Clinical trial NCT01951326
Conditions: Crohn's Disease
Keywords: Crohn's Disease moderate to severe remission MAP antibiotic
Sponsor: RedHill Biopharma Limited
Start date: 2013-09-01; Completion date: 2019-08-01
Enrollment: 331 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators hypothesize that RHB-104 will have greater efficacy than placebo in Crohn's disease.

Detailed description:
A 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.

Arms: arm 1: 5 RHB-104 capsules administered orally BID arm 2: 5 placebo capsules administered orally BID
Interventions: intervention 1: RHB-104 intervention 2: Placebo
Intervention descriptions: intervention 1: 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine intervention 2: 5 placebo capsules administered orally BID

Protocol documents:
Prot_001.pdf: 
 
 
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  
 
 
 
 
 
 
Protocol Number:   
US IND Number: 
RHB-104-01 
73,479 
Principal Investigator: 
David Graham MD 
Sponsor’s Medical Director: 
 
Ira Kalfus MD 
Version and Date: 
Final Version 11.0 / 29 September 2017 
 
 
 
 
 
 
 
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-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
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.) 
• 
ICH E6; Consolidated Guidelines on Good Clinical Practices (1997)   
• 
Appropriately identified sponsor/CRO and local clinical SOPs 
 
 


CONFIDENTIAL 
Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
Page 3 of 8 
 
 
Title: 
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  
Phase: 
Phase III 
Study Population: 
Subjects with active, moderate to severe Crohn’s Disease (CD). 
The following inclusion criteria apply: 
• 
Males and females 18 to 75 years of age. 
• 
Signed fully informed consent provided as per this protocol. 
• 
Diagnosis of Crohn’s Disease confirmed by endoscopy or radiography and/or 
histology at least 6 months prior to randomization into the study. 
• 
CD involving the ileum and/or colon 
• 
Moderately to severely active CD (Crohn’s Disease Activity Index (CDAI) 
score of ≥ 220 and ≤450) at baseline. 
• 
Current treatment with at least one of the following therapies:  
o 
Oral 5-aminosalicylic acid (5-ASA) compounds 
▪ 
Dose must be stable for at least 4 weeks before baseline 
o 
Corticosteroid therapy  
▪ 
Dose must be stable for at least 2 weeks before baseline  
o 
Azathioprine or 6-mercaptopurine (6-MP) or methotrexate 
▪ 
Dose must be stable for at least 8 weeks before baseline  
o 
Infliximab or adalimumab 
▪ 
Dose must be stable for at least 14 weeks before baseline  
• 
White blood cell count ≥ 3.5x109 at screening. 
• 
Active Crohn’s disease, defined by at least one of the following: C-reactive 
protein > Upper Limit of Normal (ULN) at screening, fecal calprotectin > Upper 
Limit of Normal (ULN) at screening, OR radiographic (MRE or CTE) or 
endoscopic confirmation of the presence of active CD within 5 weeks of 
screening visit. 
• 
Subject agrees to use the following effective contraceptive methods only  
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: 
• 
Crohn’s disease involvement isolated to the mouth, upper gastrointestinal 
tract, or anus. 


CONFIDENTIAL 
Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
Page 4 of 8 
 
• 
History of total colectomy with ileorectal anastomosis or a proctocolectomy. 
• 
Presence of active fistulizing Crohn’s Disease or healed fistula within 2 months 
prior to screening.  
• 
Subject has postoperative stoma, ostomy, or ileoanal pouch. 
• 
Subject has short bowel syndrome. 
• 
Subject is scheduled for surgical bowel resection. 
• 
Subject has known symptomatic obstructive strictures or bowel perforation in 
the 6 months prior to screening. 
• 
Change in dose or discontinuation of oral 5-aminosalicylic acid (5-ASA) 
compounds less than 4 weeks prior to baseline. 
• 
Change in dose or discontinuation of corticosteroids less than 2 weeks prior to 
baseline. 
• 
Change in dose or discontinuation of azathioprine, 6-mercaptopurine (6-MP) 
or methotrexate less than 8 weeks prior to baseline.  
• 
Change in dose or discontinuation of infliximab or adalimumab less than 14 
weeks prior to baseline. 
• 
Treatment with vedolizumab less than 120 days prior to baseline or biological 
therapies (apart from infliximab or adalimumab) less than 60 days prior to 
baseline. 
• 
Previous treatment with rifabutin and/or clofazimine. 
• 
Oral or parenteral antibiotics in the 4 weeks prior to baseline (topical 
antibiotics are permitted). 
• 
Treatment with probiotics (excluding yogurt and yogurt-derived products) in 
the 4 weeks prior to baseline. 
• 
Females who have a positive pregnancy test or are lactating. 
Number of 
Subjects:   
Estimated total: 410 subjects, curtailed to 324 with Protocol Version 11.0, will be 
randomized into the study.   
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 study is a multicenter, Phase III, randomized, placebo-controlled, double-blind 
study designed to evaluate the efficacy and safety of RHB-104 compared to placebo to 
treat subjects with moderate to severe CD. RHB-104 consists of 3 antibiotics with activity 
against Mycobacterium avium subsp. paratuberculosis (MAP), a potential cause of CD. 
Subjects with active CD will be randomized at baseline in a 1:1 fashion to receive up to 
52 weeks of RHB-104 or placebo. Randomization will be performed within strata defined 
by whether subjects use protocol permitted anti-TNF agents (yes or no). Subjects will 
remain on stable doses of their baseline CD treatment although steroids may be tapered 
after Week 8 at the discretion of the investigator.  
The study is designed to assess remission at Week 26 as the primary endpoint. 
However, as MAP are slow growing mycobacteria without a proven antibiotic treatment, 
the duration of antibiotic treatment needed to achieve remission in subjects with CD 
caused by MAP may be longer than 26 weeks. Subjects with response at week 26 may 
ultimately achieve remission at a later time point with continued treatment for MAP. Also, 
subjects with CD treated for underlying MAP infection may experience benefits with a 
longer period of time in response or remission with RHB-104 treatment compared to 
placebo. Thus, the study is also designed to assess response, remission, and 
maintenance of remission in subjects on randomized treatment through week 52.  


CONFIDENTIAL 
Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
Page 5 of 8 
 
Blood samples will be collected at baseline and at every visit after the initial 4 weeks of 
treatment to test for MAP in the serum using a polymerase chain reaction (PCR) assay. 
MAP cultures will be prepared from whole blood collected at the baseline visit and after 
26 and 52 weeks of treatment. 
Safety and pharmacokinetics of the fixed-dose combination product, RHB-104, will also 
be assessed. 
Colonoscopy will be done in consenting subjects prior to initiation of study drug and after 
26 weeks of study drug to assess for mucosal healing as well as MAP status via PCR 
and culture.  Optional biopsies will also be collected for possible measurement of tissue 
drug levels and archived for future MAP determinations. 
 
Study Visit Schedule:                                                                                 
Screening, baseline, and follow-up visits at weeks 2, 4, 6 (+/- 3 days), 8, 12, 16, 20, 26, 
35, 44, 52, and 56 (+/- 7 days). Subjects undergoing colonoscopy will have a procedural 
visit after week 26 assessment so as to not interfere with data collection. 
Subject 
Participation 
Duration: 
Subjects are expected to participate up to 62 weeks.  However, subjects who complete 
26 weeks of study drug administration and remain out of remission e.g. CDAI ≥150, 
will be eligible for open label treatment with RHB-104 in an extension study (protocol 
RHB-104-04).  Subjects may elect to continue in the RHB-104-01 study, and will 
remain in the RHB-104-01 study until study drug administration in the RHB-104-04, if 
applicable. 
Treatment:  
RHB-104; a fixed-dose combination of 95 mg clarithromycin, 45 mg rifabutin, and 10 
mg clofazimine. Placebo is a capsule with a similar appearance as RHB-104. 
Route of 
Administration: 
Oral capsule. 
Dosage Regimen 
for Investigational 
Product: 
The target dose of RHB-104 will be 5 capsules administered bid. 
In order to reach this target with minimal adverse effects, the subject’s dose will be 
titrated up over the first 4 weeks of treatment, and the dose will remain stable thereafter 
(see schedule below). Subjects randomized to placebo will receive the same number of 
capsules as the RHB-104 group according to the schedule 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. 
Dose Titration by Week for initiating RHB-104 
Week 
1 
2 
3 
4 
5-52 
Study 
Drug  
1 capsule   
bid 
2 capsules 
bid 
3 capsules 
bid 
4 capsules 
bid 
5 capsules 
bid 
Outcome 
Measures 
Remission (primary outcome measure) – Remission in a subject is defined as a CDAI 
score of <150.  
Response – A response in the individual subject is defined as reduction in CDAI score 
of ≥100 from baseline. 
Time to remission – The time (weeks after randomization) 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 randomization) 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 26 through week 52. 


CONFIDENTIAL 
Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
Page 6 of 8 
 
 
Other Outcome Measures 
MAP Detection:  
• Proportion of randomized subjects with a MAP positive blood PCR assay at 
baseline 
• Proportion of subjects with a change in MAP blood PCR assay status after 26 
weeks of treatment compared to baseline 
• Proportion of subjects with a change in MAP blood PCR assay status after 52 
weeks of treatment compared to baseline 
• Sequential comparison of MAP blood PCR assay results per subject 
• Proportion of randomized subjects with a MAP positive blood culture at baseline 
• Proportion of subjects with a change in MAP blood culture status after 26 weeks 
of treatment compared to baseline 
• Proportion of subjects with a change in MAP blood culture status after 52 weeks 
of treatment compared to baseline 
• Proportion of randomized subjects with a MAP positive colon biopsy PCR assay 
at baseline 
• Proportion of subjects with a change in MAP positive colon biopsy PCR assay 
status after 26 weeks of treatment compared to baseline 
• Proportion of randomized subjects with a MAP positive colon biopsy culture at 
baseline 
• Proportion of subjects with a change in MAP positive colon biopsy MAP culture 
status after 26 weeks of treatment compared to baseline 
• These measures of MAP status will be assessed for diagnostic performance 
against MAP culture as the definitive status measure. Performance measures 
include sensitivity and specificity and other measures of diagnostic performance 
derived there from, and will be computed by arm for assessments from samples 
following initiation of study intervention. 
Endoscopic Changes in Those Subjects Who Undergo Colonoscopy: 
• Change from baseline in the mean Crohn’s Disease Endoscopic Index of Severity 
(CDEIS and SES-CD) after 26 weeks of treatment 
• Correlation between the change from baseline in the endoscopic index (∆CDEIS 
and ∆SES-CD) and the clinical index (∆CDAI) after 26 weeks of treatment 
Health-Related Quality-of-life (HRQoL): 
• Change from baseline in the SF-36 questionnaire total score and domain scores 
• Change from baseline in the mean Inflammatory Bowel Disease Questionnaire 
(IBDQ) score 
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 


CONFIDENTIAL 
Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
 ____________________________________________________________________________________________  
Page 7 of 8 
 
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 assess whether subjects randomized to receive RHB-104 
have a higher probability of being in a state of remission at the 26 week assessment 
as compared to subjects randomized to receive placebo.  
Key Secondary Objectives  
1. Assess whether subjects randomized to receive RHB-104 have a higher 
probability of being in a state of response at the 26 week assessment as 
compared to subjects randomized to receive placebo. 
2. Assess whether subjects randomized to RHB-104 have a higher probability of 
being in a state of remission at the 52 week assessment as compared to 
subjects randomized to receive placebo 
3. Assess whether subjects randomized to  RHB-104 have a higher probability of 
being in a state of remission in assessments from week 26 through week 52 as 
compared to subjects randomized to receive placebo 
4. Assess whether subjects randomized to receive RHB-104 have a higher 
probability of being in a state of remission at the 16 week assessment as 
compared to subjects randomized to receive placebo 
5. Assess whether subjects randomized to receive RHB-104 have a higher 
probability of being in a state of steroid free remission at the 52 week 
assessment as compared to subjects randomized to receive placebo. Subjects 
must be maintained off steroids for 3 weeks in order to be determined to be in 
steroid free remission e.g. by week 49. 
Selected Other Supportive Objectives  
1. To compare the arm-specific time to remission and response. 
2. To compare the arm-specific duration of remission and response. 
3. To compare the proportion of subjects who have maintained remission from 
week 16 through week 52. 
4. Assess whether subjects randomized to receive RHB-104 have a higher 
probability of being in a state of response at the 16 week assessment as 
compared to subjects randomized to receive placebo. 
5. To assess the difference between arms in health-related quality-of-life using the 
IBDQ and SF-36 questionnaire.  
6. To compare arm-specific endoscopic 26-week changes using the CDEIS and 
SES-CD score in those subjects who consent to undergo colonoscopy 
7. To assess the effect of RHB-104 on markers of inflammation. 
8. To assess the proportion of subjects in steroid free remission in each 
treatment arm at weeks 26. Subjects must be maintained off steroids for 3 
weeks in order to be determined to be in steroid free remission e.g. by week 
23 
Other Exploratory Objectives  
9. To characterize the pharmacokinetic profiles of each of the active agents (and 
active metabolites for clarithromycin and rifabutin) using a population PK 
approach. 


