Clinical trial NCT03009396
Conditions: Crohn Disease
Keywords: Crohn's Disease, moderate to severe remission Mycobacterium avium paratuberculosis antibiotic
Sponsor: RedHill Biopharma Limited
Start date: 2017-03-18; Completion date: 2019-08-19
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An open label extension to the RHB-104-01 Study.

Detailed description:
An Open Label Phase III Study to Assess the Efficacy and Safety of Fixed-Dose Combination RHB-104 in Subjects with Active Crohn's Disease Despite 26 Weeks of Participation in the MAP US RHB-104-01 Study.

Arms: arm 1: Subjects who were on the active therapy arm in the RHB-104-01 clinical study will continue to receive RHB-104 at 5 capsules twice a day in addition to the standard of care they received in the RHB-104-01 clinical study arm 2: Subjects who were on the active therapy arm in the RHB-104-01 clinical study will receive RHB-104 at 5 capsules twice a day in addition to the standard of care they received in the RHB-104-01 clinical study. The RHB-104 will be ramped up beginning at 1 capsule twice per day in week 1 increasing to 2 capsules twice per day in week 2, 3 capsules twice per day in week 3, 4 capsules per day in week 4 and achieving 5 capsules per day for the remainder of the study.
Interventions: intervention 1: RHB-104 (fixed-dose combination: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine)
Intervention descriptions: intervention 1: For patients on ACTIVE or PLACEBO in the parent study (RHB-104-01), who were not in remission after 26 weeks

Protocol documents:
Prot_001.pdf: 
An Open Label Study to Assess the Efficacy and Safety of Fixed-Dose Combination RHB-104 in 
Subjects with Active Crohn’s Disease Despite 26 Weeks of Participation in the MAP US           
RHB-104-01 Study  
 
(MAP US2) 
 
 
 
 
 
 
Protocol Number:   
US IND Number: 
RHB-104-04 
73,479 
Principal Investigator: 
David Graham MD 
Sponsor’s Medical Director: 
 
Ira Kalfus MD 
Version and Date: 
Final Version 1.0 / 16 December 2016 
 
 
 
 
 
 
 
Statement of Confidentiality 
The information contained in this document is confidential and is not to be disclosed without the express 
consent of RedHill Biopharma Ltd. 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 2 of 8 
 
 
STATEMENT OF COMPLIANCE 
 
This study will be carried out in accordance with Good Clinical Practices (GCP) as identified 
and/or required by the following regulations and guidance: 
• 
Declaration of Helsinki (Tokyo, 2004)  
• 
US Code of Federal Regulations: 45 CFR Part 46, 21 CFR Parts 50, 56, and 312 
• 
Canadian Food and Drug Regulations F-27 – C.R.C., c. 870: Division 5 (C.05.) 
• 
EU Directive 2001/20/EC and 2005/28/EC 
• 
ICH E6; Consolidated Guidelines on Good Clinical Practices (1997)   
• 
Appropriately identified sponsor/CRO and local clinical SOPs 
 
 
 
 
 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 3 of 8 
Title: 
An Open Label Study to Assess the Efficacy and Safety of Fixed-Dose 
Combination RHB-104 in Subjects with Active Crohn’s Disease Despite 26 
Weeks of Participation in the MAP US RHB-104-01 Study  (MAP US2) 
Phase: 
Phase III 
Study Population: 
Active subjects in the RHB-104-01 A Phase III Randomized, Double Blind, 
Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy 
and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately 
to Severely Active Crohn’s Disease (MAPUS) study with CDAI of greater than or 
equal to 150 despite 26 weeks of treatment with investigational drug. 
The following inclusion criteria apply: 
• 
Participation in RHB-104-01 for: 
o 
26 weeks, and a Crohn’s Disease Activity Index (CDAI) score of ≥ 150 at 
Visit Week 26 
OR 
o 
More than 26 weeks, with a CDAI ≥150 at Visit Week 26 and all 
subsequent visits, and subject is between Week 26 and 52 within 4 weeks 
(28 days) of site activation 
• 
White blood cell count ≥ 3.5x109 at screening. 
• 
Subject agrees to use the following effective contraceptive methods  
o 
diaphragm, cervical cap, contraceptive sponge or condom with spermicidal 
foam/gel/cream/suppository 
o 
IUD/IUS 
o 
progestogen injection (Depo-Provera®)  
throughout the study and for at least 6 weeks after last study drug administration, 
unless subject or partner of subject is post-menopausal or otherwise incapable of 
becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. 
In regions where local regulatory contraceptive requirements differ, the ICF will   
reflect local policies 
 
The following key exclusion criteria apply: 
• 
Treatment with any medication that causes QT prolongation or Torsades de 
Pointes, including but not limited to: amiodarone, amitriptyline, astemizole, 
cisapride, citalopram dose greater than 20 mg/day, dihydroergotamine, 
disopyramide, dofetilide, dronedarone, ergotamine, ibutilde, ondansetron or other 
5-HT3 receptor antagonists, pimozide, procainamide, quinidine, quinine, 
quinolones, ranolazine, risperidone, sotalol, terfenadine and tolteridine. QT 
prolonging drugs may be referenced at the CredibleMeds® web site:  
https://crediblemeds.org/index.php/drugsearch  
• 
Treatment with the following CYP3A4 interactive medications: alfentanyl, 
alprazolam, amlodipine, anti-retroviral agents, apixabin, aprepitant, aripiprazole, 
atorvastatin, boceprevir,  buspirone, carbamazepine, carvedilol, colchicine, 
cyclosporine, digoxin, diltiazem, estrogens, felodipine, fluconazole, fluvoxamine, 
grapefruit juice,  haloperidol, ketoconazole, lovastatin, lurasidone, metoprolol, 
nefazodone, nifedipine, nisoldipine, nitrendipine, propranol, roflumilast, 
simvastatin,  St. John’s wort, and voriconazole. 
• 
Positive stool results for C. difficile. 
• 
Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 4 of 8 
optometrist. 
• 
Evidence of any significant hematological, hepatic, renal, cardiac, pulmonary, 
metabolic, neurological, psychiatric or other disease (e.g. porphyria) that might 
interfere with subject’s ability to safely enter and or complete the study 
requirements.  
• 
Clinically significant abnormalities of hematology or biochemistry as confirmed by 
repeat testing based on investigator’s discretion, including but not limited to, 
elevations greater than 2 times the upper limit of normal of Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT), or creatinine clearance 
less than 60 ml/min at screening via estimated Cockcroft-Gault formula:  
Creatinine Clearance = [140 - age in years] * weight (kg) / 72 * Serum Creatinine 
(mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight. 
• 
QTcF>450ms in males and QTcF>460ms in females, bundle branch block, or major 
ST or T wave abnormalities that make the assessment of the QT impossible. 
• 
Females who have a positive pregnancy test or are lactating. 
Number of 
Subjects:   
Estimated total: Approximately 100 subjects  
Number of Sites: 
The study will be conducted at up to 150 sites in the USA, Canada, Israel, Australia, New 
Zealand, Poland, Bulgaria, Czech Republic, Romania, Slovakia and Serbia 
Study Design: 
This is an open label, multicenter, Phase III, study designed to evaluate the efficacy and 
safety of RHB-104 to treat subjects with active CD as defined by CDAI ≥ 150 despite 26 
weeks of treatment with study drug in RedHill Biopharma Study RHB-104-01. RHB-104 
consists of 3 antibiotics with activity against Mycobacterium avium subsp. paratuberculosis 
(MAP), a potential cause of CD. Eligible subjects with active CD who have completed 26 
weeks of study drug as part of the RHB-104-01 study will receive up to 52 weeks of open 
label RHB-104. Subjects enrolled in the open label study may have current CD therapies 
adjusted or withdrawn as clinically indicated by their local investigator after 8 weeks of open 
label RHB-104 treatment. Sites should begin tapering steroids upon completion of 4 weeks 
of RHB-104 treatment with the goal of being steroid free by week 14 – Refer to Appendix 13.  
MAP are slow growing mycobacteria without a proven antibiotic treatment, and the duration 
of antibiotic treatment required to achieve remission in subjects with CD caused by MAP is 
believed to be approximately 16-26 weeks. Subjects with response at week 26 may 
ultimately achieve remission at a later time point with continued treatment for MAP. Similarly, 
some subjects may achieve response or achieve remission prior to week 26.  This study is 
designed to assess response, remission, and maintenance of remission in subjects on open 
label RHB-104 through week 52, as well as corticosteroid free remission at week 16.   
Blood samples will be collected at Screening and at every visit after the initial 8 weeks of 
treatment to test for MAP in the serum using a polymerase chain reaction (PCR) assay. 
Similarly, MAP cultures will be prepared from whole blood collected at Screening and at 
weeks 16, 26 and 52.    
Safety of the fixed-dose combination product, RHB-104, will also be assessed. 
Colonoscopy will be done in consenting subjects at baseline (prior to initiation of open label 
RHB-104) and after 16 and 52 weeks of open label RHB-104 to assess for mucosal healing 
as well as MAP status via PCR and culture.   
Study Visit Schedule:                                                                                 
Screening, Baseline, and follow-up visits at weeks 2, 4, 8, 16, 26, 39, 52, and 56. Subjects 
undergoing colonoscopy will have a procedural visit after week 16 and 52 assessment so as 
to not interfere with data collection. 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 5 of 8 
Subject 
Participation 
Duration: 
Subjects will receive RHB-104 for up to 52 weeks  
Treatment:  
RHB-104; a fixed-dose combination of 95 mg clarithromycin, 45 mg rifabutin, and 10 mg 
clofazimine.  
Route of 
Administration: 
Oral capsule. 
Dosage Regimen 
for Investigational 
Product: 
The target dose of RHB-104 is 5 capsules administered bid. 
In order to reach this target with minimal adverse effects, subjects who received placebo 
during the RHB-104-01 study will be titrated up over the first 4 weeks of treatment, and the 
dose will remain stable thereafter. Subjects who received RHB-104 will continue to receive 
RHB-104.  In order to maintain blinding in the RHB-104-01 study all subjects will receive 5 
blinded capsules bid for the duration of the RHB-104-04 study as detailed below. The study 
drug will be taken with food. Subjects who fail dose escalation to 5 capsules bid will be 
considered treatment failures and withdrawn from the study. 
Blinded bid Dose Titration and Maintenance Dosing in RHB-104-04 
RHB-104-01 
Study Drug 
WK 1 
WK 2 
WK 3 
WK 4 
WK 5-36 
 
Placebo 
1 capsule 
RHB-104 
+ 
4 capsules 
PBO 
Bid 
2 capsules  
RHB-104 
+ 
3 capsules 
PBO 
bid 
3 capsules 
RHB-104 
+ 
2 capsules 
PBO 
bid 
4 capsules 
RHB-104 
+ 
1 capsules 
PBO 
bid 
 
5 capsules 
RHB-104 
bid 
 
 
RHB-104  
5 capsules 
RHB-104 
Bid 
5 capsules 
RHB-104 
bid 
5 capsules 
RHB-104 
bid 
5 capsules 
RHB-104 
bid 
5 capsules 
RHB-104 
bid 
Outcome 
Measures 
 
