered in the study 
database. 
The initial notification of SAEs will also be entered in the PAREXEL safety database for 
coding, medical evaluation and notification to the health authorities and independent ethics 
committees (EC) according to national regulatory requirements. 
10.2. Data Management 
The Data Management routines include procedures for handling of eCRFs, database setup and 
management, data entry and verification, data validation, quality control of database, and 
documentation of the performed activities, including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the clinical study protocol. 
10.2.1. Electronic Case Report Form  
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 
11-compliant electronic data capture system. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete or inaccurate. Clinical data will be entered directly from the source 
documents. 
Authorised study site personnel designated by the principal investigator (PI) will complete 
data collection. Appropriate training and security measures will be completed with the PI and 
all authorised study site personnel prior to the study being initiated and any data being entered 
into the system for any study patients. 
10.2.2. Entry of Data  
All data must be entered in English. The eCRFs should always reflect the latest observations 
of patients participating in the study. Therefore, the eCRF is to be completed as soon as 
possible during or after the patient’s visit (within 3 days). All terms will be coded using the 
MedDRA Dictionary. The PI must verify that all data entries in the eCRF are accurate and 
correct. If some assessments are not done, or if certain information is not available, not 
applicable or unknown, the PI should indicate this in the eCRF. The PI will be required to 
electronically sign off the clinical data. 
The patient will fill in eDiary data on a daily basis. 
10.2.3. Query Process 
The monitor will review the eCRF and evaluate for completeness and consistency. Each 
eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections and alterations are to be made by 
the PI or his/her designee. The contract research organisation (CRO) staff cannot enter data in 
the eCRFs. Once clinical data of the eCRF have been submitted to the central server, 
corrections to the data fields will be audit trailed, meaning that the reason for change, the 
name of the person who performed the change, along with time and date will be logged. Rules 
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determined in advance. If additional corrections are needed, the responsible monitor or Data 
Manager will raise a query in the electronic data capture application. The appropriate 
investigational staff will answer queries sent to the PI. This will be audit trailed by the 
electronic data capture application meaning that the names of investigational staff, time and 
date are logged. 
10.2.4. Source Documents 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used 
by the PI or hospital that relate to the patient’s medical history, that verify the existence of the 
patient, the inclusion and exclusion criteria, and all records covering the patient’s 
participation in the study. They include laboratory notes, memoranda, material dispensing 
records, patient files etc. 
The PI is responsible for maintaining source documents. These will be made available for 
inspection by the study monitor at each monitoring visit. The PI must submit a completed 
eCRF for each patient who signed the written ICF. All supportive documentation submitted 
with the eCRF, such as laboratory or hospital records should be clearly identified with the 
study number and the patient number. Any personal information, including patient name, 
should be removed or rendered illegible to preserve individual confidentiality. 
10.2.5. User Identification 
eCRF records will be automatically appended with the identification of the creator, by means 
of their unique UserID. Specified records will be electronically signed by the PI to document 
his/her review of the data and acknowledgement that the data are accurate. This will be 
facilitated by means of the PI’s unique UserID and password; Date and time stamps will be 
added automatically at time of electronic signature. If an entry in an eCRF requires change, 
the correction should be made in accordance with the relevant software procedures.  
10.2.6. Audit Trail 
All changes will be fully recorded in a protected audit trail, and a reason for the change will 
be required. 
Once all data has been entered, verified, and validated, the database will be locked. 
10.2.7. Medical Review of Safety Data 
All available demographic and safety data (including, but not limited to, cumulative listings 
of AE and SAE reports, laboratory data, ECGs, vital signs and physical examinations) will be 
reviewed in a blinded fashion on an ongoing basis by the PAREXEL study medical monitor. 
The Study Medical Monitor will inform the DSMB in case of any findings. Based on these 
ongoing reviews, the DSMB may make recommendations and InDex Pharmaceuticals AB 
may halt the enrolment, modify dose level, add or modify safety procedures or discontinue the 
study.  
10.3. Study Monitoring and Auditing 
This study will be monitored at all stages of its development by InDex Pharmaceuticals´ AB 
representative PAREXEL. Monitoring will include personal visits and telephone 
communication to assure that the investigation is conducted according to the protocol and in 
order to comply with guidelines of ICH-GCP. On-site review of CRFs will include a review 
of forms for completeness and clarity, and consistency with source documents available for 
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Any data recorded directly in the eCRF, for which no other written or electronic record will 
be maintained in the patient’s medical record, will be considered source data and should be 
signed by the investigator (e.g. results of physical examinations, vital signs, or the study drug 
administration procedure). During monitoring visits the data recorded in the eCRFs, source 
document, and other study-related records will be compared against each other in order to 
ensure accurate data that reflects the actual experience of the patient in the study, i.e., source 
data verification. 
Safety Monitors and Clinical Research Associates or assistants may request to witness patient 
evaluations occurring as part of this protocol. The Investigator and appropriate personnel will 
be periodically requested to attend meetings/workshops organised by PAREXEL to assure 
acceptable protocol execution. The study may be audited by InDex Pharmaceuticals AB or by 
regulatory agencies. If such an audit occurs, the investigator must agree to allow access to 
required patient records. By signing this protocol, the investigator grants permission to 
personnel from InDex Pharmaceuticals AB, its representatives, and appropriate RAs for on-
site monitoring of all appropriate study documentation, as well as on-site review of the 
procedures employed in the eCRF generation, where clinically appropriate. 
10.4. Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the relevant 
regulatory agencies. In addition, because this is an international study, the retention period 
must meet the requirements of the most stringent authority. The investigator should take 
measures to prevent accidental or premature destruction of these documents. 
10.5. Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified 
of the investigator’s name, address, qualifications and extent of involvement. Clinical study 
reports covering clinical and biometric aspects of the study will be prepared by PAREXEL. 
11. ETHICAL REQUIREMENTS 
11.1. Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, regulatory requirements, GCP 
and the ethical principles of the Declaration of Helsinki. The final study protocol, including 
any substantial amendments and the final version of the patient information and consent form, 
will be reviewed and approved by regional ECs and by the regulatory authorities in each 
country prior to inclusion of patients.  
11.2. Indemnification 
InDex Pharmaceuticals AB’s indemnification of the Investigator and institution during the 
conduct of this study is addressed in a letter of indemnification provided as a separate 
document. Other indemnification or insurance will be provided as necessary under local 
regulations. 
With respect to any injury directly or indirectly caused by the study drug to the patient during 
this study, InDex Pharmaceuticals AB assumes liability by law on behalf of the 
Investigator(s), providing the Investigator/delegate has followed the instructions of InDex 