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Protocol RHB-104-01 
 
Version 11.0 / 29 September 2017 
 
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10. To assess the efficacy outcome measures for interaction with the baseline assay 
results for MAP infection (positive versus negative) to use in development of 
MAP blood PCR testing. 
11. To compare the arm-specific changes in MAP PCR status (positive to 
negative) from pre- to post-treatment at week 26 and week 52.  
12. To compare arm-specific 26-week change from baseline in the endoscopic 
index (∆CDEIS and ∆SES-CD) and the clinical index (∆CDAI). 
13. To compare the arm-specific changes in MAP culture status (positive to 
negative) from pre- to post-treatment at week 26 and week 52. 
14. To assess the tissue levels of the active agents of RHB-104 in colon biopsy 
samples if possible. 
Safety Objective: Assess the safety impact of treatment with RHB-104. 
 
Study 
Completion: 
Upon completion of clinical activities and safety follow-up. 
Statistical 
Considerations 
Using data published by Sandborn et al. (2013), it was determined that the placebo rate 
of remission would be 21%. Using this information, the overall power and sample size 
calculations have been modified since the original assumptions concerning overall 
remission rates were different.  Using this new information, it is proposed that a total of 
410 patients (205 per group) be enrolled.  There will still be one stratification factor in 
this design – use of protocol permitted anti-TNF agents (yes/no).   With this sample size 
there is 90% power (with alpha=0.05 2-sided) to detect a difference between groups i.e. 
placebo and RHB-104, assumed that the observed difference will be 15% in absolute 
percent.  The proportion of remission success is assumed to be 21% in the Placebo 
group and 36% (or higher) in the treatment group.  The test statistic used for this analysis 
will be a two-sided Cochran-Mantel-Haenszel (CMH) test controlling for the stratification 
variable (anti-TNF agents (yes/no) under the ITT principle. These calculations were 
made to allow for two sequential tests to be made using the O'Brien-Fleming spending 
function to determine the test boundaries.  The interim analysis (first sequential test) will 
occur when 50% of the patients have their outcome data measured (i.e., reach 26 weeks 
of follow-up).  The 2-sided alpha level for stopping the trial for efficacy at the interim 
analysis is 0.003.  If this criterion is not met the trial will be continued and the final 
analysis (second sequential test) will be performed using a 2-sided alpha level of 0.049 
for testing the primary outcome.  In all analyses, subjects with missing 26 week 
assessments will be assumed to not be in a state of remission at 26 
weeks.  Furthermore, the primary assessment will be for all subjects randomized 
according to randomized group (intent-to-treat). It should be noted that the anticipated 
effect of the intervention will be a 15% improvement in 26-week remission success, 
however a clinically meaningful difference in this measure (26 week remission success 
proportion) is 9% (in absolute percent) based on clinical expert opinion.  Therefore, any 
statistically significant difference between groups that has an observed percent 
difference of 9% or larger would indicate that treatment is effective. 
Protocol Version 11.0 curtails the number of expected enrolled patients to 324 (162 per 
group). Final analysis of the data is to be carried out when approximately 324 patients 
have completed the Week 26 primary endpoint assessment. This sample size 
curtailment reflects the study’s current accrual trends. The anticipated power will be at 
least 80% given the study design stage assumptions regarding the treatment groups 
primary efficacy endpoint (36% RHB-104 vs. 21% Placebo).  
The secondary endpoints will be analyzed under the ITT approach to be described in 
detail in the Statistical Analysis Plan  
 

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-01 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
RedHill Biopharma Ltd. 
21 Ha’arba’a St., 
Tel-Aviv 64739, Israel 
 
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 
 
Protocol No. RHB-104-01 
 
 
 
 
 
 
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-104-01 
Final Version 3.0, 05 April 2018 
 
CONFIDENTIAL 
2 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
REVISION HISTORY 
 
Statistical Analysis Plan Text FINAL 3.0 based on 29 September 2017 Final Protocol 
(Protocol Amendment 11.0) 
 
Summary of Changes from version 2.0 
 
1. Section 5: updated definition for per protocol population. 
2. Section 2.2.1, added a paragraph to indicate that use of rescue medication is considered as 
treatment failure. 
3. Section 6.1.5: clarified the rule for AE end date imputation when day is missing. 
4. Sections 2.2.3.4, 6.3.3.6: removed SF-36 total scores and indicated that the derived scores 
are from QualityMetric. 
5. Section 6.3.3.7: for IBDQ added some clarifications on handling missing data. 
6. Sections 2.2.3.3, 6.3.3.10: CDEIS and SES-CD, removed all week 52 related summaries 
and outputs as week 52 is not collected. 
7. Section 8.1: Remove ECG tables as they are listings only and removed DSMB TLF from 
list as they are not applicable for final analysis. Some outputs are renumbered for 
continuity. 
8. Sections 6.3 and 8.1: added reference for addendum under section 6.3 and related output in 
section 8.1. 
9. Section 6.3.4.1: added clarifications for planned MAP analysis as the first paragraph. 
10. Throughout: Fixed a few typos and grammar correction. 
11. Added Shuhong Zhao as one co-author and  Jed Henke as sr. review. 
12. Updated protocol version on cover page. 
 
 
Statistical Analysis Plan Text FINAL 2.0 based on 29 March 2017 Final Protocol 
(Protocol Amendment 10.0) 


STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-01 
Final Version 3.0, 05 April 2018 
 
CONFIDENTIAL 
3 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS ...................................................................................... 5 
1. 
INTRODUCTION............................................................................................................................. 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................. 10 
2.1 
Study Objectives ............................................................................................................................ 10 
2.1.1 
Primary Efficacy Objective ............................................................................................... 10 
2.1.2 
Key Secondary Efficacy Objectives .................................................................................. 10 
2.1.3 
Other Supportive Secondary Efficacy Objectives ............................................................. 10 
2.1.4 
Other Exploratory Efficacy Objectives .............................................................................. 11 
2.1.5 
Safety Objective ................................................................................................................ 11 
2.2 
Outcomes/Endpoints ...................................................................................................................... 11 
2.2.1 
Primary Efficacy Endpoint/Variable: Remission ............................................................... 11 
2.2.2 
Key Secondary Efficacy Endpoints/Variables ................................................................... 11 
2.2.3 
Supportive Efficacy Endpoints/Variables .......................................................................... 12 
2.2.4 
Other Exploratory Efficacy Endpoints/Variable(s) ............................................................ 14 
2.2.5 
Safety Endpoints/Variables................................................................................................ 15 
3. 
STUDY DESIGN ............................................................................................................................ 15 
4. 
SCHEDULE OF ASSESSMENTS AND TREATMENT ASSIGNMENT .................................... 16 
4.1 
Schedule of Assessments ............................................................................................................... 16 
4.1.1 
Study Visit Schedule.......................................................................................................... 16 
4.2 
Dosage and Administration of Study Drug .................................................................................... 17 
4.3 
Randomization and Treatment Assignment Procedures ................................................................ 17 
5. 
ANALYSIS POPULATIONS ......................................................................................................... 18 
6. 
STATISTICAL METHODOLOGY................................................................................................ 18 
6.1 
Statistical and Analytical Issues .................................................................................................... 18 
6.1.1 
Statistical Methods............................................................................................................. 18 
6.1.2 
Multiplicity and Testing Strategy ...................................................................................... 19 
6.1.3 
Subgroups .......................................................................................................................... 20 
6.1.4 
Baseline Definition ............................................................................................................ 20 
6.1.5 
Missing Data and Handling of Dropouts ........................................................................... 20 
6.1.6 
Conversion of time interval ............................................................................................... 22 
6.1.7 
Pooling of Investigator Sites .............................................................................................. 22 
6.1.8 
Efficacy Data with High Doses of Steroids Use and Rescue Medications Use ................. 22 
6.1.9 
Determination of Sample Size ........................................................................................... 23 
6.2 
Subject Characteristics .................................................................................................................. 23 
6.2.1 
Subject Disposition ............................................................................................................ 24 
6.2.2 
Protocol Deviations ........................................................................................................... 24 
6.2.3 
Demographics and Background Baseline Characteristics.................................................. 25 
6.2.4 
Treatment Exposure and Drug Accountability .................................................................. 25 
6.2.5 
Physical Examination ........................................................................................................ 26 
6.2.6 
Medical History (excluding Crohn's disease) .................................................................... 26 
6.2.7 
Prior and Concomitant Medications and Steroids .............................................................. 27 
6.3 
Efficacy Analysis ........................................................................................................................... 28 
6.3.1 
Primary Efficacy Analysis ................................................................................................. 28 
6.3.2 
Key Secondary Efficacy Endpoints Analyses .................................................................... 29 
6.3.3 
Supportive Secondary Efficacy Endpoints ........................................................................ 31 
6.3.4 
Other Exploratory Endpoints ............................................................................................. 37 
6.4 
Population PK Analysis ................................................................................................................. 38 
6.5 
Safety Analysis .............................................................................................................................. 38 


 
STATISTICAL ANALYSIS PLAN 
RedHill Biopharma Ltd. 
Protocol No. RHB-104-01 
Final Version 3.0, 05 April 2018 
 
CONFIDENTIAL 
4 
6.5.1 
Adverse Events .................................................................................................................. 38 
6.5.2 
Laboratory Parameters ....................................................................................................... 39 
6.5.3 
Vital Signs ......................................................................................................................... 40 
6.5.4 
12-Lead ECG ..................................................................................................................... 40 
6.5.5 
Uveitis Assessment ............................................................................................................ 40 
6.6 
Data and Safety Monitoring Board (DSMB) ................................................................................. 41 
6.7 
Interim Analysis ............................................................................................................................ 41 
6.8 
Changes to Statistical Analysis Methods Planned in the Protocol ................................................. 42 
7. 
ADDITIONAL OTHER EXPLOATORY ANALYSES ................................................................ 42 
8. 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 43 
8.1 
Tables, Listings and Graphs (TLFs) for Study Report................................................................... 43 
9. 
REFERENCES ................................................................................................................................ 51 


 
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RHB-104-01 
Page 5 
 
Final Version 3.0, 05 April 2018 
 
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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 
ANCOVA 
Analysis of Covariance 
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  
CABG 
Coronary Artery Bypass Graft 
C. difficile 
Clostridium difficile 
CCFA 
Crohn’s and Colitis Foundation of America 
CD 
Crohn’s Disease 
CDAI  
Crohn’s Disease Activity Index 
CDEIS 
Crohn’s Disease Endoscopic Index of Severity 
CE 
Covered Entity 
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 


 
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RHB-104-01 
Page 6 
 
Final Version 3.0, 05 April 2018 
 
CONFIDENTIAL 
6 
Abbreviation  
Term 
DHHS  
Department of Health and Human Service 
DO 
Doctor of Osteopathy 
DSMB 
Data And Safety Monitoring Board 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
°F 
Fahrenheit  
FDA 
Food and Drug Administration 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GMP 
Good Manufacturing Practices 
HDPE  
High-density Polyethylene 
HE 
Health Economic(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-Related Quality-of-life 
IB  
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
IBDQ  
Inflammatory Bowel Disease Questionnaire 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC  
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
ITT 
Intent-To-Treat 
kg 
Kilogram 
L 
Liter 


 
 
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Abbreviation  
Term 
lb 
Pound 
LDH 
Lactate Dehydrogenase  
MAP  
Mycobacterium avium subsp. paratuberculosis 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS 
Mental Component Summary 
MI 
Myocardial Infarction 
mITT 
Modified intent-to-treat 
mg 
Milligram 
n 
Number of Subjects 
Min 
Minimum 
NCR  
No Carbon Required 
PA  
Physician’s Assistant 
PIPEDA 
Personal Information Protection and Electronic Documents Act 
PCR 
Polymerase Chain Reaction 
PCS 
Physical Component Summary 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
popPK 
Population Pharmacokinetics 
popPKAP 
Population PK Analysis Plan 
QD 
Once-Daily 
QTc  
Corrected Q-T Interval 
QTcF 
Corrected Q-T Interval using Fridericia's Formula 
REB  
Research Ethics Board 
RHB 
RedHill Biopharma Ltd. 
RBC 
Red Blood Cell  
SAE 
Serious Adverse Event 
SAF 
Safety Population 


 
 
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Abbreviation  
Term 
SAP 
Statistical Analysis Plan 
SAS®  
Statistical Analysis System Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SF-36 
Short Form-36 Health Survey 
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 require 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 
years on this therapy 
 


 
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2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Study Objectives 
 
2.1.1 Primary Efficacy Objective 
 
The primary objective is to assess whether subjects randomized to receive RHB-104 have a 
higher probability of being in a state of remission (CDAI score <150) at week 26 assessment as 
compared to subjects randomized to receive placebo. 
 
2.1.2  Key Secondary Efficacy Objectives 
 
1.  Assess whether subjects randomized to receive RHB-104 have a higher probability of being 
in a state of response at the 26 week assessment as compared to subjects randomized to 
receive placebo. 
2. Assess whether subjects randomized to receive RHB-104 have a higher probability of being 
in a state of remission at the 52 week assessment as compared to subjects randomized to 
receive placebo. 
3. Assess whether subjects randomized to receive RHB-104 have a higher probability of being 
in a state of durable (long-term) remission in assessments from week 26 through week 52 as 
compared to subjects randomized to receive placebo. 
4. Assess whether subjects randomized to receive RHB-104 have a higher probability of being 
in state of early remission at the 16 week assessment as compared to subjects randomized to 
receive placebo. 
5. Assess whether subjects randomized to receive RHB-104 have a higher probability of being 
in a state of steroid free remission at the 52 week assessment as compared to subjects 
randomized to receive placebo. Subjects must be maintained off steroids for 3 weeks in order 
to be determined to be in steroid free remission, e.g., by week 49. 
 