Remission (primary outcome measure) – Remission in a subject is defined as a CDAI 
score of <150 at 16 weeks. 
Response – A response in the individual subject is defined as reduction in CDAI score of 
≥100 from baseline where baseline is the measure taken at Screening of this trial (Visit Week 
26 of RHB-104-01).  
Time to remission – The time (weeks after initiation) that a subject first records a state of 
remission.  
Duration of remission – The time that a subject is in a state of remission. 
Time to response – The time (weeks after initiation) that a subject first achieves a state of 
response. 
Duration of response – The time that a subject is in a state of response. 
Maintenance of Remission – Remission in a subject from week 16 through week 52. 
Other Outcome Measures 
MAP Detection:  
• Proportion of subjects with a MAP positive blood PCR assay at baseline (week 0 of 
the open label phase). 
• Proportion of subjects with a change in MAP blood PCR assay status after 16 weeks 
of treatment compared to baseline (week 0 of the open label phase). 
• Proportion of subjects with a change in MAP blood PCR assay status after 52 weeks 
of treatment compared to baseline (week 0 of the open label phase). 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 6 of 8 
• Sequential comparison of MAP blood PCR assay results per subject 
• Proportion of enrolled subjects with a MAP positive blood culture at baseline (week 
0 of the open label phase). 
• Proportion of subjects with a change in MAP blood culture status after 26 weeks of 
treatment compared to baseline (week 0 of the open label phase). 
• Proportion of subjects with a change in MAP blood culture status after 52 weeks of 
treatment compared to baseline (week 0 of the open label phase). 
Endoscopic Changes in Those Subjects Who Undergo Colonoscopy: 
• Change from baseline in the mean Crohn’s Disease Endoscopic Index of Severity 
(CDEIS) after 16 and 52 weeks of treatment 
• Change from baseline in the mean Simple Endoscopic Activity Score (SES-CD) after 
16 and 52 weeks of treatment 
• Success rates of (∆CDEIS and SES-CD) defined by 25% and 50% improvements  
• Correlation between the change from baseline in the endoscopic index (∆CDEIS) and 
the clinical index (∆CDAI) after 16 and 52 weeks of treatment 
• Comparison of success rates of (∆CDEIS) defined by 25% and by 50% improvements 
in CDEIS vs CDAI defined remission  
• Comparison of success rates of (∆CDEIS) defined by 25% and by 50% improvements 
in CDEIS vs CDAI defined response 
• Correlation between the change from baseline in the endoscopic index (∆SES-CD) 
and the clinical index (∆CDAI) after 16 and 52 weeks of treatment 
• Comparison of success rates of (∆CDEIS) defined by 25% and by 50% improvements 
in SES-CD vs CDAI defined remission  
• Comparison of success rates of (∆CDEIS) defined by 25% and by 50% improvements 
in SES-CD vs CDAI defined response 
Health-Related Quality-of-life (HRQoL): 
• Change from baseline (initiation of open label phase) in the SF-36 questionnaire total 
score and domain scores to 16, 26 and 52 weeks. 
• Change from baseline (initiation of open label phase) in the mean Inflammatory Bowel 
Disease Questionnaire (IBDQ) score to 16, 26, and 52 weeks. 
Inflammation: 
• Changes from baseline in a serum marker of inflammation: C-reactive Protein (CRP) 
• Changes from baseline in a stool marker of inflammation: fecal calprotectin 
Safety: The incidence of adverse events during the study and changes from baseline in 
vital signs, Clostridium difficile toxin, ECG, hematology and chemistry laboratory 
parameters 
Objectives: 
 
Primary Objective 
The primary objective is to estimate the remission rate, defined as a CDAI score of less 
than 150, at 16 weeks after the initiation of the open-label phase. 
Secondary Objective  
To estimate the response rate of patients, defined by a reduction of CDAI score of ≥100 
points at week 16 after the initiation of the open-label phase.  
Selected Other Secondary Objectives  
• To estimate the average duration of remission among participants. 
• To estimate the average time to first response among participants. 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 7 of 8 
• To estimate the average duration of response among participants. 
• To estimate the proportion of participants who maintain a state of remission from 
week 16 through week 52. 
Selected Other Objectives  
MAP Detection:  
• To estimate the proportion of subjects with a MAP positive blood PCR assay at 
baseline (week 0 of the open label phase). 
• To estimate the proportion of subjects with a change in MAP blood PCR assay status 
after 16 weeks of treatment compared to baseline (week 0 of the open label phase). 
• To estimate the proportion of subjects with a change in MAP blood PCR assay status 
after 52 weeks of treatment compared to baseline (week 0 of the open label phase). 
• To make sequential comparisons of MAP blood PCR assay results per subject 
• To estimate the proportion of enrolled subjects with a MAP positive blood culture at 
baseline (week 0 of the open label phase). 
• To estimate the proportion of subjects with a change in MAP blood culture status after 
26 weeks of treatment compared to baseline (week 0 of the open label phase). 
• To estimate the proportion of subjects with a change in MAP blood culture status after 
52 weeks of treatment compared to baseline (week 0 of the open label phase). 
Endoscopic Changes in Those Subjects Who Undergo Colonoscopy: 
• To estimate the change from baseline in the mean Crohn’s Disease Endoscopic Index 
of Severity (CDEIS) after 16 and 52 weeks of treatment 
• 
To estimate the change from baseline in the mean Simple Endoscopic Activity 
Score (SES-CD) after 16 and 52 weeks of treatment  
• 
To make a comparison of success rates of (∆CDEIS and SES-CD) defined by 25% 
and 50% improvements  
• To estimate the correlation between the change from baseline in the endoscopic index 
(∆CDEIS) and the clinical index (∆CDAI) after 16 and 52 weeks of treatment 
• To make a comparison of success rates of (∆CDEIS) defined by 25% and 50% 
improvements and CDAI defined remission  
• To make a comparison of success rates of (∆CDEIS) defined by 25% and 50% 
improvements and CDAI defined response 
• To make a comparison of success rates of (∆SES-CD) defined by 25% and 50% 
improvements and CDAI defined remission 
• To make a comparison of success rates of (∆SES-CD) defined by 25% and 50% 
improvements and CDAI defined response 
 
Safety Objective: Assess the safety impact of treatment with RHB-104. 
Study 
Completion: 
Upon completion of clinical activities and safety follow-up. 
Statistical 
Considerations 
 
This study will provide numerous descriptive statistics with corresponding 95% confidence 
intervals for each of the outcomes described above.  Since there is no randomization 
involved in this study, there will be no formal between group comparisons made. The primary 
outcome measure, remission rate defined as a CDAI score of less than 150 at week 16, is 
measured as a dichotomous variable (yes/no) for each participant.  Thus, the overall rate 


CONFIDENTIAL 
Protocol RHB-104-04 
 
Version 1.0 / 16 December 2016  
Page 8 of 8 
and the corresponding 95% confidence interval will be estimated.  This will be examined 
overall and then by anti-TNF agent use (yes/no).  The secondary endpoint, response rate, 
will also be estimated with a corresponding 95% confidence interval.  This too will be 
presented overall and then by anti-TNF agent use (yes/no).   For each secondary endpoint 
measured on a dichotomous scale the overall proportion and corresponding 95% confidence 
interval will be estimated.  For outcomes measured on a continuous scale descriptive 
statistics including means, standard deviations and 95% confidence intervals will be 
estimated.  For variables that are not normally distributed medians and inter-quartile ranges 
will be estimated.  For outcomes that are measured at multiple time points with short time 
intervals between measures (i.e., 4 weeks or less), time to event curves can be developed 
using Kaplan-Meier survival methods.  A formal SAP will be developed prior to the 
completion of the study to describe in greater detail all statistical analyses to be performed. 
Safety will be assessed including routine laboratory work and adverse events. 
 

SAP_000.pdf: 
  
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-04 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
RedHill Biopharma Ltd. 
21 Ha’arba’a St., 
Tel-Aviv 64739, Israel 
 
An Open Label Study to Assess the Efficacy and Safety of 
Fixed-Dose Combination RHB-104 in 
Subjects with Active Crohn’s Disease Despite 26 Weeks of 
Participation in the MAP US 
RHB-104-01 Study 
 
Protocol No. RHB-104-04 
 
 
 
Prepared by 
Shuhong Zhao, PhD 
Principal Research Biostatistician 
 
Syneos Health  
 
 
 
 
 
This document contains confidential information of RedHill Biopharma Ltd. Any viewing or 
disclosure of such information that is not authorized in writing by RedHill Biopharma Ltd. is 
strictly prohibited.  Such information may be used solely for the purpose of reviewing or 
performing this study. 


  
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-04 
 
Version 1.0, 23 Dec 2019 
 
CONFIDENTIAL 
1 
 
STATISTICAL ANALYSIS PLAN 
SIGNATURE PAGE* 
 
RedHill Biopharma Ltd. 
21 Ha’arba’a St., 
Tel-Aviv 64739, Israel 
 
An Open Label Study to Assess the Efficacy and Safety of 
Fixed-Dose Combination RHB-104 in 
Subjects with Active Crohn’s Disease Despite 26 Weeks of 
Participation in the MAP US 
RHB-104-01 Study 
 
Protocol No. RHB-104-04 
Final version 1.0 Dated 16 December 2016 
 
 
 
 
M. Scott Harris MD 
Medical Lead 
RedHill Biopharma Ltd. 
Approval Date 
 
 
Shuhong Zhao, PhD 
Principal Research Biostatistician 
inVentiv Health Clinical 
Approval Date 
 
 
Jed Henke 
Manager, Biostatistics  
inVentiv Health Clinical 
Approval Date 
 
 
 


  
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-04 
 
Version 1.0, 23 Dec 2019 
 
CONFIDENTIAL 
2 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
REVISION HISTORY 
 
This is first version


  
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-04 
 
Version 1.0, 23 Dec 2019 
 
CONFIDENTIAL 
3 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS ...................................................................................... 5 
1. 
INTRODUCTION............................................................................................................................. 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................... 9 
2.1 
Study Objectives .............................................................................................................................. 9 
2.1.1 
Primary Objective ................................................................................................................ 9 
2.1.2 
Secondary Objective ............................................................................................................ 9 
2.1.3 
Selected Other Secondary Objectives .................................................................................. 9 
2.1.4 
Selected Other Objectives .................................................................................................... 9 
2.1.5 
Safety Objective ................................................................................................................ 10 
2.2 
Outcomes/Endpoints ...................................................................................................................... 10 
2.2.1 
Primary Endpoint/Variable: Remission ............................................................................. 10 
2.2.2 
Key Secondary Endpoint/Variable .................................................................................... 11 
2.2.3 
Selected Other Secondary Endpoints/Variables ................................................................ 11 
2.2.4 
Selected Other Endpoints/Variables .................................................................................. 11 
2.2.5 
Safety Endpoints/Variables................................................................................................ 13 
3. 
STUDY DESIGN ............................................................................................................................ 13 
4. 
SCHEDULE OF ASSESSMENTS AND TREATMENT ASSIGNMENT .................................... 14 
4.1 
Schedule of Assessments ............................................................................................................... 14 
4.1.1 
Study Visit Schedule.......................................................................................................... 15 
4.2 
Dosage and Administration of Study Drug .................................................................................... 16 
4.3 
Subject Number ............................................................................................................................. 16 
5. 
ANALYSIS POPULATIONS ......................................................................................................... 16 
6. 
STATISTICAL METHODOLOGY................................................................................................ 17 
6.1 
Statistical and Analytical Issues .................................................................................................... 17 
6.1.1 
Statistical Methods............................................................................................................. 17 
6.1.2 
Baseline Definition ............................................................................................................ 17 
6.1.3 
Missing Data and Handling of Dropouts ........................................................................... 17 
6.1.4 
Conversion of time interval ............................................................................................... 19 
6.1.5 
Pooling of Investigator Sites .............................................................................................. 19 
6.1.6 
Rescue Medications Use .................................................................................................... 19 
6.1.7 
Determination of Sample Size ........................................................................................... 20 
6.2 
Subject Characteristics .................................................................................................................. 20 
6.2.1 
Subject Disposition ............................................................................................................ 20 
6.2.2 
Protocol Deviations ........................................................................................................... 20 
6.2.3 
Demographics and Background Baseline Characteristics.................................................. 21 
6.2.4 
Treatment Exposure and Drug Accountability .................................................................. 21 
6.2.5 
Physical Examination ........................................................................................................ 22 
6.2.6 
Medical History (excluding Crohn's disease) .................................................................... 22 
6.2.7 
Prior and Concomitant Medications and Steroids .............................................................. 22 
6.3 
Outcome Analysis.......................................................................................................................... 23 
6.3.1 
Primary Outcome Analysis ................................................................................................ 23 
6.3.2 
Key Secondary Outcome Analysis .................................................................................... 24 
6.3.3 
Selected Other Secondary Endpoints/Variables ................................................................ 24 
6.3.4 
Selected Other Endpoints/Variables .................................................................................. 25 
6.4 
Safety Analysis .............................................................................................................................. 28 
6.4.1 
Adverse Events .................................................................................................................. 28 
6.4.2 
Laboratory Parameters ....................................................................................................... 29 
6.4.3 
Vital Signs ......................................................................................................................... 30 
6.4.4 
12-Lead ECG ..................................................................................................................... 30 
6.4.5 
Uveitis Assessment ............................................................................................................ 30 