 
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Pharmaceuticals AB in accordance with this protocol and any amendments thereto, that the 
study drug administered to the patient in this study have been supplied by InDex 
Pharmaceuticals AB and that the Investigator/delegate have generally performed this study in 
accordance with scientific practice and currently acceptable techniques and know-how. 
The patients are covered by insurances held by InDex Pharmaceuticals AB. 
11.3. Sponsor Discontinuation Criteria 
InDex Pharmaceuticals AB reserves the right to discontinue the study at a site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does not recruit 
at a reasonable rate or is non-compliant with the study protocol or study procedure may be 
discontinued. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and study drug pertaining to the study must be returned to InDex 
Pharmaceuticals AB or its representative. 
12. STUDY COMMITTEES 
12.1. Data Safety Monitoring Board 
An independent DSMB will evaluate the safety data in the context of the overall trial and the 
currently existing information about the study drug. The DSMB will be composed of 
representatives from outside of InDex Pharmaceuticals AB who are experts in their respective 
disciplines of medicine, statistics and clinical trial methodology and conduct. 
The DSMB will together with InDex Pharmaceuticals AB determine the appropriate time 
frame for reviewing the data during the course of the study, and will draw up a charter 
delineating their guidelines for operating and stopping rules for terminating individual 
patients, a portion or all of the trial prematurely. 
In the context of overall patient safety, the DSMB will receive online access to all data 
including a pre-defined safety data package containing a summary update and individual data 
for selected variables, recruitment rates, number of patients for each visit, dropouts, 
completeness of eCRFs and data entry and information on AEs and SAEs.  
Furthermore, the DSMB will be notified of abnormal laboratory test values (defined by the 
laboratory standard reference range for normal) of defined variables included in the safety 
data package. 
The DSMB will have access to all trial data. It may request and will be provided with 
whatever data it deemed necessary or useful for it to carry out its duties. The data provided 
will be blinded to treatment group unless specific unblinding is requested by the DSMB. 
13. PUBLICATION/DATA SHARING POLICY 
Results from this study are the property of InDex Pharmaceuticals AB and the data from this 
study will first be published by InDex Pharmaceuticals AB. Authors will be decided by InDex 
Pharmaceuticals AB. The Investigators will be acknowledged in the publication(s). In the case 
individual Investigator(s) wish to publish own data from this study, InDex Pharmaceuticals 
AB will be given not less than 60 days for review and comments for a manuscript and at least 
30 days for an abstract. In case of a difference in opinion, in order to protect their proprietary 
interests, InDex Pharmaceuticals AB has the right to delay the submission an additional 60 
days. 
 