2.1.3 Other Supportive Secondary Efficacy Objectives 
 
1. To compare the arm-specific time to remission and time to response. 
2. To compare the arm-specific duration of remission and duration of response. 
3. To compare the proportion of subjects who have maintained remission from week 16 through 
week 52.  
4. To assess whether subjects randomized to receive RHB-104 have a higher probability of 
being in a state of response at the 16 week assessment as compared to subjects randomized to 
receive placebo.  
5. To assess the difference between the treatment groups in health-related quality-of-life using 
the IBDQ and SF-36 questionnaire instruments.  
6. To compare arm-specific endoscopic 26-week changes using the CDEIS and SES-CD score 
in those subjects who consent to undergo colonoscopy. 
7. To assess the effect of RHB-104 on markers of inflammation. 
8. To assess the proportion of subjects in steroid free remission in each treatment arm at week 
26. Subjects must be maintained off steroids for 3 weeks in order to be determined to be in 
steroid free remission e.g. by week 23.   
 


 
 
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2.1.4 Other Exploratory Efficacy Objectives 
 
1.   To characterize the pharmacokinetic profiles of each of the active agents (and active 
metabolites for clarithromycin and rifabutin) using a population PK approach. 
2. To assess the efficacy outcome measures for interaction with the baseline assay results for 
MAP infection (positive versus negative) to use in development of MAP blood PCR testing. 
3. To compare the arm-specific changes in MAP PCR status (positive to negative) from pre- to 
post-treatment at week 26 and week 52. 
4.   To compare arm-specific 26-week change from baseline in the endoscopic index (ΔCDEIS 
and ΔSES-CD) and the clinical index (ΔCDAI) 
5.   To compare the arm-specific changes in MAP culture status (positive to negative) from pre- 
to post-treatment at week 26 and week 52. 
6.  To assess the tissue levels of the active agents of RHB-104 in colon biopsy samples if 
possible. 
 
2.1.5 Safety Objective  
 
Assess the safety impact of treatment with RHB-104. 
 
2.2 Outcomes/Endpoints 
 
The efficacy endpoints for statistical comparison between the RH-104 treatment and Placebo are 
grouped into 4 families for statistical analysis: (i) Primary efficacy endpoint; (ii) Key Secondary 
efficacy endpoints; (iii) Other Supportive Secondary efficacy endpoints; and (iv) Other 
Exploratory efficacy endpoints.  The endpoints in families (i) and (ii) that are for potential 
treatment efficacy labeling claim will have multiplicity adjustment to control type 1 error rate. 
  
2.2.1 Primary Efficacy Endpoint/Variable: Remission 
 
In general use of rescue medication is considered as treatment failure (not achieve 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 6.1.8 for more details. 
 
 
The primary efficacy variable is the proportion of subjects experienced  remission at Week 26, 
where remission is defined as a subject having a Crohn’s Disease Activity Index (CDAI) score of 
<150.  Subjects who have a Week 26 CDAI measurement ≥ 150 or who do not have a CDAI 
measurement at Week 26 will be classified as not achieved remission. 
 
The CDAI is used to assess the activity of CD; higher scores indicate more active disease. 
 
2.2.2 Key Secondary Efficacy Endpoints/Variables 
 
 Key Secondary efficacy endpoints include the following: 
 


 
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• 
Proportion of subjects experienced response at week 26, where response is defined as 
reduction from baseline of ≥100 in CDAI score.  Subjects who have a change from 
baseline to week 26 in CDAI score which is not a reduction of ≥ 100 or who do not have 
a change from baseline to week 26 in CDAI score will be classified as not experienced 
response. 
• 
Proportion of subjects in remission Week 52, where remission is defined as a subject 
having a CDAI score of <150.  Subjects who have a week 52 CDAI measurement ≥ 150 
or who do not have a CDAI measurement week 52 will be classified as not achieved 
remission. 
• 
Proportion of subjects experienced Durable Remission (CDAI score < 150) from week 26 
through week 52.  Subjects experiencing a CDAI score ≥ 150 at any visit time point 
assessment between week 26 and week 52 or have no CDAI measurement week 26 or 
week 52 will be considered not achieved Durable Remission. 
• 
Proportion of subjects in Early Remission week 16, where remission is defined as a 
subject having a CDAI score of <150.  Subjects who have a week 16 CDAI score ≥ 150 
or who do not have a CDAI measurement week 16 will be classified as not achieved early 
remission.   
• 
Proportion of subjects in steroid free remission week 52, where remission is defined as a 
subject having a CDAI score of <150. Subjects must be maintained off steroids for 3 
weeks in order to be determined to be in steroid free remission, e.g., by week 49. 
 
2.2.3 Supportive Efficacy Endpoints/Variables 
 
2.2.3.1 Other Remission and Response Endpoints/Variables 
 
• 
Proportion of subjects in remission from week 16 through week 52, where remission is 
defined as maintaining 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 at  week 16 or week 52 will be considered 
not achieved Remission for this endpoint analysis. 
• 
Proportion of subjects experienced early response week 16, where early 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 
experienced early response. 
• 
Proportion of subjects experienced response week 52, where response is defined as 
reduction from baseline of ≥100 in CDAI score. Subjects who have a change from 
baseline to week 52 in CDAI score which is not a reduction of ≥ 100 or who do not have 
a change from baseline to week 52 in CDAI score will be classified as not experienced 
response. 
2.2.3.2 Time to Event Endpoints/Variables 
 
• 
Time to remission – Number of weeks after randomization 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 baseline visit (Visit 1), plus 1 day, 
divided by 7.  For subjects still on study and not achieved remission at the time of 


 
 
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assessment, time to remission will be censored at the date of the last assessment of CDAI 
score.   
 
• 
Duration of remission – Duration of remission defined as 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 baseline 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 baseline visit (Visit 1), plus 
1 day, divided by 7.  For those subjects not experienced response, time to response will 
be censored at the date of the last assessment of CDAI score.   
 
• 
Duration of response – Defined as 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.  
 
2.2.3.3 Endoscopic Change Variables 
 
• 
Change from baseline to week 26 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. 
 
• 
Correlations between the change from baseline to week 26 in CDEIS and SES-CD and 
the change from baseline to week 26 in CDAI. 
 
• 
Proportion of subjects in remission by visit time post-baseline based on CDEIS and SES-
CD measurements. Remission is defined as 0-3 score based on CDEIS measurement and 
defined as 0-2 score based on SES-CD measurement.  
 
• 
Proportion responders based on CDEIS and SEC-CD at week 26. Responders based on 
CDEIS and SES-CD scores are defined and classified into two categories as 50% 
reduction from baseline score; and 25% reduction from baseline score to week 26. 
 
2.2.3.4 Health Related Quality of Life Variables 
 
• 
Change from baseline in the Short Form-36 Health Survey (SF-36) domain and 
component scores at each follow-up visit time point.   


 
 
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• 
Change from baseline in the IBDQ score at each follow-up visit time point.  
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. 
 
2.2.3.5 Markers of Inflammation Variables 
 
Inflammation parameters include the following: 
 
• 
Change from baseline in C-reactive protein 
 
• 
Change from baseline in Fecal calprotectin 
 
2.2.4 Other Exploratory Efficacy Endpoints/Variable(s) 
 
2.2.4.1 Map Detection Endpoints/Variable 
 
As specified in the objectives, the variables/endpoints in this section are intended to be for 
exploratory analysis. Depending on the availability of data, specific details of additional 
exploratory analyses to be conducted will be determined at the time of analyses. 
  
Mycobacterium avium subsp. paratuberculosis (MAP) detection parameters include the 
following: 
 
• 
Proportion of subjects with a MAP positive PCR blood assay at baseline. 
 
• 
Proportion of subjects with a change in MAP blood PCR assay status after week 26 and 
after week 52 of treatment compared to baseline. 
 
• 
Proportion of subjects with a MAP positive blood culture at baseline. 
 
• 
Proportion of subjects with a change in MAP blood culture status after 26 weeks of 
treatment compared to baseline. 
 
• 
Proportion of subjects with a change in MAP blood culture status after 52 weeks of 
treatment compared to baseline. 
 
• 
Proportion of subjects with MAP positive colon biopsy PCR assay at baseline. 
 
• 
Proportion of subjects with a change in MAP positive colon biopsy PCR assay status 
after 26 weeks of treatment compared to baseline. 
 
• 
Proportion of subjects with a change in MAP positive colon biopsy PCR assay status 
after 52 weeks 
 


 
 
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2.2.4.2 Other Endpoints 
 
• 
Proportion of subjects tapered off steroids in each treatment arm. 
 
• 
Assess tissue levels of the active agents of RHB-104 in colon biopsy samples if possible. 
 
2.2.5 Safety Endpoints/Variables 
 
Safety parameters include the following. 
• 
Adverse events 
• 
Incidence of uveitis 
• 
Laboratory parameters (hematology, chemistry, urinalysis) 
• 
Vital signs 
• 
ECG 
• 
Physical examination 
• 
Concomitant medications 
 
3. STUDY DESIGN 
 
This study is a multicenter, Phase III, randomized, placebo-controlled, parallel group, double-
blind study designed to evaluate the efficacy and safety of RHB-104 compared to placebo to treat 
subjects with moderate to severe CD. RHB-104 consists of 3 antibiotics with activity against 
Mycobacterium avium subsp. paratuberculosis (MAP), a potential cause of CD. Subjects with 
active CD will be randomized at baseline in a 1:1 fashion to receive up to 52 weeks of RHB-104 
or placebo. Subjects will remain on stable doses of their baseline CD treatment although steroids 
may be tapered after Week 8 at the discretion of the investigator. 
 
The study is designed to assess remission at Week 26 as the primary endpoint. However, as MAP 
are slow growing mycobacteria without a proven antibiotic treatment, the duration of antibiotic 
treatment needed to achieve remission in subjects with CD caused by MAP may be longer than 
26 weeks. Subjects with response at week 26 may ultimately achieve remission at a later time 
point with continued treatment for MAP. Also, subjects with CD treated for underlying MAP 
infection may experience benefits with a longer period of time in response or remission with 
RHB-104 treatment compared to placebo. Thus, the study is also designed to assess response, 
remission, and maintenance of remission in subjects on randomized treatment through week 52. 
 
Blood samples will be collected at baseline and at every visit after the initial 4 weeks of treatment 
to test for MAP in the serum using a polymerase chain reaction (PCR) assay. MAP cultures will 
be prepared from whole blood at the baseline visit and after 26 and 52 weeks of treatment in 
subjects enrolled at North American study sites. 
 
Safety and pharmacokinetics of the fixed-dose combination product, RHB-104, will also be 
assessed. Colonoscopy will be done in consenting subjects prior to initiation of study drug and 
after26 weeks of study drug to assess for mucosal healing as well as MAP status via PCR and 
culture. Optional biopsies will also be collected for possible measurement of tissue drug levels 
and archived for future MAP determinations. 


 
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4. SCHEDULE OF ASSESSMENTS AND TREATMENT ASSIGNMENT  
 
4.1 Schedule of Assessments 
 
The study schedule is summarized in the study visit schedule table below.  
 