  
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Protocol No. RHB-104-04 
 
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6.5 
Changes to Statistical Analysis Methods Planned in the Protocol ................................................. 30 
7. 
ADDITIONAL OTHER EXPLOATORY ANALYSES ................................................................ 31 
8. 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 32 
8.1 
Tables, Listings and Graphs (TLFs) for Study Report................................................................... 32 
9. 
REFERENCES ................................................................................................................................ 37 
10. 
Appendix I: Subject Data Migration from RHB-104-01 to RHB-104-04 (eCRF Completion 
Guidelines - Inform) ...................................................................................................................................... 37 
Subject Migration ............................................................................................................................ 37 


 
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CONFIDENTIAL 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation  
Term 
5-ASA  
5-acetyl salicylic acid 
6-MP  
6-mercaptopurine 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase 
AST (SGOT) 
Aspartate Aminotransferase 
ATC 
Anatomical–Therapeutic–Chemical 
bid 
Twice-daily 
BPM 
Beats per Minute 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
°C                  
Celsius  
C. difficile 
Clostridium difficile 
CD 
Crohn’s Disease 
CDAI  
Crohn’s Disease Activity Index 
CDEIS 
Crohn’s Disease Endoscopic Index of Severity 
cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel 
CRA  
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP  
C-reactive Protein 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
°F 
Fahrenheit  


 
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Abbreviation  
Term 
IBD 
Inflammatory Bowel Disease 
IBDQ  
Inflammatory Bowel Disease Questionnaire 
ICF  
Informed Consent Form 
ITT 
Intent-to-Treat 
kg 
Kilogram 
L 
Liter 
lb 
Pound 
LDH 
Lactate Dehydrogenase  
MAP  
Mycobacterium avium subsp. paratuberculosis 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
n 
Number of Subjects 
Min 
Minimum 
PCR 
Polymerase Chain Reaction 
PCS 
Physical Component Summary 
QD 
Once-Daily 
QTc  
Corrected Q-T Interval 
QTcF 
Corrected Q-T Interval using Fridericia's Formula 
RHB 
RedHill Biopharma Ltd. 
RBC 
Red Blood Cell  
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SAS®  
Statistical Analysis System Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SF-36 
Short Form-36 Health Survey 


 
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7 
Abbreviation  
Term 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure 
TB  
Mycobacterium Tuberculosis 
TEAE 
Treatment-Emergent Adverse Event 
TLFs 
Tables, Listings, Figures  
TNF  
Tumor Necrosis Factor 
UK 
United Kingdom 
ULN  
Upper Limit of Normal 
US 
United States 
VF  
Ventricular Fibrillation 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO DD 
World Health Organization Drug Dictionary coding system   
 


 
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1. INTRODUCTION 
 
Crohn's Disease (CD) is an inflammatory bowel disease (IBD) that is serious, debilitating, and 
potentially life-threatening. The disease is termed a “disease of the young” because it usually 
strikes children, teens, and young adults. Typically onset is between the ages of 15 to 25 years. Its 
inflammation can cause severe pain, diarrhea, and other intestinal problems. CD affects men and 
women equally and appears to show a familial predisposition. Approximately 20-30% of people 
with CD have a direct blood relative with some form of IBD. World-wide, an estimated 1.4 
million people suffer from CD (700,000 US) and the number of sufferers is growing at a rate of at 
least 1% each year. The disease is now considered to be the second most common chronic 
inflammatory disorder after rheumatoid arthritis. 
One of the potential causes of CD is thought to be gastrointestinal infection with Mycobacterium 
avium subspecies paratuberculosis (MAP) and mycobacterial molecules have been shown to 
dysregulate immune signaling pathways as part of the organism’s evolved survival strategy. MAP 
has been difficult to isolate from CD patients and it is postulated that it asserts its pathological 
effect either as an infectious agent or by modifying local cytokine responses. 
One of the hindrances to testing for MAP infection in CD patients is that MAP is a very slow 
growing mycobacterium. MAP shed their cell walls when they infect humans, a tactic that 
enables them to escape identification and attack by human immune system defenses.  
Studies conducted to demonstrate the presence of MAP noted it in 55.4% (range 16-92%) of CD 
subjects vs. 8.2% (range of 0-49%) of control groups across multiple diagnostic specimens e.g. 
blood, tissue and culture. Recent work in Israel, Japan, and Ireland has shown that human tissue 
and white cells can be infected with MAP and this infection results in cytokine production, 
especially TNF-α and therefore indicates that MAP plays a role in CD. 
Current therapies for the treatment of CD aim towards alleviation of the disease symptoms and 
offer limited efficacy while often causing significant side effects. In addition, the cost of a 
number of these available therapies is prohibitive, thereby providing limited access to some 
patients. As a result, there continues to be a significant unmet need for more effective disease 
management of CD. 
Several studies evaluating antimicrobial treatment directed at MAP to treat patients with CD have 
been reported. Given their slow growth and periods of latency, treatment of mycobacterial 
diseases requires multiple antibiotics including triple therapy to avoid the development of 
resistance. 
RHB-104 consists of three antimicrobial agents with known activity against mycobacteria, i.e., 
clarithromycin, rifabutin, and clofazimine. The rationale for the development of RHB-104 is to 
demonstrate the efficacy of an antimicrobial therapy consisting of clarithromycin: 95mg, 
rifabutin: 45mg, and clofazimine: 10mg in the treatment of CD patients. These active ingredients 
and doses were selected to maximize therapeutic effectiveness against MAP. The dosing rationale 
of each active ingredient is supported by the following: 
• 
 prescriber information for each active ingredient 
• 
 the study by Selby et al. utilizing a sub-optimal treatment regimen 
• 
 a long-term, retrospective Australian study where 52 subjects were treated for up to nine 
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Subjects who have completed 26 weeks of blinded study drug administration in the RHB-104- 
01 study (MAP US) and remain out of remission with CDAI ≥150 will be eligible for 
participation in this study designed to offer open label therapy with active RHB-104. 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Study Objectives 
 
2.1.1 Primary Objective 
 
The primary objective is to estimate the remission rate, defined as a CDAI score of less than 150, 
at 16 weeks after the initiation of the open-label phase. 
 
2.1.2  Secondary Objective 
 
 The secondary objective is to estimate the response rate of patients, defined by a reduction of 
CDAI score of ≥100 points at week 16 after the initiation of the open-label phase. 
 
2.1.3 Selected Other Secondary Objectives 
 
1.   To estimate the average duration of remission among participants. 
2. To estimate the average time to first response among participants.  
3. To estimate the average duration of response among participants.  
4. To estimate the proportion of participants who maintain a state of remission from week 16 
through week 52.  
 
2.1.4 Selected Other Objectives 
 
MAP Detection: 
 
1.   To estimate the proportion of subjects with a MAP positive blood PCR assay at baseline 
(week 0 of the open label phase).  
2. To estimate the proportion of subjects with a change in MAP blood PCR assay status after 16 
weeks of treatment compared to baseline (week 0 of the open label phase). 
3. To estimate the proportion of subjects with a change in MAP blood PCR assay status after 52 
weeks of treatment compared to baseline (week 0 of the open label phase). 
4.   To make sequential comparisons of MAP blood PCR assay results per subject. 
5.   To estimate the proportion of enrolled subjects with a MAP positive blood culture at baseline 
(week 0 of the open label phase). 
6.   To estimate the proportion of subjects with a change in MAP blood culture status after 26 
weeks of treatment compared to baseline (week 0 of the open label phase). 
7.   To estimate the proportion of subjects with a change in MAP blood culture status after 52 
weeks of treatment compared to baseline (week 0 of the open label phase). 
 
Because the buffy coat is the actual component of blood that is cultured, MAP blood culture 
should be considered equivalent to MAP buffy coat culture. Because the development of a MAP 


 
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blood PCR assay is still in progress, MAP detection objectives 1-4 will comprise the contents of a 
later report and will not be addressed in tables, listings, or figures of this clinical study report.  
 
Endoscopic Changes in Those Subjects Who Undergo Colonoscopy: 
 
8.   To estimate the change from baseline in the mean Crohn’s Disease Endoscopic Index of 
Severity (CDEIS) after 16 and 52 weeks of treatment).  
9. To estimate the change from baseline in the total Simple Endoscopic Activity Score weeks 
(SES-CD) after 16 and 52 weeks of treatment. 
10. To make a comparison of success rates of (ΔCDEIS and SES-CD) defined by 25% and 50% 
improvements. 
11.  To estimate the correlation between the change from baseline in the endoscopic index 
(ΔCDEIS) and the clinical index (ΔCDAI) after 16 and 52 weeks of treatment.  
12.  To make a comparison of success rates of (ΔCDEIS) defined by 25% and 50% improvements 
and CDAI defined remission. 
13.  To make a comparison of success rates of (ΔCDEIS) defined by 25% and 50% improvements 
and CDAI defined response. 
14.  To make a comparison of success rates of (ΔSES-CD) defined by 25% and 50% 
improvements and CDAI defined remission. 
15.  To make a comparison of success rates of (ΔSES-CD) defined by 25% and 50% 
improvements and CDAI defined response. 
 
2.1.5 Safety Objective  
 
Assess the safety impact of treatment with RHB-104. 
 
2.2 Outcomes/Endpoints 
 
The outcome endpoints for summaries by treatment from the parent study (RHB-104 treatment 
and Placebo) and overall are grouped into 4 families based on level of objectives: (i) primary 
endpoint; (ii) key secondary endpoint; (iii) selected other secondary endpoints; and (iv) selected 
other endpoints.   
 
2.2.1 Primary Endpoint/Variable: Remission 
 
In general use of rescue medication is considered as treatment failure (not achieving remission or 
response) if there are any new use of rescue medication to treat CD or increased rescue 
medication dose from baseline prior to any remission or response assessment.  Please refer to 
section 6.1.6 for more details.  
 
The primary variable is the proportion of subjects who experienced remission at Week 16 after 
the initiation of open-label phase, where remission is defined as a subject having a Crohn’s 
Disease Activity Index (CDAI) score of <150.  Subjects who have a Week 16 CDAI 
measurement ≥ 150 or who do not have a CDAI measurement at Week 16 will be classified as not 
having achieved remission at that time point.  Initiation of open-label phase is the first dosing 
time of open-label phase and from here and after it would be reference as initiation. 
 