 


 
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14. REFERENCES 
1. 
Irvine, E. J. (2008). "Quality of life of patients with ulcerative colitis: past, present, and 
future." Inflamm Bowel Dis 14(4): 554-565 
2. 
Sutherland, L., F. Martin, S. Greer, M. Robinson, N. Greenberger, F. Saibil, T. Martin, 
J. Sparr, E. Prokipchuk and L. Borgn (1987). "5-Aminosalisylic acid enema in the 
treatment of ulcerative colitis, proctosigmoiditis and proctitis." Gastroenterology 92: 
1894-1898 
3. 
Domenech, E., M. Manosa and E. Cabre (2014). "An overview of the natural history of 
inflammatory bowel diseases." Dig Dis 32(4): 320-327. 
4. 
Prantera, C. and S. Marconi (2013). "Glucocorticosteroids in the treatment of 
inflammatory bowel disease and approaches to minimizing systemic activity." Therap 
Adv Gastroenterol 6(2): 137-156. 
5. 
Khan, K. J., M. C. Dubinsky, A. C. Ford, T. A. Ullman, N. J. Talley and P. Moayyedi 
(2011). "Efficacy of immunosuppressive therapy for inflammatory bowel disease: a 
systematic review and meta-analysis." Am J Gastroenterol 106(4): 630-642. 
6. 
Fausel, R. and A. Afzali (2015). "Biologics in the management of ulcerative colitis - 
comparative safety and efficacy of TNF-alpha antagonists." Ther Clin Risk Manag 11: 
63-73. 
7. 
Feagan, B. G., P. Rutgeerts, B. E. Sands, S. Hanauer, J. F. Colombel, W. J. Sandborn, 
G. Van Assche, J. Axler, H. J. Kim, S. Danese, I. Fox, C. Milch, S. Sankoh, T. Wyant, 
J. Xu, A. Parikh and G. S. Group (2013). "Vedolizumab as induction and maintenance 
therapy for ulcerative colitis." N Engl J Med 369(8): 699-710. 
8. 
CharlesRiver-31048 (2011). DIMS0150: 13 Week Toxicity Study in the Rat with 
Administration by Multiple Dose Routes followed by a 4 Week Recovery Period. 
Edinborough, UK, Charles River Laboratories. 
9. 
CharlesRiver-31847 (2011). DIMS0150: 13 Week Toxicity Study in the Rat dosed by 
the Rectal Route of Administration with a 4 Week Recovery Period. Edinburgh, UK, 
Charles River Laboratories. 
10. 
CharlesRiver-30436 (2011). DIMS0150: 19 day toxicity study in Cynomolgus monkeys 
with intravenous infusion or subcutaneous administration followed by a 28 day recovery 
period. Edinburgh, UK, Charles River Laboratories  
11 
InDex-HICS-98-01 (2001). Antisense NF-κB(65) p65 treatment in active distal colonic 
inflammatory bowel disease, a clinical study report Stockholm, Sweden, Index 
Pharmaceuticals AB.  
12. 
InDex-CSUC-01-02 (2004). A double-blind, randomised, placebo controlled, single-
dose, multi-center, dosefinding study of NF-κB (p65) antisense oligonucleotide in 
patients with mild or moderately active ulcerative colitis. Stockholm, Sweden, Index 
Pharmaceutcials AB.  
13 
InDex-CSUC-01-06 (2009). A placebo-controlled, randomized, double-blind single 
dose proof of concept study of Kappaproct, in steroid resistant or steroid dependent 
patients with ulcerative colitis of mild to moderate degree. Stockholm, Sweden, InDex 
Pharmaceuticals AB.  
 