4.1.1 Study Visit Schedule 
 
 
Screening 
(Day -42 
to 
screening 
Day -7) 
Baseline 
Day 1 / 
Week 06 
Week 
2  
Week 
4 
Week 
6  
Weeks 
8, 12, 
16 and 
20 
Week 
26 
Weeks 
35 and 
44 
Week 
52 
Week 
56 
Study Visit Window 
 
 
± 3 
days 
± 3 
days 
± 3 
days 
± 7 days 
± 7 
days 
± 7 
days 
± 7 
days 
± 7 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
Demography and Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
CDAI collection1 
 
X 
 
X 
 
X 
X 
X 
X 
 
Subject Assessments: IBDQ 
and SF-36 
 
X 
 
 
 
 
X 
 
X 
 
Uveitis Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG2 
X 
X 
X 
X 
 
Weeks 
8 and12 
X 
 
X 
 
Hematology and Biochemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Levels of RHB-1044 
 
 
 
 
 
 
X 
 
 
 
Hep B S Ag, Hep C Ab,  HIV 
and  QuantiFERON®-TB  
X 
 
 
 
 
 
 
 
 
 
C-Reactive Protein (CRP) 
X 
X 
 
 
 
X 
X 
X 
X 
 
MAP Testing Blood with 
Additional Sample for Future 
Use 
 
X 
 
X 
 
X 
X 
X 
X 
 
MAP culture from blood   
 
X 
 
 
 
 
X 
 
X 
 
Fecal calprotectin 
X 
X 
 
 
 
Week 
12 
X 
 
X 
 
Stool Testing other5  
X 
 
 
 
 
 
X 
 
X 
 
Pregnancy Test Urine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Colonoscopy6 and CDEIS, 
storage of images, MAP 
testing , archive samples and 
possible analysis of drug 
levels 
X 
 
 
 
 
X 
 
 
 
Population PK Blood 
Sampling4  
 
 
X 
X 
X 
Week 
8, 12 
and 20 
 
X 
X 
X8 
Randomization (after meeting 
inclusion/exclusion criteria)7 
 
X 
 
 
 
 
 
 
 
 


 
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Study Drug and Diary 
Dispensing (with instructions 
for drug administration & diary 
completion1) 
Diary 
only 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Return & Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Telephone reminder of dose 
escalation 
 
Day 7 
Day 
21 
 
 
 
 
 
 
 
1 CDAI: Subjects will complete a CDAI diary for the 7 days preceding their next study visit. To ensure compliance, site 
personnel will contact subjects prior to initiation of the CDAI-recording period, to review the process for adequate CDAI data 
collection. At the screening visit the 7-Day CDAI diary will be distributed to the subject for completion before the Baseline 
visit and if applicable, before the colonoscopy preparation/procedure takes place.  
2 ECG: Five minute continuous digital 12-lead ECG after resting 10 minutes in a supine position 
3 Urine Testing:  Dipstick test only, unless results are abnormal  
4 Frozen plasma sample: For Week 26 clarithromycin, rifabutin, clofazimine, 14-hydroxy-clarithromycin, and 25-O-
desacetyl-rifabutin plasma concentration measurement. 
5 Stool testing: E, coli 0157 toxin, culture (includes salmonella, campylobacter, yersinia), ova, and parasites testing done at 
Screening only. C. difficile toxin and stored sample for potential analysis of fecal microbiome done at Screening, Weeks 26 
and 52 
6 Colonoscopy: to be performed at least 8 days before or at the Week 0 visit. If performed at the Week 0 visit, then the 7 days 
prior to the start of the colonoscopy preparation will be used to calculate the baseline CDAI score.  At visit week 26: the 
colonoscopy must be performed 3-4 days post visit week 26. Only CDEIS compatible colonoscopies will have biopsies and 
CDEIS performed, although biopsies are optional. 
7 Randomization: At screening, IWRS will be accessed to record the subject’s screening information. Randomization and 
study drug kit assignment will be confirmed in the IWRS at the baseline visit, after subject eligibility is confirmed. 
8 PK Blood Sampling: single time point.  
 
4.2 Dosage and Administration of Study Drug 
 
Study treatment will be taken twice-daily (bid) with food. Subjects will self-administer study drug 
orally, as per the following dosage schedule: 
 
 
Weeks 
1 
2 
3 
4 
 
5-52 
(1 bid) 
2 
capsules 
(2 bid) 
4 
capsules 
(3 bid) 
6 
capsules 
(4 bid) 
8 
capsules 
 
(5 bid) 
10  
capsules 
 
 
 
Active Daily Dose (mg) 
Active 
Treatment 
Arm 
RHB-104 
Clarithromycin 
Rifabutin 
Clofazimine 
 
190mg 
90mg 
20mg 
 
380mg 
180mg 
40mg 
 
570mg 
270mg 
60mg 
 
760mg 
360mg 
80mg 
 
950mg 
450mg 
100mg 
Placebo 
Arm 
Placebo  
placebo 
placebo 
placebo 
placebo 
placebo 
 
4.3 Randomization and Treatment Assignment Procedures 
 
A total of 410 subjects that meet study eligibility requirements will be randomly assigned in 
permuted blocks  to receive active (RHB-104) or placebo treatment in a 1:1 ratio using an 
Interactive Web Randomization System (IWRS). Randomization will be performed within strata 
defined by whether subjects use protocol permitted anti-TNF agents (yes/no). The randomization 


 
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code will only be available to personnel responsible for the randomization of subjects or labeling 
of the study drug. The sponsor and all personnel involved in the conduct of the study will be 
blinded to the treatment assigned to each subject.    
 
5. ANALYSIS POPULATIONS 
 
All screened subjects who signed informed consent will be included in the disposition table 
counts.  
The following populations will be used for data analysis. 
 
The Intent-to-Treat (ITT) Population: The primary efficacy analyses will be based on the ITT 
population, which is defined as all subjects randomized. Subjects will be analyzed according to 
the treatment group to which they were randomized.  
 
The Modified Intent-to-Treat (mITT) Population: The Modified Intent-to-treat population is 
defined as patients who fulfill all inclusion/exclusion criteria. The sensitivity analyses will be 
performed using the mITT population. Subjects will be analyzed according to the treatment group 
to which they were randomized. 
 
The Safety Population (SAF): The safety population includes subjects who are randomized and 
receive at least one dose of study medication. The primary safety analyses will be based on the 
SAF population.  Subjects will be analyzed according to the treatment which they actually 
received. 
 
Per-Protocol Population (PP): The PP Population includes all randomized subjects who receive 
at least one dose of RHB-104 or placebo and complete dose escalation to target dose of 5 
capsules bid, as well as all subjects without major protocol deviations that would have a 
significant impact on clinical outcome. Relevant protocol deviations may include errors in 
treatment assignment, the use of excluded medication that might affect study drug bioavailability, 
poor compliance (< 80% compliant over study duration), and subjects lost to follow-up. Protocol 
deviations will be reviewed and the list of major deviations warranting exclusion from the PP 
Population will be finalized prior to study unblinding. Subjects will be analyzed according to the 
treatment group to which they were randomized. 
 
The primary and key secondary efficacy sensitivity analyses may be repeated on the PP 
Population. 
 
6. STATISTICAL METHODOLOGY 
 
6.1 Statistical and Analytical Issues 
             
6.1.1 Statistical Methods 
 
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, efficacy, and safety endpoints. Continuous data summary descriptive statistics will 


 
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include the number of observations, means, standard deviations, medians, and ranges.  
Categorical variables will be summarized with frequencies and percentages.  
 
The primary hypothesis testing will be two-sided statistical significance testing (alpha level = 
0.05) comparing active treatment to placebo and mainly dedicated to assessing the primary 
endpoint and the key secondary endpoints. Point and interval estimates (95% confidence 
intervals) will be calculated and presented by treatment group for each parameter. Computed 
p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as '< 
0.0001' and p-values greater than 0.9999 will be presented as ‘> 0.9999’ in the tables. 
 
All statistical analyses will be performed using SAS statistical software (Version 9.3 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 and the version used will 
be footnoted in the respective summary tables. Concomitant medications will be coded using the 
most recent version of World Health Organization (WHO) Drug dictionary. 
 
6.1.2 Multiplicity and Testing Strategy 
 
Multiplicity issues in statistical inference in this study may arise from repeated tests on several 
multiple endpoints specified in the protocol. Additionally, the impact of the Type I error 
probability (α) because of the formal planned interim analysis to be conducted needs to be 
understood.  
 
The protocol specified α-spending for the planned interim analysis is 0.003. Hypotheses tests at 
the final analysis will be conducted at significance level of α = 0.049. The multiple efficacy tests 
for the study final analysis will employ a serial sequential gatekeeper strategy to maintain the 
Type 1 error rate at α = 0.049 across two families of analyses that support the primary, and key 
secondary objectives. The protocol pre-specified strategy is to use a hierarchy of significance 
tests where each test acts as a gatekeeper to tests below it. The endpoints will be tested in a 
sequential manner and will follow the sequential order given below starting with Remission 
ranked 1. Any inferential and hypothesis testing of a subsequent endpoint will be performed only 
if the test for the preceding endpoint is significant. In other words, the endpoint hypothesis 
examined earlier serves as gatekeeper. For this study as listed below in sequence of clinical 
importance, Remission week 26 is first rank (1) and will be tested first followed by Response 
week 26 (rank 2), followed by Remission week 52 (rank 3), Durable Remission week 26 through 
week 52 (rank 4), followed by Remission week 16 (rank 5), and followed by Steroid free 
Remission week 52 (rank 6).   Again it is important to note that once one hypothesis is tested and 
found not to be significant at α = 0.049, all subsequent tests will not be performed. The 
multiplicity adjustment following hierarchal testing procedure comparing RHB-104 with Placebo 
will only be performed on the following key clinical efficacy endpoints listed in order of clinical 
importance:  
 
1. Remission (CDAI score < 150) week 26 - Primary Efficacy Endpoint. 
Key Secondary Efficacy Endpoints: 
2. Response (reduction from baseline of ≥100 in CDAI score) week 26. 
3. Remission (CDAI score < 150) week 52 
4. Durable Remission (CDAI score < 150) from week 26 through week 52 in remission.  


 
 
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5. Remission (CDAI score < 150) week 16 
6. Proportion of subjects in steroid free remission week 52 (CDAI score < 150 and no steroids use 
by week 49). 
 
For the endpoints not included in the above pre-specified multiple testing, the P-values and 
confidence intervals will be presented with NO adjustment for multiplicity. Nominal P-values and 
confidence intervals are consequently supplementary/supportive to the primary efficacy analyses.  
 
6.1.3 Subgroups 
 
To further assess consistence of the study outcome data, the primary efficacy, key secondary 
efficacy, and select safety data may be further broken down and summarized by the following 
baseline subgroups characteristics with potential differing influence on outcome: 
 
• 
Sex: male, female 
• 
Race: White, Black, Other 
• 
Region: Countries will be grouped into geographical regions, e.g., US, Canada, Europe, 
etc. 
• 
Alcohol consumption: (Yes/No) 
• 
Smoking: (previous smoker, currently smoking, Nonsmoker) 
• 
Prior CD treatments (e.g., surgery/no surgery) 
• 
Years of CD (Categories to be determined at the time of analysis) 
• 
Prior use of anti-TNF agents (yes or no) 
• 
Prior use of immunomodulators (yes or no) 
• 
Prior use of Corticosteroids (yes/no) 
• 
CRP level at baseline  
• 
Fecal Calprotectin level at baseline 
 
The final subgroups to be assessed will be completed at the time of analysis depending on the 
available data by each subgroup. 
 
6.1.4 Baseline Definition 
 
Baseline period consists of 42 days (covering screening period) immediately preceding first 
administration of study treatment. Any assessment performed during these 42 days before first 
administration of study treatment will be considered baseline assessment. Study day 1 will be the 
first day of study drug administration. For all endpoints requiring baseline results, e.g., 
comparison with post-baseline, the baseline is the last non-missing result prior to first dose. 
 
6.1.5 Missing Data and Handling of Dropouts 
 
All available efficacy and safety data will be included in data listings and tabulations. All patients 
who prematurely discontinue for any reason will be considered failures for the different 
proportion based endpoints. 
 
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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 the protocol, subjects with missing week 26 assessment will be assumed to not be in a 
state of remission at week 26 (i.e., non-responders).  Similarly, for subjects with missing week 52 
assessments will be assumed not to be in state of remission at week 52. Sensitivity analyses may 
be performed on Observed Case (completer analysis) only. 
 
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. 
 
6.1.6 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 
 
6.1.7 Pooling of Investigator Sites 
 
The primary analysis will use data pooled across all investigative sites.  The Regions (UK, US, 
Canada, New Zealand, Israel, Slovakia, etc.) and site differences may be explored in preliminary 
analyses depending on how many subjects randomized by each site/region. Preliminary 
exploratory analyses may be conducted to determine potential influence of treatment-by-
investigative site/region interaction on the primary and key secondary efficacy endpoints by 
graphical visualization and tabulations of the data and where necessary, using statistical models 
incorporating treatment, site, and treatment-by-site interaction. A significance level of 0.10 will 
be used in any of the analyses in identifying potential treatment-by-site interactions. The 
exploratory results indicating non-significant interaction will be indicative that pooled data across 
sites/regions was free of the impact of any extreme investigative sites/regions. It is recognized 
that the power to detect an interaction will be limited due to some sites with limited enrollments.   
 
6.1.8 Efficacy Data with High Doses of Steroids Use and Rescue Medications Use 
 
Corticosteroids Use: 
A subject may use corticosteroids or increased dose levels of corticosteroids for reasons other 
than CD, and may start corticosteroid tapering at 8 weeks. If the subject experiences a worsening 
of disease activity during the taper, and/or the oral corticosteroid dose temporarily increased, in 
these circumstances the subject will be considered a treatment failure in the steroid free remission 
analysis but will continue to remain on the study and complete all scheduled visits. 
 
Use of Rescue Medications: 


 
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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 
• 
Antibiotics as treatment of CD 
• 
Total parenteral nutrition as treatment of CD 
• 
Systemic or rectal corticosteroid therapy 
• 
Anti-TNF or other biologic agent 
 
In the ITT efficacy analyses, subjects who initiate or modify dose/regimens to treat CD symptoms 
will be considered as treatment failures. 
 