 
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The CDAI is used to assess the activity of CD; higher scores indicate more active disease. 
 
2.2.2 Key Secondary Endpoint/Variable 
 
The key secondary variable is the proportion of subjects who experienced response at week 16 
after initiation, where response is defined as reduction from baseline of ≥100 in CDAI score.  
Subjects who have a change from baseline to week 16 in CDAI score which is not a reduction of 
≥ 100 or who do not have a change from baseline to week 16 in CDAI score will be classified as 
not having experienced response at that time point. 
 
2.2.3 Selected Other Secondary Endpoints/Variables 
 
• 
Time to remission – Number of weeks after initiation that a subject first records a state of 
remission (CDAI score < 150). It will be calculated as the date on which remission is first 
observed minus the date of the first dosing date plus 1 day, divided by 7.  For subjects 
still on study and not achieved remission at the time of assessment, time to remission will 
be censored at the date of the last assessment of CDAI score.   
• 
Duration of remission – The number of weeks the subject is in remission (CDAI score < 
150). It will be calculated as the first date following remission at which CDAI is ≥150 
minus the date of remission, plus 1 day, divided by 7.  Those subjects who experienced 
remission and continue to be in remission at the time of their last CDAI assessment will 
be censored at the date of their last CDAI assessment. Duration of remission will be 
calculated only for patients achieving remission.  
• 
Time to response – Number of weeks after initiation that a subject first achieves a state of 
response (a reduction from baseline of ≥100 in CDAI score). It will be calculated as the 
date on which response is first observed minus the date of the first dose, plus 1 day, 
divided by 7.  For those subjects who have not experienced response, time to response 
will be censored at the date of the last assessment of CDAI score.   
• 
Duration of response – Time in weeks that a subject is in a state of response (a reduction 
from baseline of ≥ 100 in CDAI score). It will be calculated as the first date following 
response at which the reduction from baseline in CDAI is <100 minus the date of 
response, plus 1 day, divided by 7.  Those subjects who experienced response and 
continue to be in response at the time of their last CDAI assessment will be censored at 
the date of their last CDAI assessment. Duration of response will be calculated only for 
patients achieved response.  
• 
Proportion of subjects experienced maintenance of remission (CDAI score < 150) from 
week 16 through week 52.  Subjects experiencing a CDAI score ≥ 150 at any visit time 
point assessment between week 16 and week 52 or have no CDAI measurement week 16 
or week 52 will be considered as having not achieved maintenance of remission. 
 
2.2.4 Selected Other Endpoints/Variables 
 
2.2.4.1 Map Detection Endpoints/Variable 
 
Mycobacterium avium subsp. paratuberculosis (MAP) detection parameters include the following 
with baseline defined as week 0 of the open label phase: 
 


 
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• 
Proportion of subjects with positive MAP buffy coat culture at baseline, weeks 26 and 52. 
 
• 
Proportion of subjects with a change in MAP buffy coat culture after 26 and 52 weeks of 
treatment compared to baseline. 
 
 
2.2.4.2 Endoscopic Change Endpoint/Variables 
 
• 
Change from baseline to week 16 and 52 in Crohn’s Disease Endoscopic Index of 
Severity (CDEIS) and Simple Endoscopic Score for Crohn’s Disease (SES-CD). The 
CDEIS and SES-CD are endoscopic scoring systems for the assessment of CD. 
 
• 
Success rate by 25% improved in CDEIS from baseline to week 16 and 52.  Success is 
achieved if the CDEIS score is decreased by 25%. 
 
• 
Success rate by 50% improved in CDEIS from baseline to week 16 and 52. Success is 
achieved if the CDEIS score is decreased by 50%. 
 
• 
Success rate by 25% improved in SES-CD from baseline to week 16 and 52.  Success is 
achieved if the SES-CD score is decreased by 25%. 
 
• 
Success rate by 50% improved in SES-CD from baseline to week 16 and 52. Success is 
achieved if the SES-CD score is decreased by 50%. 
 
• 
Comparison of success rate of by 25% and 50% improved in CDEIS from baseline to 
week 16 and 52 vs CDAI defined remission. 
 
• 
Comparison of success rate of by 25% and 50% improved in CDEIS from baseline to 
week 16 and 52 vs CDAI defined response. 
 
• 
Comparison of success rate of by 25% and 50% improved in SES-CD from baseline to 
week 16 and 52 vs CDAI defined remission. 
 
• 
Comparison of success rate of by 25% and 50% improved in SES-CD from baseline to 
week 16 and 52 vs CDAI defined response. 
 
2.2.4.3 Health Related Quality of Life Endpoint/Variables 
 
• 
The Short Form-36 Health Survey (SF-36) domain and component scores at week 16 and 
52.   
 
• 
Change from baseline in the total IBDQ score to week 16 and 52.  Inflammatory Bowel 
Disease Questionnaire (IBDQ) score is designed to measure effects of subject’s 
inflammatory bowel disease on their daily functions and quality of life during last 2 
weeks. 
 


 
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2.2.4.4 Markers of Inflammation Endpoint/Variables 
 
Inflammation parameters include the following: 
 
• 
Change from baseline in C-reactive protein (CRP) 
• 
Change from baseline in fecal calprotectin 
 
2.2.5 Safety Endpoints/Variables 
 
Safety parameters include the following: 
 
• 
Incidence of adverse events 
• 
Laboratory parameters (hematology, chemistry, urinalysis) 
• 
Clostridium difficile toxin  
• 
Vital signs 
• 
ECG 
• 
Physical examination 
• 
Concomitant medications 
 
3. STUDY DESIGN 
 
This is an open label, multicenter, Phase III, study designed to evaluate the efficacy and safety of 
RHB-104 to treat subjects with active CD as defined by CDAI ≥ 150 despite 26 weeks of 
treatment with study drug in RedHill Biopharma Study RHB-104-01. RHB-104 consists of 3 
antibiotics with activity against Mycobacterium avium subsp. Paratuberculosis (MAP), a 
potential cause of CD. Eligible subjects with active CD who have completed 26 weeks of study 
drug as part of the RHB-104-01 study will receive up to 52 weeks of open label RHB-104. 
Subjects enrolled in the open label study may have current CD therapies adjusted or withdrawn as 
clinically indicated by their local investigator after 8 weeks of open label RHB-104 treatment. 
Sites should begin tapering steroids upon completion of 4 weeks of RHB-104 treatment with the 
goal of being steroid free by week 14 – Refer to Appendix 13 of protocol. 
 
MAP are slow growing mycobacteria without a proven antibiotic treatment, and the duration of 
antibiotic treatment required to achieve remission in subjects with CD caused by MAP is believed 
to be approximately 16-26 weeks. Subjects with response at week 26 may ultimately achieve 
remission at a later time point with continued treatment for MAP. Similarly, some subjects may 
achieve response or achieve remission prior to week 26. This study is designed to assess 
response, remission, and maintenance of remission in subjects on open label RHB-104 through 
week 52, as well as corticosteroid free remission at week 16. 
 
Blood samples will be collected at Screening and at every visit after the initial 8 weeks of 
treatment to test for MAP in the serum using a polymerase chain reaction (PCR) assay. Similarly, 
MAP cultures will be prepared from whole blood collected at Screening and at weeks 16, 26 and 
52. 
 
Safety of the fixed-dose combination product, RHB-104, will also be assessed. 
 


 
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Colonoscopy will be done in consenting subjects at baseline and after 16 and 52 weeks of open 
label RHB-104 to assess for mucosal healing as well as MAP status via PCR and culture. 
 
 
4. SCHEDULE OF ASSESSMENTS AND TREATMENT ASSIGNMENT  
 
4.1 Schedule of Assessments 
 
Appendix 1 provides reference information from eCRF guidelines about subject data migration 
from the parent study. 
 
 
The study schedule is summarized in the study visit schedule table on next page.  


 
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4.1.1 Study Visit Schedule 
 
 


 
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4.2 Dosage and Administration of Study Drug 
 
The target dose of RHB-104 is 5 capsules administered bid. In order to reach this target with 
minimal adverse effects, subjects who received placebo during the RHB-104-01 study will be 
titrated up over the first 4 weeks of treatment, and the dose will remain stable thereafter. Subjects 
who received RHB-104 will continue to receive RHB-104. In order to maintain blinding in the 
RHB-104-01 study all subjects will receive 5 blinded capsules bid for the duration of the RHB-
104-04 study as detailed below. The study drug will be taken with food. Subjects who fail dose 
escalation to 5 capsules bid will be considered treatment failures and withdrawn from the study. 
 
Blinded bid Dose Titration and Maintenance Dosing in RHB-104-04 is  
 
 
4.3 Subject Number 
 
Subjects will maintain the identification number that was assigned in RHB-104-01.    
 
5. ANALYSIS POPULATIONS 
 
All subjects who signed informed consent will be included in the disposition table counts.  
The following populations will be used for data analysis. 
 


 
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The Intent-to-Treat (ITT) Population: The ITT population is defined as all subjects who are 
enrolled in this open-label study and signed the consent form. Efficacy endpoint analyses will be 
based on ITT population or specified otherwise.  
 
The Safety Population (SAF): The safety population includes subjects who received any amount 
of study medication. The safety analyses will be based on the SAF population.   
 
6. STATISTICAL METHODOLOGY 
 
6.1 Statistical and Analytical Issues 
             
6.1.1 Statistical Methods 
 
In general, if there is disagreement between this SAP and the statistical methods outlined in the 
protocol, the SAP would supersede the protocol. 
 
Descriptive statistics summary results will be produced and presented for all the data collected on 
the different assessments that include demographics, baseline characteristics, concomitant 
medications, outcome, and safety endpoints. Continuous data summary descriptive statistics will 
include the number of observations, means, standard deviations, medians, and ranges.  
Categorical variables will be summarized with frequencies and percentages or specified 
otherwise.  
 
In the parent study, there was one randomization stratification factor, use of protocol permitted 
anti-TNF agents (yes/no).   In the current study, treatment comparisons will be performed without 
taking this stratification factor into consideration unless specified otherwise.   
 
All statistical analyses will be performed using SAS statistical software (Version 9.4 or an 
updated latest higher version available at the time of analysis).  Adverse events will be coded 
using the most recent MedDRA version available at the time of analysis. Concomitant 
medications will be coded using the most recent version of World Health Organization (WHO) 
Drug dictionary. The actual version of each dictionary will be footnoted in the respective outputs. 
 
6.1.2 Baseline Definition 
 
For subject who received any dose of study drug, baseline is the last non-missing result prior to 
first dose including the data collected during the parent study for SES-CD, CDEIS, Calprotectin, 
CRP and all lab assessment.  For subjects who are enrolled into this open-label study but never 
received any study drug, baseline is either assessment collected at baseline visit if available or 
screening visit or as specified otherwise.   
 
For fecal calprotectin, the baseline is the last available assessment up to day 3. 
 
6.1.3 Missing Data and Handling of Dropouts 
 
All available outcome and safety data will be included in data listings and tabulations.  
 


 
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CDAI Missing Data: 
 
The computation of CDAI requires 7 days of consecutive diary daily data. For subjects with 
CDAI diary data reported that is less than 7 days of data, the reported data will be standardized to 
7 days by dividing the sum of CDAI score over the number of days of data by total number of 
days of reported data multiplied by 7.  If less than 4 days of diary data is available, the subject 
will be categorized as a non-responder and the CDAI score will be considered missing. As 
specified in section 2.2, subjects with missing assessment will be assumed to not be in a state of 
remission/success for each scheduled visit (week 16, 26, or 52).   
 