 
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14 
Van Assche, G. Dalle, I. Noman, M. Aerden, I. Swijsen, C. Asnong, K. Maes,B. 
Ceuppens, J. Geboes, K. Rutgeerts, P. "A Pilot Study on the Use of Humanized Anti-
Interleukin-2 Receptor Antibody Daclizumab in Active Ulcerative Colitis" Am J 
Gastroenterol. 2003 Feb;98(2):369-76 
15. 
InDex-CU-UC-01-11 (2013). Collection of fourteen case reports of patients treated with 
Kappaproct on a named-patient basis in Germany and subsequent analysis of the results. 
Stockholm, Sweden,  
16 
InDex Pharmaceuticals AB InDex-CSUC-01-10 (2014). A placebo-controlled, double-
blind, randomised study to assess the efficacy and safety of Kappaproct as an add-on to 
current practice in chronic active treatment refractory ulcerative colitis patients. 
Stockholm, Sweden, InDex Pharmaceuticals AB 
17 
Marchal-Bressenot, A .Salleron,J. Boulagnon-Rombi, C. Bastien, C. Cahn, V. Cadiot, G. 
Diebold, M-D. Danese, S. Reinisch, W. Schreiber S. Travis, S. Peyrin-Biroulet, L 
(2015)."Development and validation of the Nancy histological index for UC" 
gut.bmj.com/on November 11, 2015 
18 
Marchal-Bressenot A, Scherl A, Salleron J, Peyrin-Biroulet L (2016) A practical guide 
to assess the Nancy histological index for UC Gut. 2016 Aug 26. pii: gutjnl-2016-
312722. doi: 10.1136/gutjnl-2016-312722 
19 
Cheung, W. Garratt, I. Russel, I. Williams, J (2000) "The UK IBDQ- A British version 
of the inflammatory bowel disease questionnaire: development and validation". Journal 
oc Clinical Epidemology 53 (2000) 297-306 
20 
Levine J, Burakoff R. Extraintestinal Manifestations of Inflammatory Bowel Disease. 
Gastroenterol Hepatol (N Y). 2011 Apr; 7(4): 235–241 
21 
Schroder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
1987;317(26):1625-9 
22  
D´Haens G, Sandborn W, Feagan B, Geboes K, Hannauer J, Lémann M, Schölmerich J,  
Sutherland L. A Review of Activity Indices and Efficacy End Points for Clinical Trials 
of Medical Therapy in Adults with Ulcerative Colitis.Gastroenterology 2007;132:763–
786 
23. 
May S, Bigelow C. Modeling non-lineardose-response relationship in epidemiologic 
studies:statistical approaches and practical changes Dose-Response, 3: 474–490, 2005
 
 
24  
European Medicin Agency. Draft Guideline on development of new medicinal products 
for the treatment of ulcerative colitis. 2016, july 21. 
25  
Food Drug and Administration. Draft Guidance for industry, Clinical Trial Ulcerative 
Colitis Endpoints. 2016, august 
 
 
 
 
 
 


 
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15. Appendices 
15.1. Mayo Scoring System for Assessment of Ulcerative Colitis Activitya 
Grade 
Stool 
frequencyb 
Rectal 
Bleedingc 
Physician´s 
global 
assessmentd 
Colonoscopy/sigmoidoscopy 
finding 
0 
Normal 
number of 
stools for this 
patient 
No blood 
seen 
Normal or no 
disease 
Normal or inactive disease 
1 
1 to 2 stools 
more than 
normal 
Streaks of 
blood with 
stool less 
than half the 
time 
Mild disease 
 
Mild disease (erythema, 
decreased vascular pattern, 
mild friability) 
2 
3 to 4 stools 
more than 
normal 
Obvious 
blood with 
stool most of 
the time 
Moderate 
disease 
Moderate disease (marked 
erythema, lack of vascular 
pattern, friability, erosions) 
3 
5 or more 
stools more 
than normal 
Blood alone 
passed 
 
Severe 
disease 
Severe disease (spontaneous 
bleeding, ulceration) 
 
a The Modified Mayo score (excluded friability at grade 1) ranges from 0-12, with higher 
scores indicating more severe disease. Partial Mayo score excludes endoscopy. 
b Each patient serves as his or her own control to establish the degree of abnormality of the 
stool frequency. 
c The daily bleeding score represents the most severe bleeding of the day 
d The physicians global assessment acknowledges the 3 other criteria, the patients daily 
recollection of abdominal discomfort and general sense of well-being, and other 
observations, such as physical findings and the patient´s performance status. 
 
Adapted from: Schroder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
1987;317(26):1625-9 
 
 
 
 
 
 


 
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15.2. Definitions of stool frequency and rectal bleeding 
Items 
Definition 
Definition of Stool 
Patients should be instructed that a stool is defined as a trip 
to the toilet when the patient has either a bowel movement, 
or passes blood alone, blood and mucus, or mucus only 
Reference Remission Stool 
Frequency (over 24 hours) 
The patient should be asked to identify at the visit 1a how 
many stools he or she had in a 24-hour period when in 
remission from UC 
• If the patient does not report that he or she has achieved 
remission, then the patient should be asked to identify the 
number of stools he or she had per day before initial onset of 
signs and symptoms of UC 
• Sponsors should record if the reference remission stool 
frequency is based on reported stool frequency when the 
patient was in remission or reported stool frequency before 
initial onset of signs and symptoms of UC. 
• Both the remission and pre-UC stool frequency should be 
collected at baseline. This allows exploration of the natural 
history of pre diagnosis stool frequency versus remission 
stool frequency. 
Most Severe Category of 
Rectal Bleeding (in a given 
24-hour period) 
Patients should be instructed to indicate the most severe 
category that describes the amount of blood they had in their 
stools for a given day 
• Categories of rectal bleeding should be defined as 
follows: 
- No blood seen 
- Streaks of blood with stool less than half the time 
- Obvious blood (more than just streaks) or streaks  
of blood with stool most of the time 
- Blood alone passed 
Patients should be instructed to select “No Blood Seen” in 
the rectal bleeding section if they do not have stool during a 
given day 
 