6.1.9 Determination of Sample Size 
 
The sample size justification is provided in the protocol and was based on the review of published   
literature in similar patient population (Sandborn et al., 2013). A total sample size of 410 subjects 
(205 per treatment arm) was computed to be sufficient with one stratification anti-TNF agent use 
(yes/no) to detect a minimum difference of 15 percentage points between RHB-104 treatment 
(36% Remission) and Placebo (21% Remission) with 90% Power at two-sided significance level, 
α=0.05. The test statistic used for this analysis was a two-sided Cochran-Mantel-Haenszel (CMH) 
test controlling for the stratification variable (anti-TNF agents (yes/no) under the ITT principle. 
These calculations were made to allow for two sequential tests to be made using the O'Brien-
Fleming spending function to determine the test boundaries. The interim analysis (first sequential 
test) will occur when 50% of the patients have their outcome data measured (i.e., reach 26 weeks 
of follow-up). The 2-sided alpha level for stopping the trial for efficacy at the interim analysis is 
0.003. If this criterion is not met the trial will be continued and the final analysis (second 
sequential test) will be performed using a 2-sided alpha level of 0.049 for testing the primary 
outcome (Elashoff, 2007). In all analyses, subjects with missing 26 week assessments will be 
assumed to not be in a state of remission at 26 weeks. 
 
It should be noted that the  intervention effect used in the sample size derivation for the study is  
15% improvement in 26 week remission success, however a clinically meaningful difference in 
this measure (26 week remission success proportion) is 9% (in absolute percent) based on clinical 
expert opinion. Therefore, any statistically significant difference between groups that has an 
observed percent difference of 9% or larger would indicate that treatment is effective. 
 
Protocol Version 11.0 curtails the number of expected enrolled patients to 324 (162 
per group). Final analysis of the data is to be carried out when approximately 324 
patients have completed the Week 26 primary endpoint assessment. This sample size 
curtailment reflects the study’s current accrual trends. The anticipated power will be at 
least 80% given the study design stage assumptions regarding the treatment groups 
primary efficacy endpoint (36% RHB-104 vs. 21% Placebo). 
 
6.2 Subject Characteristics 
 


 
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All subject characteristics data will be listed by subject, and summarized for the ITT and safety 
populations, except as noted otherwise. 
 
6.2.1 Subject Disposition 
 
Subject disposition will be presented for all subjects by treatment group and overall for the 
Enrolled, randomized, ITT and SAF populations. Disposition information that will be 
summarized will include number of subjects who completed the study, number who withdrew 
prematurely, and reasons for withdrawal.  
 
All screened subjects will be summarized in subject disposition summary tables. The number and 
percent of screened subjects in each of the following categories will be presented.   
 
• 
Subjects screened 
• 
Screen failures and by criteria 
• 
Subjects randomized 
• 
Subjects completing weeks 26 and  52  
• 
Subjects discontinued from the study and by reason of discontinuation.  
  
The number and percentage of randomized patients who are ITT evaluable, mITT evaluable, 
safety evaluable (SAF), and PP evaluable will be summarized by treatment group and overall. 
 
The number and percentage of randomized subjects, who complete the study through weeks 26, 
and 52, and who discontinue the study by reason will be summarized by treatment group and 
overall. 
 
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 treatment group and overall based 
on the safety population and ITT population. The summary will be grouped into different 
categories of violations such as: 
• 
Errors in treatment assignment 
• 
Violation of inclusion/exclusion criteria 
• 
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 


 
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to the database lock.  
   
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. 
Demographics variables will be summarized descriptively for the ITT and SAF population by 
treatment group and will include the following variables: 
• 
Age at enrollment continuous variable [Years] 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
BMI  
 
6.2.3.2 Background/Baseline Characteristics 
 
The following list of variables will be summarized to further characterize the patient population at 
baseline by treatment group: 
• Crohn’s disease (CD) characteristics: CD Surgical history; duration of CD since first 
diagnosis, baseline CDAI score; baseline CDEIS and SES-CD scores  
• Age at first diagnosis 
• Stratification anti-TNF agents (yes or no)  
• Smoking   
• Alcohol consumption 
• MAP Test status: PCR Blood Assay: (Positive/Negative) Baseline 
• Map Test status: Blood Culture (Positive/Negative) Baseline 
•  Baseline serum inflammation marker: C-reactive protein (CRP) 
• Baseline stool inflammation marker: Fecal calprotectin 
• Baseline IBDQ 
• Prior use of steroids (yes/no) 
• Prior use of immunomodulators (yes/no) 
   
The final analysis list of baseline characteristics will be completed at the time of analysis 
depending on the available data. The baseline characteristics will be summarized descriptively for 
the ITT population by treatment group. 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. 
 
6.2.4 Treatment Exposure and Drug Accountability 
 
6.2.4.1 Treatment Exposure 
 


 
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Exposure will be summarized for the ITT population and 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 treatment group and also presented as subject data 
listing for the ITT population and Safety population.  
 
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.  
 
Extent of compliance of each subject data will be presented in subject listing for the SAF 
population. 
 
6.2.5 Physical Examination 
 
Physical examination of 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) at baseline and post-baseline visits will be tabulated for each body 
system with the number and percentage of subjects.  
 
All physical examination results will be presented in a subject data listing, including the 
description of abnormalities. 
 
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 and at baseline on the medical history 
eCRF. 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 and baseline on the history eCRF. Data will be 
presented descriptively by treatment group and also presented as data listing for the ITT 
population.  


 
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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 
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 prior medications and concomitant 
medications by treatment group. 
 
 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 tem, and date. 
 
Any concomitant procedures recorded on CRF will be presented in a data listing with procedure 
name, date and reason. 
  


 
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6.3 Efficacy Analysis 
 
The efficacy primary analyses will be based on the ITT population as the primary population. 
Any Supportive/sensitivity analyses may be assessed on subgroup populations of subjects that 
will be defined for each endpoint as needed for implementing specific sensitivity analysis.  
Additional analyses as defined in SAP addendum will be performed accordingly as specified. 
 
 
6.3.1  Primary Efficacy Analysis 
 
The primary efficacy analysis will be performed on ITT population. Sensitivity analyses may be 
performed on Observed Case (completers only), on subjects with no violation of key 
inclusion/exclusion criteria (mITT population), and on PP population.   
 
The primary efficacy variable is the proportion of subjects experienced remission week 26, where 
remission is defined as a subject having a Crohn’s Disease Activity Index (CDAI) score of < 150.  
Subjects who have a week 26 CDAI measurement ≥ 150 or who do not have a CDAI 
measurement week 26 will be classified as not achieved remission. The primary analysis will 
compare the RHB-104 treated group to Placebo treated group on ITT population using Cochran-
Mantel-Haenszel (CMH) chi-square test controlling for the stratification variable anti-TNF agents 
use (yes/no).  The null and alternative hypotheses are as follows, where πR and πP are the 
proportion of subjects with remission in the RHB-104 and placebo treated groups, respectively. 
 
Null hypothesis                                  Ho: πR = πP  
 
“Proportion (%) of subjects in Remission in RHB-104 Treatment is equal to Proportion (%) of 
subjects in Remission in Placebo Treatment at week 26” 
 
Alternative hypothesis                     H1: πR ≠ πP  
 
“Proportion of subjects in Remission for RHB-104 Treatment is not equal to Proportion of 
subjects in Remission for Placebo treatment at week 26” 
 
For each treatment group, descriptive statistics will be presented including the number of 
observations, proportion (%) of subjects in remission. 
 
The primary analysis will compare RHB-104 group to the placebo group using a two-sided test at 
the α = 0.049 level of significance. 
 
The statistical criterion for primary objective success will be met if the CMH chi-square test p-
value comparing the RHB-104 arm with the placebo arm (Higher proportion in RHB-104 than 
placebo) is less than 0.049 based on a 2-sided test taking into account the pre-specified protocol 
alpha spent at interim equal to 0.003. 
 
 For each treatment group, parameter estimates with 95% confidence interval will be presented 
including the number of observations and proportion (%) of subjects in remission. 
 


 
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To assess the robustness of the primary results, sensitivity analysis will be performed on mITT 
and on observed case (only completers with 26 weeks of data). The observed case population will 
include only subjects that have 26 weeks assessment.   
 
Logistic regression modeling will be implemented as additional exploratory analysis to assess the 
modifying effect of prognostic baseline characteristics identified prospectively as clinically 
important baseline factors/variables on the remission outcome in both treatment groups at week 
26. This will model a categorical response variable Remission (< 150 CDAI score) at week 26 
(yes/no) as a function of treatment, stratification anti-TNF agents (yes/no) use, and treatment-by- 
baseline clinical factor interaction. The aim is to assess consistence/inconsistence of the treatment 
differences across each of the pre-defined clinically important baseline characteristics (one-
variable-at-a-time). Each prognostic factor will be fitted separately (one-variable-at-a-time) in the 
model and output results including 95% confidence intervals presented in forest plots showing 
consistence/inconsistence by treatment group. The following baseline factors are considered 
prospectively to be potentially clinically important:   
• 
Baseline serum inflammation marker: C-reactive protein (Normal/High)  
• 
Baseline stool inflammation marker: Fecal calprotectin (Normal/High) 
• 
Baseline CDEIS score (0-3; >3 score) 
• 
Baseline SES-CD score (0-2; >2 score) 
• 
Baseline IBDQ Score 
• 
Duration of  CD 
• 
Prior surgical treatment for CD (yes/no) 
• 
MAP-Test PCR Blood assay (Positive/Negative) Baseline 
• 
MAP-Test Blood culture (Positive/Negative) Baseline 
• 
Gender (male/female) 
• 
Age at first Diagnosis of CD 
• 
Smoking (yes/no) 
• 
Alcohol consumption (yes/no) 
• 
Use of Immunomodulators (yes/no)  
• 
Use of steroids (yes/no) 
 
The continuous variables may be categorized into different classification categories depending on 
the number of observations and final decisions on categories for each variable will be determined 
at the time of analysis.    
 
6.3.2  Key Secondary Efficacy Endpoints Analyses 
 
Five key secondary efficacy endpoints of clinical importance are considered for primary 
inferential claims. Since gate keeping hierarchical sequential testing strategy is required for 
multiplicity adjustment, any claim on these key secondary efficacy endpoints will be made only if 
the primary efficacy endpoint parameter meets the criterion for statistical success. The 
hierarchical sequence hypothesis testing for multiplicity adjustment is summarized in section 
6.1.2 above. The hypothesis testing will be done in a sequential manner following the sequential 
order given in section 6.1.2 with the understanding that any hypothesis test of a subsequent 
endpoint will be performed only if the test for the preceding endpoint is significant. In other 
words, the endpoint hypothesis examined earlier serves as gatekeeper. 
 


 
 
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6.3.2.1 Response week 26 
 
The Response week 26 is defined as the proportion (%) of subjects that experienced reduction 
from baseline of ≥ 100 in CDAI score. The same statistical analysis strategy as described for the 
primary endpoint including sensitivity and exploratory analyses will be repeated for the 
proportion responders (%) at 26 weeks comparing the two treatment groups. Summary parameter 
estimates generated from the statistical analyses will be presented by treatment group, and will 
include the number and proportion of subjects achieving response along with the model estimated 
odds ratio (including 95% confidence interval) and p-value comparing RHB-104 treatment to 
placebo. The same sensitivity and exploratory analyses as for primary endpoint analysis may be 
conducted and summarized. 
 
6.3.2.2 Remission week 52 
 
Remission at week 52 will be derived following similar strategy as for the primary endpoint.  The 
subjects in remission will include subjects experienced remission (CDAI < 150 score) at week 26 
and also at week 52, and subjects that were non-responders at week 26 but are responders at week 
52 (Late responders). 
 
The same statistical methods as used for the primary endpoint will be used for this analysis. The 
proportion of subjects experienced remission at 52 weeks will be summarized for each treatment 
group and compared between the two treatments using Cochran-Mantel-Haenszel (CMH) chi-
square test. Summary parameter estimates generated from the statistical analyses will be 
presented by treatment group, and will include the number and proportion of subjects achieving 
response along with the model estimated odds ratio (including 95% confidence interval) and p-
value comparing RHB-104 treatment to placebo. The same sensitivity and exploratory analyses as 
for primary endpoint analysis may be conducted and summarized. 
 
6.3.2.3 Durable (or Sustained) Remission 
 
This analysis is intended to compare the two treatment groups considering only the subjects that 
experienced remission (CDAI < 150 score) week 26 through week 52 (Sustained Remission). 
Subjects who are not in remission at any visit point assessment between 26 and 52 weeks will be 
considered as non-responders for this analysis. The same statistical method as used for the 
primary endpoint will be used for this analysis.  The proportion (%) of subjects experienced 
sustained remission will be summarized for each treatment group and compared between the two 
treatments using Cochran-Mantel-Haenszel (CMH) chi-square test. Summary parameter estimates 
generated from the statistical analyses will be presented by treatment group, and will include the 
number and proportion of subjects achieving response along with the model estimated odds ratio 
(including 95% confidence interval) and p-value comparing RHB-104 treatment to placebo. The 
same sensitivity and exploratory analyses as for primary endpoint analysis will be conducted and 
summarized. 
 
An additional complementary analysis and summary will be presented for the Proportion of 
subjects that maintained durable remission at least 3 out of the 4 visits assessed (i.e. ≥ 75% of the 
visits in remission) week 26 through week 52.  
 


 
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6.3.2.4 Early Remission week 16 
 
Early Remission week 16 will be derived following similar strategy as for the primary endpoint.  
The summary results will show the number and proportion (%) of subjects experienced early 
remission (CDAI < 150 score) week 16. 
 