Handling of missing date information for AEs: 
The term missing date refers to a completely missing date or to partial date where month or/and 
day or/and year is/are missing, e.g. missing month/day/year. Missing start and end dates will be 
imputed conservatively, i.e. missing values will be imputed in such a way that the duration of the 
AE is considered with the longest possible duration. The missing start date and end date of AE 
will be imputed for the purpose of defining treatment emergent adverse events (TEAE) and for 
assigning events to treatment periods using the following definitions:  
 
(i) Adverse Event Start Date:  
Event Missing Day: If Adverse event day is missing but month and year present, then impute the 
1st of the month unless month and year are the same as first dose of study drug then impute day 
first day of dose. 
Event Missing day and month – If adverse event day and month both are missing but year is 
present then impute 1st January unless year is the same as first dose date then impute day and 
month first dose day and month. 
Completely missing – impute first dose date unless the end date suggests it could have started 
prior to this in which case impute the 1st January of the same year as the end date.  
 
(ii) Adverse Event End Date: 
Missing day – If AE day is missing but month and year is present then impute the last day of the 
month. 
Missing day and month – If AE has missing day and month but year is present then impute 31st 
December. 
Completely Missing – Required to look at whether the AE is still ongoing before imputing a date 
and also when it started in relation to study drug. If the ongoing flag is missing then assume that 
AE is still present (i.e. do not impute a date). If the AE has stopped and start date is prior to first 
dose date then impute the 1st dose date, if it started on or after first dose date then impute a date 
that is after the last dose date. 
 
(iii) TEAE definition with missing start and stop dates: If the start date of an adverse event is 
incomplete or missing, the event will be assumed to be a treatment-emergent adverse event 
(TEAE), unless the incomplete start date (month and/or year) or the stop date (complete or 
incomplete) clearly indicates that the event started prior to dosing. Missing/incomplete 
information will be reported as missing/incomplete in the subject listings. 
 


 
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(iv) Adverse event relationship: If the relationship for an adverse event is not recorded, it will be 
assumed to be treatment related in the presentation of the statistical summary of incidence results.  
Missing information will be reported as missing in the subject listings. 
 
(v) Adverse event severity: If the severity of an adverse event is missing, the severity will be 
assumed to be severe when summarizing data. Missing information will be reported as missing in 
the subject listings. 
 
(vi) Non-study medication (concomitant medications, steroids) start and stop dates: If the start 
and/or stop dates of non-study medication use are incomplete or missing, the use will be assumed 
to be concomitant, unless the incomplete date information clearly indicates that the use stopped 
prior to study medication dosing. Missing/incomplete information will be reported as 
missing/incomplete in the subject listings. 
 
6.1.4 Conversion of time interval 
 
In case time interval was calculated in days and need to be converted into weeks, months or years 
the following conversion factors need to be used: 
 
1 week = 7 days 
1 month = 30.4 days 
1 year = 365.25 days 
 
6.1.5 Pooling of Investigator Sites 
 
All summaries and analysis will use data pooled across all investigative sites.   
 
6.1.6 Rescue Medications Use 
 
Subjects rescued with the following treatments or whose baseline doses/regimens are increased to 
treat new or unresolved CD symptoms may remain on the study drug at the discretion of the 
investigator and continue to be assessed at all scheduled study visits: 
• 
 Oral or rectal 5-ASA compounds 
• 
Azathioprine or 6-mercaptopurine (6-MP) or methotrexate 
• 
Total parenteral nutrition as treatment of CD 
• 
Systemic or rectal corticosteroid therapy 
• 
Anti-TNF or other biologic agent 
 
In analyses of remission or response, subjects who initiate new treatment or increase concomitant 
medication to treat CD symptoms will be considered as treatment failures. 
 


 
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6.1.7 Determination of Sample Size 
 
This study is anticipated to enroll 100 patients. With that number of patients, a two-sided 95% 
confidence interval (using the exact Clopper-Pearson method) will have a maximum width of 
0.203 (i.e., +/- 10.15%) conservatively assuming the measure of interest has proportion of 
successes of 50%. This confidence interval will be narrower for any other possible observed 
proportion. 
 
6.2 Subject Characteristics 
 
All subject characteristics data will be listed by subject, and summarized for the ITT population, 
except as noted otherwise. 
 
6.2.1 Subject Disposition 
 
Subject disposition will be presented for all subjects by parent study treatment group and overall 
for the ITT population. Disposition information that will be summarized will include number of 
subjects who completed the study, number who withdrew prematurely, and reasons for 
withdrawal.  
 
The number and percent of subjects in each of the following categories will be presented.   
• 
Safety population 
• 
Subjects completing weeks 16 and 52  
• 
Subjects discontinued from the study and by reason of discontinuation.  
 
6.2.2 Protocol Deviations 
 
Subjects with major protocol deviations will be identified by the medical or clinical data review 
prior to database lock. The deviations will be summarized by parent treatment group and overall 
based on the safety population. The summary will be grouped into different categories of 
violations such as below as example: 
• 
Inclusion/Exclusion Criteria Deviations  
• 
Non-compliance with study procedures 
• 
Inappropriate intake of prohibited medications 
• 
Poor compliance with study medications 
• 
Lost to follow-up 
• 
Administrative decision of investigator or sponsor 
 
Multiple deviations can occur in the same subject and thus a subject may be counted in more than 
one deviation category.   
A listing of subjects with major deviations will be presented.   
All decisions regarding major deviations will be discussed and agreed upon with the sponsor prior 
to the database lock.  
   


 
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6.2.3 Demographics and Background Baseline Characteristics 
 
6.2.3.1 Subject Demographics data. 
 
Demographics data is collected at time of screening after informed consent is obtained and 
migrated from the parent study (please refer to Appendix for details). Demographics variables 
will be summarized descriptively for ITT subjects by parent study treatment group and overall 
and will at least include the following variables: 
 
• 
Age at screening as continuous variable [Years] 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
Smoking status and alcohol consumption  
• 
BMI  
 
6.2.4 Treatment Exposure and Drug Accountability 
 
6.2.4.1 Treatment Exposure 
 
Exposure will be summarized for the SAF population. Subjects are instructed to bring their study 
medication and all empty packaging to the clinic visit. Cumulative treatment exposure per subject 
will be calculated as sum of all dosage of treatment consumed. Time on treatment (in days) will 
be calculated per subject as the number of days of study medication intake during the trial. This 
will be calculated as: 
 
Date of last study medication administration – Date of first study medication administration + 1. 
 
Dosing data will be presented descriptively by parent study treatment group and overall and also 
presented as subject data listing for the Safety population.  
 
In addition, treatment duration (RHB-104 or Placebo) of combined parent study and current study 
will be descriptively summarized by parent study treatment group. Combined treatment duration 
in weeks will also be categorically summarized displaying the number and percentage of patients 
with treatment duration by every 10 weeks and by parent study treatment group. 
 
6.2.4.2 Accountability/Compliance 
 
Drug compliance will depend upon capsule counts at each visit. Subjects are instructed to bring 
their study medication and all empty packages to each clinic visit. Compliance will be assessed 
by capsule counts recorded by each site for each subject. The details of medication used will be 
recorded and reconciled against expected medication use. Compliance will be calculated as the 
reported medication used by subject as percentage (%) of expected usage. Summary descriptive 
statistics will be presented for the number and proportion of subjects non-compliant (< 80% 
compliant) for safety population.  


 
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Extent of compliance of each subject data will be presented in subject listing for the SAF 
population. 
 
6.2.5 Physical Examination 
 
Complete physical examination is performed at screening and includes each subject’s major body 
systems: general appearance, head/eyes/ears/nose/throat, neck, lungs, heart, abdomen, 
genitourinary, extremities, neurological, skin, and lymphatics and other. Results (normal, 
abnormal and clinically significant abnormal and not clinically significant) will be tabulated for 
each body system with the number and percentage of subjects.  
 
Number of percent of subjects with significant change in physical examination from previous 
visit at baseline and subsequent post baseline visits will be summarized.  
 
6.2.6 Medical History (excluding Crohn's disease) 
 
6.2.6.1 Medical History (excluding Crohn’s disease) 
 
Pre-existing medical conditions are recorded at screening on the medical history eCRF per 
subject data migration from the parent study (please refer to Appendix for details). For each 
subject, medical history data will be presented in a data listing.  
 
6.2.6.2 Crohn’s Disease History 
 
Crohn’s disease history is recorded at screening on the history eCRF per subject data migration 
from the parent study (please refer to Appendix for details). Data including steroid status (steroid-
refractory disease or steroid-dependent disease) will be presented descriptively by parent study 
treatment group and overall and also presented as data listing. Duration of each condition is  
based on the first dose of study medications administration for the current extension study. 
 
6.2.7 Prior and Concomitant Medications and Steroids 
 
Prior medications will be defined as medications stopped prior to Day 1 of study medication. 
Concomitant medications include medications taken on or after the first dose of study medication 
as well as medications that started prior to the first dose of study medication and continued after 
the first dose of study medication. The following algorithm will be used to define prior and 
concomitant:   
 
The medication will be assumed to be prior medication if it cannot be definitively shown that the 
medication did not start or continue during the treatment period. 
If the start date or stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug. The following approach will 
be taken: 
• 
If the start date of medication is complete and occurs on or after the day of the first dose, 
the medication will be assumed concomitant.  If the start date occurs prior to the first 


 
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dose date but the end date is on or after the first dose date or the medication is recorded 
as ongoing, the medication will be considered concomitant. 
• 
If the start day is missing but the start month and year are complete, a medication will 
only be excluded as being concomitant if the start month/year is before the month/year of 
study drug administration and if the stop date (either full date, month and year if missing 
day, or year if missing month and day) is before study drug administration. 
• 
If the start day and month are missing but the start year is complete, a medication will 
only be excluded as concomitant if the start year is before the year of study drug 
administration and if the stop date (either full date, month and year if missing day, or year 
if missing month and day) is before study drug administration. 
• 
If the start date is completely missing and the stop date is prior to first dose or completely 
missing, the medication will be assumed to be a prior medication. 
 
All prior and concomitant medications recorded on CRF will be mapped to standardized terms 
using the World Health Organization Drug Dictionary coding system (WHO DD). The 
Anatomical–Therapeutic–Chemical (ATC) Classification level 2 and preferred term will be used 
to summarize the data by treatment group. A subject having the same medication more than once 
will be counted only once in the incidence table for that medication. For each ATC classification 
and Preferred Term the number and percentage of subjects will be displayed.  Summary tables 
will be presented on SAF population separately for the following: 
 
• 
Prior Medications Use for Crohn’s Disease 
• 
Prior Medications Use 
• 
Concomitant Medications Use 
• 
Prior Biological Agents Use 
• 
Concomitant Medications Use for Crohn’s Disease 
• 
Prior Steroids Use 
• 
Concomitant Steroids Use 
• 
Concomitant Steroids Use for Crohn’s Disease 
• 
Prior Antineoplastic, Immumosupressive and Biologic Use 
• 
Concomitant Antineoplastic, Immumosupressive and Biologic Use 
 
All prior and concomitant medications/treatments will be presented in a data listing with dose, 
units, frequency, route of administration, indication, start and end dates for the safety population. 
A separate Steroids use subject listing may be presented providing the steroid coded ATC 
classification, preferred term, and date. 
 
Any concomitant procedures recorded on CRF will be presented in a data listing with procedure 
name, date and reason. 
  
6.3 Outcome Analysis 
 
The outcome analyses will be based on all ITT subjects.  
 