Adapted from Ulcerative Colitis Clinical Trial Endpoints, Guidance for Industry, FDA, draft 
AUG 2016.  
 
 


 
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15.3. Nancy Histological Index 
Definitions of grades: 
Grade 
Definition 
0 
No or mild disease – No histological significant disease 
1 
Moderate or marked increase – chronic inflammatory infiltrate with no acute inflammatory infiltrate 
2 
Mildly active disease - with acute inflammatory cells infiltrate and no ulceration 
3 
Moderately active disease – with acute inflammatory cells infiltrate and no ulceration 
4 
Severely active disease – with ulceration 
 
Further clarifications: 
Item 
Likert scale anchor points 
 
Chronic inflammatory infiltrate (defined as the 
quantity of lymphocytes and plasmacytes in the 
biopsy specimen) 
 
 
0    No increase 
1    Mild but unequivocal increase 
2    Moderate increase 
3    Marked increase 
 
 
Neutrophils in the epithelium 
 
0    None 
1    <50% crypt involved 
2    >50 % crypt involved 
 
 
Ulceration (defined as visible epithelial injury and 
regeneration and/or fibrin and neutrophils and/or tissue granulation) 
 
 
0    Absent 
1    Present 
 
Acute inflammatory cell infiltrate 
 
0    None 
1    Mild 
2    Moderate 
3    Severe 
 
 
Mucin depletion 
 
0    None 
1    Mild 
2    Moderate 
3    Severe 
 
 
Neutrophils in lamina propria 
 
0    None 
1    Mild 
2    Moderate 
3    Severe 
 
 
Basal plasmacytosis 
 
0    None 
1    Mild 
2    Moderate 
3    Severe 
 
 
Serrated architectural abnormalities (defined as the  
presence of dilated crypts showing a scalloped lumen) 
 
0    None 
1    <5% crypt involved 
2    <50% crypt involved 
3    >50% crypt involved 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol CSUC-01/16       
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15.4. Extraintestinal Manifestations of Inflammatory Bowel Disease 
 
 
Sites 
Extraintestinal manifestations 
Musculoskeletal system 
• 
Arthritis; colitic type, ankylosing spondylitis, 
isolated joint involvement 
 
• 
Hypertrophic 
osteoarthropathy: 
clubbing, 
periostitis 
 
• 
Miscellaneous 
manifestations: 
osteoporosis, 
aseptic necrosis, polymyositis 
Dermatologic and oral systems 
• 
Reactive lesions: erythema nodosum, pyoderma 
gangrenosum, 
aphthous 
ulcers, 
necrotizing 
vasculitis 
 
• 
Specific lesions: fissures, fistulas, oral Crohn´s 
disease, drug rashes 
 
• 
Nutritional 
deficiencies: 
acrodermatitis 
enteropathica, purpura, glossitis, hair loss, brittle 
nails 
 
• 
Associated 
diseases: 
vitiligo, 
psoriasis, 
amyloidosis 
Hepatopancreatobiliary system 
• 
Primary 
sclerosing 
cholangitis, 
bile-duct 
carcinoma 
 
• 
Associated inflammation, autoimmune chronic 
active hepatitis, pericholangitis, portal fibrosis, 
cirrhosis, granulomatous disease 
 
• 
Metabolic manifestations: fatty liver, gallstones 
associated with ileal Crohn´s disease 
Ocular system 
• 
Uveitis/iritis, episcleritis, scleromalacia, corneal 
ulcers, retinal vascular disease 
Metabolic system 
• 
Growth retardation in children and adolescents, 
delayed sexual maturation 
Renal system 
• 
Calcium oxalate stones 
 
 
 from: Gastroenterol Hepatol (N Y). 2011 Apr; 7(4):235-241 
 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol CSUC-01/16       
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15.5. Urgency of defecation index  
 
Grade 
Defecation 
0 
Continent 
1 
Hurry 
2 
Immediately 
3 
Incontinent 
 
One of the components in the simple clinical colitis activity index (SCCAI).