The same statistical approach as for the primary analysis will be employed to compare proportion 
(%) of subjects experienced Early Remission for the RHB-104 treated group versus Placebo 
treated group on ITT population using Cochran-Mantel-Haenszel (CMH) chi-square test 
controlling for the stratification variable anti-TNF agents use (yes/no). Summary parameter 
estimates generated from the statistical analyses will be presented by treatment group, and will 
include the number and proportion of subjects in remission along with the model estimated odds 
ratio (including 95% confidence interval) and p-value comparing RHB-104 treatment to placebo. 
The same sensitivity and exploratory analyses as for primary endpoint analysis may be conducted 
and summarized. 
 
6.3.2.5 Steroid free remission week 52 
 
This analysis is to compare the proportion (%) of subjects that achieved steroid free remission 
week 52 in the two treatment groups. To be considered to be in steroid free remission, a subject 
has to be in remission (CDAI score < 150) week 52 and is off steroids use for at least 3 weeks. 
The 3 weeks steroid free period is by week 49.   
 
The statistical analysis strategy, the statistical tests comparing the two treatment groups, summary 
and presentation of the results will be similar to the primary endpoint analysis based on CMH chi-
square tests. Summary parameter estimates generated from the statistical analyses will be 
presented by treatment group, and will include the number and proportion of subjects in steroid 
free remission along with the model estimated odds ratio (including 95% confidence interval) and 
p-value comparing RHB-104 treatment to placebo. The same sensitivity and exploratory analyses 
as for primary endpoint analysis may be conducted and summarized. 
 
6.3.3 Supportive Secondary Efficacy Endpoints 
 
This group of secondary efficacy endpoints is considered to be supportive of the efficacy for the 
primary and the key secondary endpoints. Therefore, there will be no multiplicity adjustments for 
this group of endpoints. Summary statistics and tests of hypotheses will be considered 
descriptive/supportive.  
 
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 
 


 
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The four endpoints will require time to event modeling approach.  Cox Proportional Hazard 
modeling will be used to compare the time to event in both treatments while simultaneously 
adjusting for stratification variable anti-TNF agents use (yes/no). The explanatory variables in the 
model will include treatment, and the stratification variable anti-TNF agents use (yes/no). Patients 
who do not achieve the outcome event at the end of the study will be censored on the last visit 
date recorded. Patients who discontinued early will be censored on the last date of contact. 
Censored observations and confidence intervals for the estimated median times will be presented.  
 
The null hypothesis that is tested is that of equal time to event distribution between the two 
treatments. Equality of the distributions of event times implies that there are similar response 
event rates between the two treatments not only for the entire treatment period, but also for any 
visit time point assessed post-baseline during the study. Rejection of the null hypothesis indicates 
that the event rates significantly differ between the two treatments at one or more visit time points 
assessed post-baseline. Kaplan Meier survival curves and parameters showing time-to-first 
observed response outcome will be summarized by treatment. Summary statistics that will be 
presented will include minimum, maximum, the 25th and 75th percentiles, 95% confidence 
intervals on the median (using the method of Brookmeyer and Crowley), and proportion of  the 
events and censored data.  The log-rank test will be used to test for differences between RHB-104 
treatment and placebo, and p-values from the tests will be presented.  Kaplan-Meier plots with 
descriptive summary statistics will be presented.  
 
6.3.3.2 Sustained Remission week 16 though week 52 
 
This analysis is intended to compare the two treatment groups based on the proportion (%) of 
subjects achieved Sustained Remission defied as maintaining CDAI score < 150 from week 16 
through week 52.  Subjects who are not in remission at any visit point assessment between week 
16 and week 52 will be considered as non-responders for this analysis. The same statistical 
method as used for the primary endpoint will be used for this analysis. The proportion (%) of 
subjects experienced sustained remission will be summarized for each treatment group and 
compared between the two treatments using Cochran-Mantel-Haenszel (CMH) chi-square test. 
Summary parameter estimates generated from the statistical analyses will be presented by 
treatment group, and will include the number and proportion of subjects achieving sustained 
remission along with the model estimated odds ratio (including 95% confidence interval) and p-
value comparing RHB-104 treatment to placebo. 
 
An additional complementary analysis and summary will be presented for the Proportion of 
subjects that maintained durable remission at least 5 out of the 6 visits assessed (i.e. ≥ 83% of the 
visits in remission) week 16 through week 52. 
 
6.3.3.3 Response at Week 52  
 
The Response is defined as reduction from baseline of ≥100 in CDAI score week 52.  The 
responders will include subjects who were responders week 26 through week 52 and the subjects 
that were non-responders at week 26 but were responders week 52 (Late Responders).  
 
The same statistical methods as used for the primary endpoint will be used for this analysis. The 
proportion of subjects experienced response at 52 weeks will be summarized for each treatment 


 
 
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group and compared between the two treatment groups using Cochran-Mantel-Haenszel (CMH) 
chi-square test.  
 
6.3.3.4 Early Response week 16 
 
The Early Response week 16 is defined as the proportion (%) of subjects that experienced 
reduction from baseline of ≥ 100 in CDAI score. The same statistical methods as used for the 
primary endpoint will be used for this analysis. The proportion of subjects (%)  experienced early 
response week 16 will be summarized for each treatment group and compared between the two 
treatments using Cochran-Mantel-Haenszel (CMH) chi-square test. Summary parameter estimates 
generated from the statistical analyses will be presented by treatment group, and will include the 
number and proportion of subjects achieving response along with the model estimated odds ratio 
(including 95% confidence interval) and p-value comparing RHB-104 treatment to placebo.  
 
6.3.3.5 Steroid free remission week 26 
 
This analysis is to compare the proportion (%) of subjects that achieved steroid free remission 
week 26 comparing the two treatment groups. To be considered to be in steroid free remission 
subject has to be in remission (CDAI score < 150) week 26 and maintained off steroids for at 
least 3 weeks. The 3 weeks steroid free period is by week 23. 
 
The statistical analysis strategy, the statistical tests comparing the two treatment groups, summary 
and presentation of the results will be similar to the primary endpoint analysis based on CMH chi-
square tests. Summary parameter estimates generated from the statistical analyses will be 
presented by treatment group, and will include the number and proportion of subjects achieving 
response along with the model estimated odds ratio (including 95% confidence interval) and p-
value comparing RHB-104 treatment to placebo.  
 
6.3.3.6  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 
 
 


 
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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 
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 to 
inVentiv for data summary and analysis.  
 
Summary descriptive statistics including mean, standard deviation, median and range (including 
95% confidence intervals)  will be presented in tables and bar graphs for the actual and change 
from baseline scores  for each domain and component summary score by treatment and by visit. 
The change from baseline for each domain and component summary score will be analyzed using 
an analysis of covariance (ANCOVA) model with treatment group, stratification variable anti-
TNF agents use (yes/no) as classification factors, and baseline score as covariate.  The treatment 
parameter estimates from the analysis models including means, 95% confidence intervals and 
associated 2-sided p-values will be presented. 
 
6.3.3.7 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 mean, standard deviation, median and range (including 
95% confidence intervals) will be presented in tables and bar graphs for the actual observed and 
change from baseline scores for each domain and overall by treatment and by visit. 
 
The change from baseline IBDQ score will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group, stratification variable anti-TNF agents use (yes/no) as 
classification factors, and baseline IBDQ score as a covariate.  The treatment parameter estimates 
from the analysis model including means, 95% confidence intervals and associated 2-sided p-
values will be presented. 
 
6.3.3.8 Serum Marker of Inflammation: C-reactive Protein (CRP)  
 


 
 
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The CRP is used as marker of inflammation. The C-reactive Protein (CRP) level data collected at 
different visits 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, standard deviation, median and range for each treatment by visit.  The change from 
baseline CRP comparing the two treatment groups will be analyzed using an analysis of 
covariance (ANCOVA) model with treatment group, stratification variable anti-TNF agents use 
(yes/no) as classification factors, and baseline CRP as a covariate.  The treatment parameter 
estimates from the analysis model including means, 95% confidence intervals and associated 2-
sided p-values will be presented including bar graphs. 
 
In addition, the CRP level will be classified into two categories: “Normal (≤  0.999 mg/dL)” and 
“High (> 10 mg/dL)”.  Summary results will show number of patients and proportion (%) with 
“Normal level” and with “High Level” by treatment group at baseline and at different visit time-
points with data collected post-baseline. The same statistical method and modeling as used for the 
primary endpoint will be used for this analysis. The proportion of subjects “Normal” at baseline 
and at each visit with data post-baseline will be compared between the two treatments using 
Cochran-Mantel-Haenszel (CMH) chi-square test controlling for the stratification variable anti-
TNF agents use (yes/no). 
 
Supplementary shift tables will be presented showing proportion of subjects at baseline that were 
in each category and shifted from one category to another or remained in the same category at the 
different post-baseline visits.    
 
6.3.3.9 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. Summary descriptive statistics for the actual observed and change from baseline 
will include mean, standard deviation, median and range for each treatment by visit. The change 
from baseline Fecal calprotectin comparing the two treatment groups will be analyzed using an 
analysis of covariance (ANCOVA) model with treatment group, stratification variable anti-TNF 
agents use (yes/no) as classification factors, and baseline Fecal calprotectin as a covariate.  The 
treatment parameter estimates from the analysis model including means, 95% confidence 
intervals and associated 2-sided p-values will be presented including bar graphs. 
 
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 (%) 
with “Normal level” and with “High Level” by treatment group at baseline and at different visit 
time-points with data collected post-baseline. The same statistical method and modeling as used 
for the primary endpoint will be used for this analysis. The proportion of subjects “Normal” at 
baseline and each visit with data post-baseline will be compared between the two treatments 
using Cochran-Mantel-Haenszel (CMH) chi-square test controlling for the stratification variable 
anti-TNF agents use (yes/no). 
 
Supplementary shift tables will be presented showing proportion of subjects at baseline that were 
in each category and shifted from one category to another or remained in the same category at the 
different post-baseline visits. 


 
 
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6.3.3.10 Endoscopic Assessment Based on CDEIS and SES-CD at Week 26  
 
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 drop 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, proportion of surface covered by ulcers, proportion of surface affected by disease, and 
presence and severity of stenosis). Each 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, except for the presence and extent of stenosis, which ranges from 0 to 11 (Total 
SES-CD score range 0–56). 
 
The CDEIS and SES-CD mean scores at baseline and week 26, and change from baseline scores 
to week 26 will be summarized by treatment group for subjects who consent to undergo 
colonoscopy. The change from baseline CDEIS and SES-CD scores comparing the two treatment 
groups based on each of the two scoring systems will be analyzed using analysis of covariance 
(ANCOVA) models with treatment group, stratification variable anti-TNF agents use (yes/no) as 
classification factors, and baseline CDEIS score or SES-CD as covariate.  The treatment 
parameter estimates from the analysis models including means, 95% confidence intervals and 
associated 2-sided p-values will be presented.   
 
In addition, the CDEIS and SES-CD scores will be classified into two categories: “Remission 
(CDEIS 0-3 score; SES-CD 0-2 score)” and “No Remission (CDEIS > 3; SES-CD > 2 score)”.  
Summary results will show number of patients and proportion (%) in “Remission” based on 
CDEIS and also based on SES-CD by treatment group at baseline and at different visit time-
points with data collected post-baseline. The same statistical method and modeling as used for the 
primary endpoint will be used for this analysis.  
 
The proportion of subjects  at baseline and each visit in “Remission post-baseline will be 
compared between the two treatments using Cochran-Mantel-Haenszel (CMH) chi-square test 
controlling for the stratification variable anti-TNF agents use (yes/no). The same statistical 
summary will be repeated comparing the two treatment groups on proportion of responders based 
on CDEIS and SES-CD scores defined as 50% reduction from baseline score and 25% reduction 
from baseline score to week 26.  
 
Supplementary shift tables will be presented showing proportion of subjects at baseline that were 
in “No Remission” category and shifted to “Remission” category or vice versa or remained in the 
same category at the different post-baseline visits. 
 
The following highlights the efficacy summaries in form of tables and/or figures that will be 
displayed by treatment group for both the CDEIS and SES-CD outcomes assessments: 
• 
Endoscopic Remission based CDEIS and SES-CD week 26  


 
 
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• 
Shift Tables from “No Remission” to Remission and vice versa 
• 
Endoscopic Response: 50% reduction in CDEIS and SES-CD scores from baseline 
• 
Endoscopic Response: 25% reduction in CDEIS and SES-CD scores from baseline 
 
Additional supportive analysis will be implemented to estimate the correlations between the 
change from baseline to week 26 in the SES-CD total score, CDEIS total score, and the change 
from baseline to week 26 in the CDAI total score. The results will be presented in graphs 
including Pearson and Spearman correlation coefficients estimates.  Scatter plots of the change in 
SES-CD total score and CDEIS total score versus the change in CDAI total score will be 
presented.  
 
Listing of all subjects indicating CDEIS and SES-CD scores by visit by treatment group will be 
presented.  
 