6.3.1  Primary Outcome Analysis 
 


 
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The primary outcome variable is the proportion of subjects experienced remission at week 16. 
95% exact Clopper-Pearson confidence interval (CI) of the proportion of remission will be 
provided within each parent study treatment group and overall, as well as subgroup by anti-TNF 
agent use. Parent study treatment comparison will be performed using Fisher’s exact test.   
 
For the above primary analysis, subjects with a missing week 16 CDAI will be treated as not 
achieving remission.  As a sensitivity analyses, the same analyses will be performed without 
imputation, i.e. subjects with missing week 16 CDAI will not be imputed, therefore it will be 
missing and excluded from analysis. 
 
Logistic regression modeling will be implemented as additional exploratory analysis to assess 
relationships between the primary outcomes and putative effect modifiers. The putative effect 
modifiers include the following patient level biomarker assessment: 
 
• 
Baseline serum inflammation marker: C-reactive protein (CRP ≥ 2.87 vs. < 2.87 mg/dL)  
• 
Baseline stool inflammation marker: Fecal calprotectin (≥ 250 vs. < 250 mcg/g) 
• 
Baseline SES-CD≥6, Fecal calprotectin ≥ 250 mcg/g or CRP≥ 2.87 mg/dL: Yes vs. No  
 
The logistic regression model includes remission at week 16 (yes/no) as a function of parent 
study treatment by baseline biomarker factor. The aim is to identify if the effect of each baseline 
biomarker factor has significant effect on remission outcome. The analysis will be performed to 
compare parent study treatment groups. Odds ratio of remission rate (parent study treatment 
RHB-104 vs. placebo) and 95% CI will be presented using a Forest plot for each baseline 
biomarker level.  Similar plots will be provided for week 16 response and week 52 remissions.  
 
6.3.2 Key Secondary Outcome Analysis 
 
The key secondary outcome variable is the proportion of subjects experienced response at week 
16.  95% exact Clopper-Pearson confidence interval (CI) of the proportion of responders will be 
provided within each parent study treatment group and overall, as well as subgroup by anti-TNF 
agent use. Parent study treatment comparison will be performed using Fisher’s exact test.   
 
The same logistic regression analysis as the primary output variable will also be performed. 
 
6.3.3 Selected Other Secondary Endpoints/Variables 
 
6.3.3.1 Time to Event Endpoints/Variables Analysis 
 
The Time to event endpoints that will be analyzed includes:  
• 
Time to remission 
• 
Duration of remission 
• 
Time to response 
• 
Duration of response 
 
Kaplan Meier survival curves and parameters showing time-to-first observed response outcome 
will be summarized by parent study treatment, by anti-TNF use and overall. Summary statistics 
that will be presented will include minimum, maximum, the 25th and 75th percentiles, 95% 


 
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confidence intervals on the median (using the method of Brookmeyer and Crowley), and 
proportion of the events and censored data.  Parent study treatment comparison will be performed 
using log-rank test.   
 
Kaplan-Meier plots with descriptive summary statistics will be presented.  
 
6.3.3.2 Remission from Week 16 through week 52 
 
Number and proportion of subjects experiencing maintenance of remission (CDAI score < 150) 
from week 16 through week 52 and the number and proportion of subjects experiencing remission 
at week 16 and week 52 will be provided within each parent study treatment group and overall, as 
well as subgroup by anti-TNF agent use.  95% exact Clopper-Pearson confidence interval (CI) for 
the proportion will also be presented. Parent study treatment comparison will be performed using 
Fisher’s exact test.   
 
In addition, similar summaries will be provided for remission at week 52 overall and for subjects 
who achieved remission at week 16 
 
Proportion of subjects who achieved the following response will be provided overall and by 
parent study treatment: 
 
Remission at week 16 plus 50% reduction in CRP or calprotectin from baseline 
Remission at week 52 plus 50% reduction in CRP or calprotectin from baseline 
 
6.3.4 Selected Other Endpoints/Variables 
 
6.3.4.1 MAP Buffy Coat culture 
 
All summaries will be done by parent study treatment and overall.   
 
Number and percent of subjects will be summarized for MAP buffy coat culture 
(positive/negative) by scheduled visit (baseline, weeks 16, 26 and 52), 95% exact Clopper-
Pearson confidence interval (CI) will be provided for the proportion of positive MAP buffy coat 
culture. 
 
Shift table from baseline to each post baseline visit (weeks 16, 26 and 52) will be summarized.   
 
6.3.4.2 Endoscopic Assessment Based on CDEIS and SES-CD  
 
The Crohn’s Disease Endoscopic Index of Severity (CDEIS) is a validated quantitative measure 
of disease severity upon endoscopy. The score ranges from 0-44 based upon the extent and 
severity of inflammation and ulcers seen during endoscopy of the colony. A response is a 
decrease in score from baseline. 
 
The Simple Endoscopic Score for Crohn’s Disease (SES-CD) is a validated quantitative measure 
of disease severity upon endoscopy that is based on four endoscopic variables (presence and size 
of ulcers, extent of ulcerated surface, extent of affected surface, and presence of narrowing). Each 


 
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variable is assessed in each of the five ileocolic segments: rectum, sigmoid and left colon, 
transverse colon, right colon, and ileum. Each of the four SES-CD variables is scored from 0 to 3, 
with the sum of the scores for each variable ranging from 0 to 15 (Total SES-CD score range 0–
60). 
 
CDEIS data are presented in data listing only.  
 
The SES-CD total scores by visit (baseline and weeks 16 and 52) and change from baseline 
scores to week 16 and 52 will be summarized descriptively for subjects who consent to undergo 
colonoscopy by parent study treatment and overall. The summary statistics include number of 
observations, mean with 95% CI, standard deviation, median, inter-quartile ranges, minimum, 
and maximum. 
 
Number and proportion of subjects who achieved success defined below and corresponding 95% 
exact Clopper-Pearson CI for the proportion will be provided.  
 
• 
by 25% improved in SES-CD from baseline to week 16 and 52.  Success is achieved if 
the SES-CD score is decreased by 25%. 
 
• 
by 50% improved in SES-CD from baseline to week 16 and 52. Success is achieved if the 
SES-CD score is decreased by 50%. 
 
Paired response between each of above defined improvement and corresponding CDAI remission 
(<150) at each visit will be compared using exact McNemar’s test.  Similarly, paired response 
between each of above defined improvement and corresponding CDAI response (>=100% 
decrease from baseline) at each visit will be compared using exact McNemar’s test. 
 
6.3.4.3 Quality of Life Assessment: SF-36 Questionnaire Total Score 
 
The SF-36 Health Survey is a self-administered, 36-item questionnaire designed to measure 8 
domains of functional health status and well-being. For this study, the questionnaire data is 
collected at baseline, week 26 and week 52. The SF-36 instrument guidelines will be used to 
assess and summarize the overall health status. The SF-36 consists of 8 scaled scores with range 
0-100 with higher score indicating better health. The 8 sections or domains are: 
 
• 
Vitality 
• 
Physical functioning 
• 
Bodily Pain 
• 
General Health Perceptions 
• 
Physical Role Functioning 
• 
Emotional Role Functioning 
• 
Social Role Functioning 
• 
Mental Health 
 
There are also two component scores. The Physical Component Summary Score is a composite of 
the Physical Functioning, Role Functioning, Bodily Pain and General Health scales. The Mental 


 
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Health Component Summary Score is a composite of the Vitality, Social Functioning, Role-
Emotional and Mental Health scales.   
 
All above-mentioned domain and component scores will be provided by QualityMetric and will 
be presented for data listings.  
 
6.3.4.4 Inflammatory Bowel Disease Questionnaire (IBDQ) Score 
 
IBDQ is used to assess IBD status. IBDQ is a valid and reliable quality of life instrument that 
incorporates social, systemic and emotional symptoms together with bowel-related symptoms 
into activity index. The IBDQ includes 32 questions on 4 areas of health-related quality of life:  
 
Bowel Systems (10 questions: 1, 5, 9, 13, 17, 20, 22, 24, 26, 29),  
Emotional Health Function (12 questions: 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32),  
Social Function (5 questions: 4, 8, 12, 16, 28), and  
System Function (5 questions: 2, 6, 10, 14, 18). Each item is rated on 7-point Likert scale (higher 
scores equate to higher quality of life).  
 
A total IBDQ score is calculated as sum of all 32 scores and the total ranges from 32 to 224. If 
more than 4 questions are missing, then total scores will not be calculated.  If 4 or fewer questions 
are missing, then missing questions will be imputed by the mean of the rest of available question 
scores. 
 
Summary descriptive statistics including number of observations, mean with 95% CI, standard 
deviation, median, inter-quartile ranges, minimum, and maximum will be presented in tables and 
bar graph for the actual and change from baseline scores for IBDQ total score by scheduled visits 
(week 16 and week 52).  The summaries will be done by parent study treatment and overall.  
 
6.3.4.5 Serum Marker of Inflammation: C-reactive Protein (CRP)  
 
The CRP is used as marker of inflammation. The CRP level data collected at baseline, week 16, 
26, 39 and 52 will be used to assess inflammation at baseline and at different visits post-baseline. 
Summary descriptive statistics for the actual observed and change from baseline will include 
mean with 95% CI, standard deviation, median, inter-quartile ranges and range for each parent 
study treatment and overall by visit.   
 
In addition, the CRP level will be classified into two categories: “Normal (≤ 0.999 mg/dL)” and 
“High (> 0.999 mg/dL)”.  Summary results will show number of patients and proportion (%) 
along with 95% exact Clopper-Pearson CI with “Normal level” and with “High Level” by parent 
study treatment group and overall by visit.  Shift tables from baseline to each post baseline visit 
will also be presented.  
 
6.3.4.6 Stool Marker of Inflammation: Fecal calprotectin  
 
The fecal calprotectin is used as marker of inflammation. The level of fecal calprotectin data 
collected at different visits will be used to assess inflammation at baseline and at different visits 
post-baseline (weeks 16, 26 and 52). Summary descriptive statistics for the actual observed and 


 
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change from baseline will include mean with 95% CI, standard deviation, median, inter-quartile 
ranges and range for each parent study treatment group and overall by visit.  
 
In addition, fecal calprotectin will be classified into two categories: “Normal (≤ 162.9 mcg/g)” 
and “High (> 162.9 mcg/g)”.  Summary results will show number of patients and proportion (%) 
along with 95% exact Clopper-Pearson CI with “Normal level” and with “High Level” by 
treatment group by visit. In addition, shift tables from baseline to each post baseline visit will also 
be presented.  
 
6.3.4.7 Additional Endpoints: CDAI score and PRO-2  
 
PRO-2 is defined as 7 x (mean daily number of liquid or very soft stools) + 7 x (mean daily 
abdominal pain score) based on CDAI assessment. CDAI and PRO-2 scores will be summarized 
descriptively by visit.    
 
6.4 Safety Analysis 
 
All summarization of safety data will be based on the safety population by parent study treatment 
group and overall. 
 
6.4.1 Adverse Events 
 
Each verbatim adverse event (AE) term recorded during the study will be mapped to a system 
organ class and preferred term using the current MedDRA Dictionary.  
 
A treatment-emergent AE (TEAE) is defined as an AE that based on start date information 
occurred after the first study drug administration or an AE that started before the first study drug 
administration but worsened in severity (i.e., became more severe) after administration of the 
study drug.  
 
Treatment related adverse events will be defined as the adverse events for which the investigator 
indicates the relationship to study drug as possible, probable, or definite. If the relationship to 
study drug for an AE is not recorded, it will be assumed to be treatment related in the summary 
tables. Similarly, if severity of an AE is missing, the severity will be summarized as severe. 
 
A by-subject listing of all AEs (including non-treatment-emergent AEs) will be provided and will 
include all AE data recorded on the eCRF. All summaries of AEs will present the number and 
percent of subjects reported events by system organ class and preferred term and by treatment 
group. If a subject has multiple occurrences of an AE, the subject will be counted only once in the 
respective AE. 
 
For summaries of adverse events by maximum severity or maximum relationship, if a subject has 
multiple occurrences of an AE, the subject will be counted only once for the respective Preferred 
Term at the maximum severity or maximum relationship. 
 


 
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An overall summary table by treatment and overall of AEs, SAEs, TEAEs, Serious TEAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs leading to study discontinuation and 
study deaths will be provided using number and % of subjects. 
 
Summary tables by treatment and overall will be provided by SOC and preferred term for each of 
the following types of AEs: 
• 
All Treatment emergent AEs  
• 
Study Drug related treatment emergent AEs 
• 
Treatment emergent AEs by maximum severity 
• 
Treatment emergent AEs leading to study discontinuation 
• 
Serious Treatment emergent AEs (SAEs) 
• 
Treatment-related serious AEs  
• 
Treatment emergent AEs leading to Death 
 
The following listings will be provided: 
• 
All AEs 
• 
Treatment related AEs 
• 
AEs leading to study discontinuation 
• 
SAEs 
• 
Deaths 
 
All study deaths will be listed using date and cause of death along with autopsy results as entered 
on the Death CRF.  
 
6.4.2 Laboratory Parameters 
 
Laboratory assessments will include: 
 
Biochemistry:  total protein, gamma glutamyl transferase (GGT ), lactate dehydrogenase (LDH), 
sodium, potassium, chloride, magnesium, glucose, total bilirubin, AST(SGOT), ALT(SGPT), 
alkaline phosphatase, amylase, albumin, BUN, calcium, creatinine, uric acid, HCO3, total 
cholesterol, creatinine phosphokinase, and inorganic phosphorous. 
 
Hematology:  RBC count, hemoglobin, hematocrit, platelet count, WBC count, WBC differential. 
 
Urinalysis: Pregnancy, pH (dipstick), specific gravity (dipstick), glucose (dipstick), protein 
(dipstick), ketones (dipstick), blood (dipstick), Nitrites, Leucocytes and sediment microscopy if 
indicated by the dipstick. 
 
Laboratory results will be presented in listings in measured units and summaries in conventional 
units.  
 
Continuous laboratory values will be summarized descriptively by treatment group over time for 
each visit and as change from baseline to each visit. Categorical laboratory values will be 
summarized as the number and percentages of subjects in each category by treatment group over 
time for visit. 
 


 
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Laboratory parameters will also be summarized in shift tables by treatment, to determine the 
number and percentage of subjects with measurements classified in a particular category at each 
post-baseline visit with reference to the same classification at baseline.  Biochemistry and 
hematology parameters (which are continuous in nature) will use the classifications of low, 
normal, and high relative to normal ranges, whereas appropriate categories will be selected for 
urinalysis parameters (which are categorical in nature), for example, normal and abnormal. 
 
Subjects missing a value at any time point will be excluded from the summary statistics for that 
time point. If a subject has more than one value at any time point, then the latest non missing 
value will be used for summarization. All values will be presented in the data listings.  
 
Listings of all individual laboratory data, indicating any values out of the normal range will be 
produced. A listing of lab parameter values flagged as abnormal will also be provided.   
 
6.4.3  Vital Signs    
 
Vital signs include the following: 
• 
Supine systolic blood pressure (SBP)  
• 
Supine diastolic blood pressure (DBP)  
• 
Supine pulse rate  
• 
Respiratory rate  
• 
Temperature 
• 
Height  
• 
Weight 
• 
BMI 
 
Vital signs are recorded at baseline and at different visits post-baseline. Actual and change from 
baseline values will be summarized using descriptive statistics by visit and treatment group. The 
mean, standard deviation, median, and range will be used to summarize the data. For each 
subject, vital signs data will be presented in a data listing. 
 
6.4.4 12-Lead ECG 
 
Study investigators will record each subject ECG data. The significance and interpretation of each 
ECG finding and assessments of the QTc and other ECG intervals will be made by the ECG 
specialized Lab. All ECG data will be presented in the subject data listings with annotations 
indicating any abnormal values.  For analysis details and presentation of the ECG findings, a 
specialized independent technical report will be produced by different specialized expert.   
 
6.4.5 Uveitis Assessment  
 
Results from Uveitis assessments will be listed and summarized as the number and percentage of 
subjects with Uveitis suspected (yes or no), and if suspected, with Uveitis confirmed (yes or no). 
 
6.5 Changes to Statistical Analysis Methods Planned in the Protocol 
 


 
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Because the buffy coat is the actual component of blood that is cultured, MAP blood culture 
should be considered equivalent to MAP buffy coat culture. Because the development of a MAP 
blood PCR assay is still in progress, MAP detection objectives 1-4 will comprise the contents of a 
later report and will not be addressed in tables, listings, or figures of this clinical study report.  
 
Change from baseline in the Short Form-36 Health Survey (SF-36) total score have been removed 
to be consistent with parent study.  Summary of domains are removed in SAP. 
 
Correlations between the change from baseline in SES-CD and the change from baseline in CDAI 
to week 16 and 52 are not included in SAP. 
 
 
7. ADDITIONAL OTHER EXPLOATORY ANALYSES 
 
Other exploratory subgroup analyses to characterize safety and efficacy activities of HRB-104 
may be conducted. These additional exploratory analyses will be decided at the time of final data 
analysis if deemed necessary. 
 
   


 
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8. TABLES, LISTINGS, AND FIGURES 
 
The intended layouts for unique summary tables, listings, and figures (TLFs) are presented in a 
separate document. However, it may be necessary to change the table layouts, as appropriate, 
upon review of the data available without modifying the SAP text.   
 
8.1 Tables, Listings and Graphs (TLFs) for Study Report   
 
List of Tables and Graphs: 
 
Table Number 
Title 
Analysis Populations and Disposition 
Table 14.1.1.1 
Subject Disposition: All screened subjects 
Table 14.1.1.2 
Major Protocol Deviations: Safety Population 
 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
Demographics and Baseline Characteristics: : Intent-to-Treat Population 
Table 14.1.2.2 
Physical Examination at Baseline: Safety Population 
 
Medical History 
Table 14.1.3 
Crohn's Disease History: Safety Population 
 
Prior and Concomitant Medications 
Table 14.1.4.1 
Prior Medications Use: Safety Population 
Table 14.1.4.2 
Concomitant Medications Use: Safety Population 
 
Treatment Exposure and Compliance  
Table 14.1.5.1 
Study Drug Exposure: Safety Population 
Table 14.1.5.2 
Treatment Compliance: Safety Population 
Table 14.1.5.3 
Combined Study Drug Exposure with Parent Study: Safety Population 
 
Primary and Key Secondary Outcome Endpoint 
Table 14.2.1.1 
Primary Endpoint - Remission at Week 16: Intent-to-Treat Population 
Table 14.2.1.2.1 
Remission at Week 16 for Subjects with Baseline SES-CD ≥ 6 or 
Calprotectin(mcg/g)≥ 250 or CRP(mg/dL) ≥ 2.87: Intent-to-Treat Population 
Table 14.2.1.2.2 
Remission at Week 16 and at least 50% Reduction in CRP or Calprotectin from 
Baseline: Intent-to-Treat Population: Intent-to-Treat Population 
Table 14.2.1.2.3 
Remission at Week 16 and at least 50% Reduction in CRP or Calprotectin from 
Baseline for Subjects with Baseline SES-CD ≥ 6 or Calprotectin(mcg/g)≥ 250 or 
CRP(mg/dL) ≥ 2.87: Intent-to-Treat Population 
Table 14.2.1.2.4 
Remission at Week 16 by Baseline MAP Buffy Coat Culture Status : Intent-to-
Treat Population 
Table 14.2.1.2.5 
Remission at Week 16 by Week 16 MAP Buffy Coat Culture Status: Intent-to-
Treat Population 


 
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Table 14.2.1.3 
Sensitivity Analysis - Remission at Week 16: Intent-to-Treat Population 
Table 14.2.2 
Key Secondary Endpoint - Response at Week 16: Intent-to-Treat Population 
Figure 14.2.1.1 
Forest Plots of Week 16 Remission Odds Ratio of Parent Study Treatment RHB-
104 vs Place by Selected Baseline Biomarker Categories: Intent-to-Treat 
Population  
Figure 14.2.2 
Forest Plots of Week 16 Response Odds Ratio of Parent Study Treatment RHB-
104 vs Place by Selected Baseline Biomarker Categories: Intent-to-Treat 
Population 
 
Selected Other Secondary Outcome Endpoints 
Table 14.2.3.1 
Remission from Week 16 to Week 52: Intent-to-Treat Population 
Table 14.2.3.2 
Remission at Week 16 and Week 52: Intent-to-Treat Population 
Table 14.2.3.3.1 
Remission at Week 52: Intent-to-Treat Population 
Figure 14.2.3.3.1 
Forest Plots of Week 52:Remission Odds Ratio of Parent Study Treatment RHB-
104 vs Place by Selected Baseline Biomarker Categories: Intent-to-Treat 
Population 
Table 14.2.3.3.2 
Remission at Week 52 for Subjects with Baseline SES-CD ≥ 6 or 
Calprotectin(mcg/g) ≥ 250 or CRP (mg/dL) ≥ 2.87 
Intent-to-Treat Population 
Table 14.2.3.3.3 
Remission at Week 52 and at least 50% Reduction in CRP or Calprotectin from 
Baseline: Intent-to-Treat Population: Intent-to-Treat Population 
Table 14.2.3.3.4 
Remission at Week 52 and at least 50% Reduction in CRP or Calprotectin from 
Baseline for Subjects with Baseline SES-CD ≥ 6 or Calprotectin(mcg/g)≥ 250 or 
CRP(mg/dL) ≥ 2.87: Intent-to-Treat Population 
Table 14.2.3.3.5 
Remission at Week 52 by Baseline MAP Buffy Coat Culture Status: Intent-to-
Treat Population 
Table 14.2.3.3.6 
Remission at Week 52 by Week 52 MAP Buffy Coat Culture Status: Intent-to-
Treat Population 
Table 14.2.4.1 
Time to Remission: Intent-to-Treat Population 
Table 14.2.4.2 
Duration of Remission: Intent-to-Treat Population 
Table 14.2.4.3 
Time to Response: Intent-to-Treat Population 
Table 14.2.4.4 
Duration of Response: Intent-to-Treat Population 
Figure 14.2.4.1 
Time to Remission Kaplan Meier Survival Curve: Intent-to-Treat Population 
Figure 14.2.4.2 
Duration of Remission Kaplan Meier Survival Curve: Intent-to-Treat Population 
Figure 14.2.4.3 
Time to Response Kaplan Meier Survival Curve: Intent-to-Treat Population 
Figure 14.2.4.4 
Duration of Response Kaplan Meier Survival Curve: Intent-to-Treat Population 
 
Selected Other Secondary Outcome Endpoints 
Map PCR Blood Assay and MAP Blood Culture 
Table 14.2.5.1 
Summary of MAP Buffy Coat Culture by Visit: Intent-to-Treat Population 
Table 14.2.5.2 
Shift in MAP Buffy Coat Culture from Baseline to Weeks 16, 26 and 52 
 
Endoscopic Assessments 
Table 14.2.6.1 
Baseline and Change from Baseline to Weeks 16 and 52 in SES-CD Total Scores: 
Intent-to-Treat Population 
Table 14.2.6.2 
Endoscopic Response: 25% reduction in SES-CD Total Score from baseline to 