6.3.4 Other Exploratory Endpoints 
 
6.3.4.1 MAP Detection: Blood PCR Assay, Blood Culture Test and Colon Biopsy PCR Assay 
 
Initial blood culture analyses will be performed upon unblinding of the study using data that is 
available at the time of the data lock.  However, subsequent analyses will be performed to allow 
for further development of the MAP PCR Blood Assay as well as to allow for the 6 month period 
required to grow MAP in culture for participants whose samples did not had adequate culture 
growth duration at the time of the data lock.  Subsequent analyses will occur when all baseline 
samples for participants have at least 6 months of duration to grow MAP in culture, next analyses 
will be repeated when participants with 26 and 52 week data have corresponding 6 and 12 month 
MAP culture measurements, and finally an analysis will be performed once all participants have 
their corresponding 6 month MAP culture measurements available.  Since this outcome measure 
is among the exploratory measures and not considered a primary efficacy endpoint,  performing 
analyses at several time points based on the availability of 6-month MAP culture measurements is 
justified and will not  jeopardize the rigor of the statistical testing proposed for the primary and 
secondary endpoints.   
 
MAP detection analysis is intended to be exploratory. More exploratory analyses may be done 
but the decision on additional types of analyses will depend on the available data and the final 
decisions will be made at the time of analysis. Data collected on MAP detection based on PCR 
Blood Assay, Blood Culture Test and Colon Biopsy PCR assay will be summarized and presented 
as follows:  
 
• 
Proportion of subjects (positive/Negative) for MAP at baseline and weeks 26 and week 
52 post-baseline will be summarized by treatment group. 
 
• 
Shift tables summarizing shifts in status (positive to negative; negative to positive, no 
change) from baseline to week 26 and week 52 post-baseline will be presented by 
treatment. 
 
The same statistical approach as for the primary analysis will be employed to compare proportion 
of subjects (positive/negative) for the RHB-104 treated group versus Placebo treated group on 


 
 
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ITT population week 26 and week 52 using Cochran-Mantel-Haenszel (CMH) chi-square test 
controlling for the stratification variable anti-TNF agents use (yes/no).  
 
Additional analysis will be implemented to estimate the correlations between the change from 
baseline to week 26 and week 52 in PCR Blood Assay level, Blood Culture Test, Colon Biopsy 
PCR Assay level, and the change from baseline to week 26 and week 52 in the CDAI total score. 
The results will be presented in graphs including Pearson and Spearman correlation coefficients 
estimates.  Scatter plots of the change in Blood PCR Assay, Blood Culture Test, and Colon 
Biopsy PCR Assay level versus the change in CDAI total score will be presented. 
 
6.3.4.2 Drug Levels in Tissue Samples 
 
This is an exploratory analysis and will depend on the samples available at the end of the study 
for analysis. The tissue samples being collected will be analyzed for drug levels if possible at the 
end of the study. The patient listings will be presented with correlation of drug levels with CDAI 
and the other efficacy parameters assessed.   
 
6.4 Population PK Analysis 
 
Population PK analysis will be detailed in a separate document. 
 
6.5 Safety Analysis 
 
All summarization of safety data will be based on the safety population. 
 
6.5.1 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 
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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. 
 
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.  
 
6.5.2 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 
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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. 
 
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.   
 
6.5.3  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. 
 
6.5.4 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.   
 
6.5.5 Uveitis Assessment  
 


 
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Results from Uveitis assessments will be listed and summarized by treatment and overall as the 
number and percentage of subjects with Uveitis suspected (yes or no), and if suspected, with 
Uveitis confirmed (yes or no). 
 
6.6 Data and Safety Monitoring Board (DSMB) 
 
In order to ensure the safety of study participants, a Data Safety Monitoring Board (DSMB) will 
be established to monitor data on an ongoing basis. The committee will meet periodically to 
review interim safety data. Following their review, the DSMB will recommend whether the study 
should continue as is or be modified to improve safety. The DSMB will consist of at least one 
clinician with experience in the care of patients with inflammatory bowel disease and at least one 
statistician. The DSMB charter will describe the membership, responsibilities, meeting 
procedures related to the DSMB, output to be reviewed, and interim analysis rules to be applied. 
The DSMB at regular intervals will review the following, at each of the safety analyses meetings: 
• 
Demographic and baseline characteristics 
• 
Physical exam, vital signs, clinical laboratory findings, ECG findings 
• 
Summaries of SAE, AEs and deaths 
• 
Summaries of subject withdrawals 
• 
Summaries of subject accrual and retention 
• 
Summaries of protocol violations 
 
The DSMB will carefully consider safety results and then provide a recommendation for 
continuing or stopping the trial for safety to the Sponsor after each DSMB safety meeting. There 
are three planned DSMB meetings for the study. The first meeting is planned for when 25% of 
patients reach 26 weeks of treatment. The second and third meetings are to occur after 50% and 
75% of patients have completed 26 weeks of treatment or terminated study participation early. 
Once the required numbers of patients have reached each of these thresholds, a database snapshot 
will occur. The DSMB will convene to review safety data within 3 months of the data base 
snapshot. The timing between each DSMB meeting will be at least 6 months. 
 
In addition, it is anticipated that during the second DSMB meeting, an interim efficacy (or 
inefficacy) and futility analyses will be performed and the results of this analysis evaluated by the 
DSMB. 
 
It is prospectively planned as specified in the protocol that the second DSMB meeting at 50% 
randomized subjects will comprise a formal interim of safety and efficacy (or inefficacy) and 
futility analyses will be performed and the results of this analysis evaluated by the DSMB. 
 
6.7 Interim Analysis 
 
One prospectively planned interim analysis for safety and futility is planned after 50% (205) 
patients have completed week 26 of treatment. The DSMB will evaluate the results from this 
analysis to assess RHB-104 safety, efficacy (or inefficacy), and the feasibility of continuing or 
stopping the study. The planned interim analysis is designed to have an alpha level of 0.003 as the 
criteria for stopping the trial early for efficacy or inefficacy based on using the O’Brein-Fleming 
spending function to determine the test boundaries.  For the interim analysis, the Cochran-
Mantel-Haenszel (CMH) test will be used to compare treatment groups controlling for the 


 
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stratification variable (anti-TNF agents (yes/no). The interim test is a 2-sided test (P=0.003), 
meaning that the trial can be stopped if there is overwhelming evidence of efficacy or 
overwhelming evidence of inefficacy.  Further details are provided in the DSMB charter for this 
study.   
 
The protocol specified α-spending for the prospectively plan interim analysis is 0.003. All tests at 
the final analysis will be conducted at significance level of α = 0.049. The interim analyses will 
consider subjects with missing 26 week assessments to not be in a state of remission at 26 weeks.  
 
Regarding the interim efficacy (or inefficacy) of the data, recommendations for early termination 
will be guided by the Lan-DeMets alpha-spending implementation of O’Brien-Fleming spending 
function to determine the test boundaries. The efficacy boundary preserves the overall 2-sided 
study alpha level of 0.05.  The alpha level at first & second sequential test is 0.003 & 0.049, 
respectively.  
 
The DSMB will carefully consider the safety and efficacy interim results and then provide a 
recommendation for continuing or stopping the study. The sponsor and all personnel involved in 
the conduct of the study will remain blinded to the treatment assigned to each subject. The DSMB 
will disseminate interim results in a manner that will protect the scientific and ethical aspects of 
the study. The responsibility of the DSMB, the scope of the data to be reviewed, the organization 
of the review process, dissemination requirements and procedures are described in DSMB 
charter. 
 
6.8 Changes to Statistical Analysis Methods Planned in the Protocol 
 
Changes to planned analyses from the protocol will be incorporated in the SAP, if they occur 
before the unblinding of the database. 
 
7. ADDITIONAL OTHER EXPLOATORY ANALYSES 
 
Other exploratory subgroup analyses to characterize safety and efficacy activities of HRB-104 
versus placebo may be conducted. These additional exploratory analyses will be decided at the 
time of final data analysis. 
 
   


 
 
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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 Enrolled Subjects  
Table 14.1.1.2 
Major Protocol Deviations: Intent-to-Treat Population 
Table 14.1.1.3 
Major Protocol Deviations: Safety Population (if different from ITT) 
 
Demographics and Baseline Characteristics 
Table 14.1.2.1 
Demographics and Baseline Characteristics: Intent-to-Treat Population 
Table 14.1.2.2 
Demographics and Baseline Characteristics: Safety Population (if different from 
ITT) 
Table 14.1.2.3 
Vital Signs at Baseline: Intent-to-Treat Population 
Table 14.1.2.4 
Physical Examination at Baseline: Intent-to-Treat Population 
 
Medical History 
Table 14.1.3.1 
Crohn's Disease History: Intent-to-Treat Population 
Table 14.1.3.2 
Crohn’s Disease Prior Treatments: Intent-to-Treat Population 
 
Prior and Concomitant Medications 
Table 14.1.4.1 
Prior Medications Use: Intent-to-Treat Population 
Table 14.1.4.2 
Concomitant Medications Use: Intent-to-Treat Population 
Table 14.1.4.3 
Prior anti-TNF Agents Use: Intent-to-Treat Population 
Table 14.1.4.4 
Crohn’s Disease Concomitant Medications Use: Intent-to-Treat Population 
Table 14.1.4.5 
Prior Steroids Use: Intent-to-Treat Population 
Table 14.1.4.6 
Concomitant Steroids Use: Intent-to-Treat Population 
Table 14.1.4.7 
Crohn’s Disease Concomitant Steroids Use: Intent-to-Treat Population 
Table 14.1.4.8 
Prior Immunomodulators Use: Intent-to-Treat Population 
Table 14.1.4.9 
Concomitant Immunomodulators Use: Intent-to-Treat Population 
 
Treatment Exposure and Compliance  
Table 14.1.5.1 
Study Drug Exposure: Intent-to-Treat Population 
Table 14.1.5.2 
Treatment Compliance: Intent-to-Treat Population 
 
Primary Efficacy Endpoint 
Table 14.2.1.1 
Primary Objective – Remission Week 26: Intent-to-Treat Population 


 
 
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Table 14.2.1.2 
Sensitivity Analysis:  Remission Week 26: Modified intent-to-Treat Population  
Table 14.2.1.3 
Sensitivity Analysis: Remission Week 26: Per-protocol Population 
Table 14.2.1.4 
Sensitivity Analysis: Remission Week 26: Completers Analysis (Observed 
Cases) 
Table 14.2.1.5 
Exploratory: Remission Week 26 by Treatment Group for Each Baseline 
Subgroup from Logistic Regression analysis: Intent-to-Treat Population 
Figure 14.2.1.1 
Exploratory: Remission Week 26 Forest Plots by Treatment Group for Each 
Baseline Subgroup Analysis: Intent-to-Treat Population 
 
Key Secondary Efficacy Endpoints 
Table 14.2.2.1.1 
Response Week 26: Intent-to-Treat Population 
Table 14.2.2.1.2 
Sensitivity Analysis - Response Week 26: Modified Intent-to-Treat Population 
Table 14.2.2.1.3 
Sensitivity Analysis -  Response Week 26: Per-protocol Population 
Table 14.2.2.1.4 
Sensitivity Analysis -  Response Week 26: Completers Analysis (Observed 
Cases) 
Table 14.2.2.1.5 
Exploratory: Response Week 26 by Treatment Group for Each Baseline 
Subgroup from Logistic Regression analysis: Intent-to-Treat Population 
Figure 14.2.2.1.1 
Exploratory: Response Week 26 Forest Plots by Treatment Group for Each 
Baseline Subgroup Analysis: Intent-to-Treat Population 
 
 
Table 14.2.2.1.6 
Sensitivity Analysis – Mixed Model Repeat Measures (MMRM) of CDAI Score: 
Intent-to-Treat Population 
Table 14.2.2.1.7 
Sensitivity Analysis – Mixed Model Repeat Measures (MMRM) of CDAI Score 
Change from Basleine: Intent-to-Treat Population 
Table 14.2.2.1.8 
Sensitivity Analysis – Negative Binomial Generalized Model Analysis of CDAI 
Remission: Intent-to-Treat Population 
Table 14.2.2.1.9 
Sensitivity Analysis – Poisson Generalized Model Analysis of CDAI Remission: 
Intent-to-Treat Population 
Figure 14.2.2.1.6 
Sensitivity Analysis – Mixed Model Repeat Measures (MMRM) of CDAI Score 
– Plot of Least Square Mean CDAI Score with 95% CI over time: Intent-to-Treat 
Population 
 
 
Table 14.2.2.2.1 
Remission Week 52: Intent-to-Treat Population 
Table 14.2.2.2.2 
Sensitivity Analysis - Remission Week 52: Modified Intent-to-Treat Population 
Table 14.2.2.2.3 
Sensitivity Analysis - Remission Week 52: Per-protocol Population 
Table 14.2.2.2.4 
Sensitivity Analysis -  Remission Week 52: Completers Analysis (Observed 
Cases) 
Table 14.2.2.2.5 
Exploratory: Remission Week 52 by Treatment Group for Each Baseline 
Subgroup from Logistic Regression analysis: Intent-to-Treat Population 
Figure 14.2.2.2.1 
Exploratory: Remission Week 52 Forest Plots by Treatment Group for Each 
Baseline Subgroup Analysis: Intent-to-Treat Population 
 
 
Table 
14.2.2.3.1.1 
Durable (Sustained) Remission Week 26 through Week 52: Intent-to-Treat 
Population 
Table 
14.2.2.3.1.2 
Complementary Analysis: Proportion of subjects that maintained durable 
remission at least 3 out of the 4 visits assessed (i.e. ≥ 75% of the visits in 