 
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weeks 16 and 52: Intent-to-Treat Population 
Table 14.2.6.3 
Endoscopic Response: 50% reduction in SES-CD Total Score from baseline to 
weeks 16 and 52: Intent-to-Treat Population 
 
Quality of Life Assessment 
Table 14.2.7 
Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Baseline, Week 16 
and Week 52: Intent-to-Treat Population 
Figure 14.2.7.1 
Bar Graphs of IBDQ Total Score at Baseline,  26 and 52 weeks by Treatment 
group: Intent-to-Treat Population 
Figure 14.2.7.2 
Bar Graphs of IBDQ Sub Score at Baseline,  26 and 52 weeks by Treatment 
group: Intent-to-Treat Population 
 
Inflammation Assessment 
Table 14.2.8.1.1 
Summary Serum Marker of Inflammation (CRP) Level: Intent-to-Treat 
Population 
Table 14.2.8.1.2 
Summary Stool Marker of Inflammation Level - Fecal calprotectin: Intent-to-
Treat Population 
Table 14.2.8.2.1 
Proportion of subjects  with CRP Marker of Inflammation Normal/High by Visit: 
Intent-to-Treat Population 
Table 14.2.8.2.2 
Proportion of subjects  with Fecal calprotectin Normal/High by Visit : Intent-to-
Treat Population 
Table 14.2.8.3.1 
Shift  in Serum Marker of Inflammation (CRP)  Status Normal/High from 
Baseline to Weeks 16, 26, 39 and Week 52: Intent-to-Treat Population 
Table 14.2.8.3.3 
Shift  in Stool Marker of Inflammation (Fecal calprotectin) Status Normal/High 
from Baseline to Weeks 16, 26 and Week 52 : Intent-to-Treat Population 
 
Additional endpoints 
Table 14.2.9.1 
Summary of CDAI Score by Visit: Intent-to-Treat Population 
Table 14.2.9.2 
Summary of PRO-2 Score by Visit: Intent-to-Treat Population 
 
Adverse Events 
Table 14.3.1.1.1 
Adverse Events Incidence Summary: Safety Population 
Table 14.3.1.1.2 
Adverse Events Incidence Summary by Anti-TNF Use: Safety Population 
Table 14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term: Safety Population 
Table 14.3.1.2.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
by Anti-TNF Use: Safety Population 
Table 14.3.1.2.3 
Summary of Treatment-emergent Adverse Events Occurring in at Least 5% of 
Subjects by System Organ Class and Preferred Term in Descending Frequency  
Table 14.3.1.2.4 
Summary of Treatment Related Treatment-emergent Adverse Events Occurring 
in at Least 5% of Subjects by System Organ Class and Preferred Term in 
Descending Frequency  
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Relationship to Study Medication: Safety Population 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity: Safety Population 


 
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Table 14.3.1.5 
Treatment-Emergent Adverse Events Leading to Study  Discontinuation by 
System Organ Class and Preferred Term: Safety Population 
Table 14.3.1.6 
Treatment-Emergent Serious Adverse Events by System Organ Class and 
Preferred Term: Safety Population 
Table 14.3.1.7 
Treatment-Emergent Serious Adverse Events by System Organ Class, Preferred 
Term, and Maximum Relationship to Study Drug: Safety Population 
Table 14.3.2.1 
Listing of Subjects with Adverse Events that Led to Death: Safety Population 
Table 14.3.2.2 
Listing Subjects with Treatment-Emergent Serious Adverse Events: Safety 
Population 
Table 14.3.2.3 
Listing Subjects with Adverse Events that Led to Study Discontinuation or Study 
Drug Interruption: Safety Population 
Table 14.3.2.4 
Listing of Subjects with Treatment-Emergent Adverse Events Related to Study 
Drug: Safety Population 
Table 14.3.2.5 
Listing of Deaths: Safety Population 
 
Labs Assessments 
Table 14.3.4.1 
Biochemistry Laboratory Data – Observed and Change from Baseline: Safety 
Population 
Table 14.3.4.2 
Biochemistry Laboratory Data – Shift from Baseline: Safety Population 
Table 14.3.4.3 
Hematology Laboratory Data – Observed and Change from Baseline: Safety 
Population 
Table 14.3.4.4 
Hematology Laboratory Data – Shift from Baseline: Safety Population 
Table 14.3.4.5 
Urinalysis Laboratory Data – Observed and Change from Baseline: Safety 
Population 
Table 14.3.4.6.1 
Urinalysis Laboratory Data – Shift from Baseline – Numerical Tests: Safety 
Population 
Table 14.3.4.6.2 
Urinalysis Laboratory Data – Shift from Baseline – Categorical Tests: Safety 
Population 
 
Other Safety Assessments 
Table 14.4.1 
Vital Signs – Observed and Change from Baseline by Visit: Safety Population 
Table 14.4.2 
Summary of Uveitis Assessment by Visit: Safety Population 
 
Listings: 
 
Listing Number 
Title 
Listing 16.2.1.1 
Subject Disposition and End of Participation in the Trial: Intent-to-Treat 
Population 
Listing 16.2.1.2 
Inclusion and Exclusion Criteria: Intent-to-Treat Population 
Listing 16.2.2 
Major Protocol Deviations: Intent-to-Treat Population 
Listing 16.2.3 
Analysis  Populations: Intent-to-Treat Population 
Listing 16.2.4.1 
Demographics and Baseline Disease Characteristics: Intent-to-Treat 
Population 
Listing 16.2.4.2 
Crohn's Disease History: Intent-to-Treat Population 
Listing 16.2.4.3 
Medical History (excluding Crohn's disease): Intent-to-Treat Population 


 
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Listing 16.2.4.4 
Surgical History of Crohn's disease: Intent-to-Treat Population 
Listing 16.2.4.5 
Prior Biological Agents Use: Intent-to-Treat Population 
Listing 16.2.4.6 
Prior Alcohol Consumption and Tobacco Use: Intent-to-Treat 
Population 
Listing 16.2.4.7 
Prior and Concomitant Medications Use: Intent-to-Treat Population 
Listing 16.2.4.8 
Prior and Concomitant Steroids Use: Intent-to-Treat Population 
Listing 16.2.4.9 
Crohn’s Disease Prior and Concomitant Medications: Intent-to-Treat 
Population 
Listing 16.2.4.10 
Concomitant Procedures: Intent-to-Treat Population 
Listing 16.2.5.1 
Drug Exposure and Compliance: Intent-to-Treat Population 
Listing 16.2.5.2 
Drug Administration: Intent-to-Treat Population 
Listing 16.2.6.1 
Crohn’s Disease Activity Index (CDAI) Score: Intent-to-Treat 
Population 
Listing 16.2.6.2 
Remission and Response Parameters: Intent-to-Treat Population 
Listing 16.2.6.3 
SF-36 Questionnaire Domain and Component Scores: Intent-to-Treat 
Population 
Listing 16.2.6.4 
Inflammatory Bowel Disease Questionnaire (IBDQ) Score: Intent-to-
Treat Population 
Listing 16.2.6.5 
Inflammation Assessment – CRP marker  
Listing 16.2.6.6 
Inflammation Assessment – Fecal calprotectin 
Listing 16.2.6.7 
Endoscopic Assessment – CDEIS: Intent-to-Treat Population 
Listing 16.2.6.8 
Endoscopic Assessment – SES-CD: Intent-to-Treat Population 
Listing 16.2.6.9 
MAP Detection: Intent-to-Treat Population 
Listing 16.2.7.1 
Adverse Events: Safety Population 
Listing 16.2.8.1 
Laboratory Assessments -: Biochemistry: Safety Population 
Listing 16.2.8.2 
Laboratory Assessments – Hematology: Safety Population 
Listing 16.2.8.3 
Laboratory Assessments - Urinalysis: Safety Population 
Listing 16.2.9.1 
Stool Samples - C. Difficile Toxin: Safety Population 
Listing 16.2.9.2 
Urine Pregnancy Test: Safety Population 
Listing 16.2.9.3 
Uveitis Assessment: Safety Population 
Listing 16.2.9.4.1 12-Lead ECG (Part 1): Safety Population 
Listing 16.2.9.4.2 12-Lead ECG (Part 2): Safety Population  
Listing 16.2.9.4.3 12-Lead ECG (Part 3): Safety Population 
Listing 16.2.9.5 
Vital Signs: Safety Population 
Listing 16.2.9.6.1 Physical Examination at Screening: Safety Population 
Listing 16.2.9.6.2 Physical Examination Significant Change from Previous Visit: Safety 
Population 
Excel Listing 
List of Drug Exposure - combined 01 and 04 
 


 
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9. REFERENCES 
 
1.   International Conference of Harmonization (ICH) E9 Expert Working Group. Statistical 
Principles for Clinical Trials: ICH Harmonized Tripartite Guideline. (1999) Statistics in 
Medicine; 18:1905–1942. 
2.   SAP for the parent study RHB-104-01. 
 
10. Appendix I: Subject Data Migration from RHB-104-01 to RHB-104-04 (eCRF 
Completion Guidelines - Inform) 
 
Subject Migration  
There are two types of migration, Partial and Full.  Subjects who complete the 
optional screening visit receive a Partial data migration.  Subjects who did not 
complete the optional screening visit receive a full migration.  Data migrated from 
RHB-104-01 to RHB-104-04 will be frozen upon migration.  Fields that will not be 
frozen are fields that will need to be completed during the course of the study. 
Partial Migration (subject completes optional screening visit) 
The only visit folders that will receive migrated data are Screening and Log Pages. 
The following is a list of folders/forms that will receive migrated data. 
Visit 
Form 
Screening 
Demographics 
Screening 
Crohn's Disease History 
Screening 
Medical History 
Screening 
Surgical History for Crohn's Disease 
Log Pages 
Adverse Events 
• Only adverse events that are ongoing at time of migration will be migrated 
from RHB-104-01 to RHB-104-04. 
Log Pages 
Concomitant Medications 
• Only concomitant medications that are ongoing at time of migration will be 
migrated from RHB-104-01 to RHB-104-04. 
After subject/data migration is complete any forms in the Screening visit that are 
marked as not started or incomplete require data entry to be completed. 
Full Migration (subject does not complete optional screening visit) 
The only visit folders that will receive migrated data are Screening and Log Pages. 


 
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The following is a list of folders/forms that will receive migrated data. 
Visit 
Form 
Screening 
Date of Visit 
Screening 
Demographics 
Screening 
Crohn's Disease History 
Screening 
Medical History 
Screening 
Surgical History for Crohn's Disease 
Screening 
Vital Signs Screening 
Screening 
Uveitis Assessment 
Screening 
12-Lead ECG 
Screening 
Urine Pregnancy Test   **(Only for Female subjects) 
Screening 
Urine Dipstick 
Screening 
Laboratory sample collection 
Screening 
MAP Testing 
Screening 
MAP Culture 
Screening 
Crohn's Disease Activity Index Diary 
Screening 
Crohn's Disease Activity Index (CDAI) 
Screening 
Inflammatory Bowel Disease Questionnaire 
Screening 
Short Form-36 Health Survey 
Screening 
Stool samples 
Log Pages 
Adverse Events 
• Only adverse events that are ongoing at time of migration will be migrated 
from RHB-104-01 to RHB-104-04. 
Log Pages 
Concomitant Medications 
• Only concomitant medications that are ongoing at time of migration will be 
migrated from RHB-104-01 to RHB-104-04. 
After subject/data migration is complete any forms in the Screening visit that are 
marked as not started or incomplete require data entry to be completed.