 
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remission) week 26 through week 52: Intent-to-Treat Population 
Table 14.2.2.3.2 
Sensitivity Analysis – Durable Remission Week 26 through Week 52: Modified 
Intent-to-Treat Population 
Table 14.2.2.3.3 
Sensitivity Analysis – Durable Remission Week 26 through Week 52: Per-
protocol Population 
Table 14.2.2.3.4 
Sensitivity Analysis -  Durable Remission Week 26 through Week 52: 
Completers Analysis (Observed Cases) 
Table 14.2.2.3.5 
Exploratory: Durable Remission Week 26 through Week 52 by Treatment Group 
for Each Baseline Subgroup from Logistic Regression analysis: Intent-to-Treat 
Population 
Figure 14.2.2.3.1 
Exploratory: Durable Remission Week 26 through Week 52 Forest Plots by 
Treatment Group for Each Baseline Subgroup Analysis: Intent-to-Treat 
Population 
 
 
Table 14.2.2.4.1 
Early Remission Week 16: Intent-to-Treat Population 
Table 14.2.2.4.2 
Sensitivity Analysis – Early Remission Week 16: Modified Intent-to-Treat 
Population 
Table 14.2.2.4.3 
Sensitivity Analysis - Early Remission Week 16: Per-protocol Population 
Table 14.2.2.4.4 
Sensitivity Analysis -  Early Remission Week 16: Completers Analysis 
(Observed Cases) 
Table 14.2.2.4.5 
Exploratory: Early Remission Week 16 by Treatment Group for Each Baseline 
Subgroup from Logistic Regression analysis: Intent-to-Treat Population 
Figure 14.2.2.4.1 
Exploratory: Early Remission Week 16 Forest Plots by Treatment Group for 
Each Baseline Subgroup Analysis: Intent-to-Treat Population 
 
 
Table 14.2.2.5.1 
Steroid Free Remission Week 52: Intent-to-Treat 
Table 14.2.2.5.2 
Sensitivity Analysis – Steroid Free Remission Week 52: Modified Intent-to-Treat 
Population 
Table 14.2.2.5.3 
Sensitivity Analysis - Steroid Free Remission Week 52: Per-protocol Population 
Table 14.2.2.5.4 
Sensitivity Analysis -  Steroid Free Remission Week 52: Completers Analysis 
Table 14.2.2.5.5 
Exploratory: Steroid Free Remission Week 52by Treatment Group for Each 
Baseline Subgroup from Logistic Regression analysis: Intent-to-Treat Population 
Figure 14.2.2.5.1 
Exploratory: Steroid Free Remission Week 52 Forest Plots by Treatment Group 
for Each Baseline Subgroup Analysis: Intent-to-Treat Population 
 
Supportive/Supplementary Endpoints: Time-to-Event Endpoints  
Table 14.2.3.1.1 
Time to Remission: Intent-to-Treat Population 
Table 14.2.3.1.2 
Duration of Remission: Intent-to-Treat Population 
Table 14.2.3.1.3 
Time to Response: Intent-to-Treat Population 
Table 14.2.3.1.4 
Duration of Response: Intent-to-Treat Population 
Figure 14.2.3.1.1 
Time to Remission Kaplan Meir Survival Curve: Intent-to-Treat Population 
Figure 14.2.3.1.2 
Duration of Remission Kaplan Meir Survival Curve: Intent-to-Treat Population 
Figure 14.2.3.1.3 
Time to Response Kaplan Meir Survival Curve: Intent-to-Treat Population 
Figure 14.2.3.1.4 
Duration of Response Kaplan Meir Survival Curve: Intent-to-Treat Population 
 
Supportive/Supplementary Endpoints: Remission and Response Endpoints 


 
 
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Table 
14.2.3.2.1.1 
Sustained Remission Week 16 through Week 52: Intent-to-Treat Population 
Table 
14.2.3.2.1.2 
Complementary Analysis: Proportion of subjects that maintained durable 
remission at least 5 out of the 6 visits assessed (i.e. ≥ 83% of the visits in 
remission) week 16 through week 52: Intent-to-Treat Population 
Table 14.2.3.2.2 
Early Response Week 16: Intent-to-Treat Population 
Table 14.2.3.2.3 
Response week 52: Intent-to-Treat Population 
 
Supportive/Supplementary Endpoints: Endoscopic Assessments 
Table 14.2.3.3.1 
Baseline and Change from Baseline to Weeks 26 in CDEIS Scores: Intent-to-
Treat Population 
Table 14.2.3.3.2 
Baseline and Change from Baseline to Weeks 26 in SES-CD Scores: Intent-to-
Treat Population 
Table 14.2.3.3.3 
Endoscopic Remission based on CDEIS score week 26: Intent-to-Treat 
Population 
Table 14.2.3.3.4 
Endoscopic Remission based on SES-CD scores: Intent week 26-to-Treat 
Population 
Table 14.2.3.3.5 
Shift from Remission to No Remission and Vice Versa based on CDEIS scores 
Week 26 by Treatment Group: Intent-to-Treat Population 
Table 14.2.3.3.6 
Shift from Remission to No Remission and Vice Versa based on SES-CD scores 
Week 26 by Treatment Group: Intent-to-Treat Population 
Table 14.2.3.3.7 
Endoscopic Response: 50% reduction in CDEIS scores from baseline to week 26: 
Intent-to-Treat Population 
Table 14.2.3.3.8 
Endoscopic Response: 50% reduction in SES-CD scores from baseline to week 
26: Intent-to-Treat Population 
Table 14.2.3.3.9 
Endoscopic Response: 25% reduction in CDEIS scores from baseline week 26: 
Intent-to-Treat Population 
Table 
14.2.3.3.10 
Endoscopic Response: 25% reduction in SES-CD scores from baseline week 26: 
Intent-to-Treat Population 
Table 
14.2.3.3.11 
Correlations CDEIS, SES-CD & CDAI Week 26: Intent-to-Treat Population 
Figure 14.2.3.3.1 
Scatter Plot: CDEIS Total Score  vs. CDAI Total score baseline, weeks 26: 
Intent-to-Treat Population 
Figure 14.2.3.3.2 
Scatter Plot: SES-CD Total Score  vs. CDAI Total score baseline, weeks 26: 
Intent-to-Treat Population 
 
Supportive/Supplementary Endpoints: Inflammation Assessment 
Table 14.2.3.4.1 
Summary Serum Marker of Inflammation (CRP) Level: Intent-to-Treat 
Population 
Table 14.2.3.4.2 
Summary Stool Marker of Inflammation Level - Fecal calprotectin: Intent-to-
Treat Population 
Table 14.2.3.4.3 
Proportion of subjects  with CRP Marker of Inflammation Normal/High by Visit 
by Treatment : Intent-to-Treat Population 
Table 14.2.3.4.4 
Proportion of subjects  with Fecal calprotectin Normal/High by Visit by 
Treatment : Intent-to-Treat Population 
Table 14.2.3.4.5 
Shift  in Serum Marker of Inflammation (CRP)  Status Normal/High Baseline to  


 
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Week 26t and Week 52: Intent-to-Treat Population 
Table 14.2.3.4.6 
Shift   in Stool Marker of Inflammation (Fecal calprotectin) Status  Normal/High 
Baseline to Week 26 and Week 52 : Intent-to-Treat Population 
Figure 14.2.3.4.1 
Scatter Plot: CRP  vs. CDAI Total score baseline, weeks 26 & 52: Intent-to-Treat 
Population 
Figure 14.2.3.4.2 
Scatter Plot: Fecal calprotectin vs. CDAI Total score baseline, weeks 26 & 52: 
Intent-to-Treat Population 
 
Supportive/Supplementary Endpoints: Quality of Life Assessment 
Table 14.2.3.5.1 
Short Form (SF-36) questionnaire total score and domain scores at Baseline, 
Week 26 and Week 52: Intent-to-Treat Population 
Table 14.2.3.5.2 
Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Baseline, Week 26 
and Week 52: Intent-to-Treat Population 
Figure 14.2.3.5.1 
Bar Graphs of SF-36 Total Score and Domain Scores at Baseline, 26 and 52 
Weeks by treatment group: Intent-to-Treat Population 
Figure 14.2.3.5.2 
Bar Graphs of IBDQ Score at Baseline,  26 and 52 weeks by Treatment group: 
Intent-to-Treat Population 
 
 Exploratory Endpoints: MAP Detection 
Table 14.2.4.1.1 
Baseline and Change in MAP Blood PCR Assay Status After Weeks 26 and 52: 
Intent-to-Treat Population 
Table 14.2.4.1.2 
Baseline and Change in Blood Culture Status After Weeks 26 and 52: Intent-to-
Treat Population 
Table 14.2.4.1.3 
Baseline and Change in MAP Colon Biopsy PCR Assay Status After Weeks 26 
and 52: Intent-to-Treat Population 
Table 14.2.4.2.1 
Shift in MAP Blood PCR Assay Status From Baseline to Weeks 26 and 52: 
Intent-to-Treat Population 
Table 14.2.4.2.2 
Shift in Blood Culture Status From Baseline to Weeks 26 and 52: Intent-to-Treat 
Population 
Table 14.2.4.2.3 
Shift in Colon Biopsy PCR Assay Status From Baseline to Weeks 26 and 52: 
Intent-to-Treat Population 
Table 14.2.4.3.1 
Baseline Correlations Blood PCR Assay, Blood Culture Test, Colon Biopsy PCR 
Assay and  CDAI: Intent-to-Treat Population 
Table 14.2.4.3.2 
Week 26 Correlations Blood PCR Assay, Blood Culture Test, Colon Biopsy PCR 
Assay and  CDAI: Intent-to-Treat Population 
Table 14.2.4.3.3 
Week 52 Correlations Blood PCR Assay, Blood Culture Test, Colon Biopsy PCR 
Assay and  CDAI: Intent-to-Treat Population 
Figure 14.2.4.1.1 
Scatter Plot: Blood PCR Assay Level  vs. CDAI Total score baseline, weeks 26 
& 52: Intent-to-Treat Population 
Figure 14.2.4.1.2 
Scatter Plot: Blood Culture Test  vs. CDAI Total score baseline, weeks 26 & 52: 
Intent-to-Treat Population 
Figure 14.2.4.1.3 
Scatter Plot: Colon Biopsy PCR Assay vs. CDAI Total score baseline, weeks 26 
& 52: Intent-to-Treat Population 
 
Exploratory Endpoints: General Other Endpoints 
Table 14.2.5.1 
Proportion of subjects tapered off steroids in each treatment arm by Visit Time 


 
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Points Post Baseline 
Table 14.2.5.2 
Summary Tissue Levels of Active Agents of RHB-04 in Colon Biopsy Samples 
by Visit Sample Time-Points Post-baseline 
 
Adverse Events 
Table 14.3.1.1 
Adverse Events Incidence Summary: Safety Population 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term: Safety Population 
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 
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 to Weeks 26 and 52: Safety 
Population 
Table 14.4.2 
Uveitis Assessment at Baseline, Week 26 and Week 52: Safety Population 
 


 
 
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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 16.2.2.1 
Major Protocol Deviations: Intent-to-Treat Population 
Listing 16.2.2.2 
Analysis  Populations: Intent-to-Treat Population 
Listing 16.2.3.1 
Subjects Excluded from Efficacy Analysis  
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 
Listing 16.2.4.4 
Surgical History of Crohn's disease: Intent-to-Treat Population 
Listing 16.2.4.5 
Prior anti-TNF 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 16.2.6.1 
Crohn’s Disease Activity Index (CDAI) Score: Intent-to-Treat Population 
Listing 16.2.6.2 
Remission, Response and Steroid Free  by Time On study: 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 Parameters: Intent-to-Treat Population 
Listing 16.2.6.6 
MAP Detection (yes/no): Intent-to-Treat Population 
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 Assessment – Blood PCR Assay 
Listing 16.2.6.10 
MAP Assessment – Blood Culture 
Listing 16.2.6.11 
MAP Assessment – Colon Biopsy 
Listing 16.2.6.12 
Inflammation Assessment – CRP marker  
Listing 16.2.6.13 
Inflammation Assessment – Fecal calprotectin 
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 


 
 
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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 
 


 
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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.  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. Clinical study protocol (Final 
Version 8.0 dated 17 December 2014. 
 
3.  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. aCRF (version 4.0) dated 23 
September 2013. 
 
4.    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. Data and Safety Monitoring Board 
Charter (Final Draft) dated 17 September 2013. 
 
5.  Elashoff J.D.  nQuery Advisor … Version 7, User’s Guide. 2007. Los Angeles, CA. 
 
6. Medical Dictionary for Regulatory Activities Terminology (MedDRA), Version 16.0, 
2015 Maintenance and Support Services Organization.  
 
7. Sandborn WJ et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s 
Disease Crohn’s Disease. N Engl J Med 2013; 369:711-721. 
      
8. SAS® Version 9.2.  Copyright (c) 2002–2003 by SAS Institute Inc., Cary, NC, USA. 
 
9. WHO Drug Dictionary (March 2009–Standard).  Published by World Health 
Organization, Geneva, Switzerland.