Conditions: Irritable Bowel Syndrome With Diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 127
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, 2-arm parallel group study. After qualifying for the study and signing informed consent, patients will undergo a two-week observation period during which stool consistency and frequency data and symptom data will be collected. Patients will then be randomized 60:40 to RHB-102 12 mg (BEKINDA) or placebo. Patients will continue on treatment for 8 weeks. Each medication will be given once daily.

Detailed description:
All patients will undergo baseline evaluation including full history and physical, with particular attention to gastrointestinal symptomatology and findings, a standard set of safety laboratory examinations (CBC and platelet count, biochemical profile, urinalysis, serum thyroid-stimulating hormone (TSH) and free T4, INR), and 12-lead ECG. In addition, the following studies will be performed to exclude other causes of gastrointestinal symptoms:

* Serum testing for C-reactive protein and gluten sensitivity
* Colonoscopy if required per protocol
* Patients with a history of positive tests for ova, parasites or Clostridium difficile must undergo repeat testing, which must be negative, during the screening period. Starting during the baseline observation phase, all patients will keep diaries of symptomatology and stool frequency and consistency. Stool consistency will be assessed according to the Bristol Stool Form scale (Lewis and Heaton, 1997).

Patients will keep diaries of stool frequency and consistency, symptoms, study medication compliance, and use of all medications, including rescue medications, throughout the study.

Serum electrolyte assays (bicarbonate, calcium, chloride, magnesium, potassium, and sodium) will be performed at week 3 on study. Safety laboratory examinations will be performed during and after the treatment period in accordance with the study procedures schedule below.

Patients will be questioned periodically regarding concomitant medication use and the occurrence of adverse events.

Patients must complete at least 12 days of all baseline diary entries within the 14 day screening period to be eligible to participate in the study. Patients completing fewer than 12 days of diary entries may, at the investigator's discretion, repeat the screening period diary. As long as the patent can complete and enter the study within 6 weeks, baseline laboratory studies need not be repeated. If repeating the 2 weeks' baseline diary will result in a period longer than 6 weeks from consent to start of treatment, the medical monitor must be consulted prior to randomization.

Arms:
arm 1: BEKINDA 12 mg (Ondansetron Bimodal Release Tablets), once daily for 8 weeks arm 2: Placebo, once daily for 8 weeks

Interventions: intervention 1: BEKINDA intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Protocol Number RHB-102-02 
Randomized, Double-blind, Placebo-controlled, Phase 2 Trial of RHB-
102 (Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea 
Predominant Irritable Bowel Syndrome (IBS-D) 
Sponsor: 
RedHill Biopharma Ltd. 
21 Ha’arba’a St. 
Tel-Aviv 64739, Israel 
Tel: +972 (0)3 541 3131 
Fax: +972 (0)3 541 3144 
Protocol Date: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
10 December 2015 
28 February 2016 
13 April 2016 
15 July 2016 
16 February 2017 
CONFIDENTIAL – PROPRIETARY INFORMATION 
The information in this document is confidential and is the property of RedHill Biopharma Ltd. It is understood that this 
information will not be disclosed to any third party, in any form, without prior written authorization from RedHill Biopharma, 
Ltd.  


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Amendment 4:  List of Changes 
Page/ 
section 
Amendment 3 
Amendment 4 
Rationale 
9, Synopsis and 
18, Sec 3.1 
Inclusion 
criterion 1  
Male and female patients 
age≥18 years (with a 
minimum of 35% males in 
the study)  
Male and female patients 
age≥18 years (with a 
minimum of 25% males in 
the study)  
The initial intent of the study was to 
accrue a substantial number of male 
patients so that at least suggestive 
evidence of efficacy in men might be 
obtained.  Due to the difficulty of accruing 
males, however, the Sponsor has 
decided to decrease the proportion of 
males required, understanding that this 
may make it impossible to assess the 
effect of gender on response to 
treatment.  The study will still be stratified 
by gender. 
10, Synopsis  
Second 
sentence in 
paragraph 
Patients will then be 
randomized 60:40 to RHB-
102 12 mg or placebo. 
Patients will then be 
stratified by gender and 
randomized 60:40 to RHB-
102 12 mg or placebo. 
Added the phrase “stratified by gender” 
to clarify the procedure which is in effect. 
This phrase is already in the relevant 
section, 4.3, in the body of the protocol. 
19, Sec 3.2 
Exclusion 
Criterion 1. 
Relevant abnormalities 
seen on colonoscopy if 
previously performed or if 
required per this protocol. 
If previously performed or if 
required per this protocol.. 
These include… 
Relevant abnormalities seen 
on colonoscopy if previously 
performed or if required per 
this protocol.. These 
include…. 
Removed redundancy in protocol. 
20, Sec 4.3 
Randomization 
and Blinding 
At least 35% and not more 
than 65% of patients 
entered are to be males.   
At least 25% and not more 
than 65% of patients entered 
are to be males. 
The minimum proportion of male patients 
is being reduced in order to speed 
accrual. The Sponsor understands that 
this may reduce the possibility of seeing 
a strong efficacy trend in the male 
subgroup. 
24,Sec 5.2.2 On 
Study 
Procedures 
- 
Where medically necessary, 
Investigators may request 
additional (optional) lab tests 
from the central lab; 
however sites will have to 
seek approval from the 
medical monitor prior to 
requesting these tests. 
 
25, Sec 5.2.2 
On Study 
Procedures 
- 
If patient is on every other 
day dosing:  Predose:  44 -
52 hours after prior dose  
 
Clarification for patients who are on 
every other day dose due to constipation 
 


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CONFIDENTIAL:  PROPRIETARY INFORMATION 
3 
 
Table of Contents 
 
Amendment 4:  List of Changes ............................................................................................................ 2 
Table of Contents .................................................................................................................................. 3 
Tables ................................................................................................................................................... 6 
Approvals .............................................................................................................................................. 7 
Protocol Synopsis ................................................................................................................................. 8 
List of Abbreviations ............................................................................................................................ 14 
1. 
Background and Rationale ........................................................................................................... 15 
1.1 
Irritable Bowel Syndrome-Diarrhea Predominant (IBS-D) ..................................................... 15 
1.2 
Ondansetron for IBS-D ......................................................................................................... 15 
1.3 
RHB-102 ............................................................................................................................... 15 
1.4 
Study Rationale .................................................................................................................... 16 
2. 
Objectives .................................................................................................................................... 17 
2.1 
Primary ................................................................................................................................. 17 
2.2 
Secondary ............................................................................................................................ 17 
2.3 
Exploratory ........................................................................................................................... 17 
3. 
Study Population .......................................................................................................................... 18 
3.1 
Inclusion Criteria ................................................................................................................... 18 
3.2 
Exclusion Criteria .................................................................................................................. 19 
4. 
Study Design ............................................................................................................................... 20 
4.1 
Overview ............................................................................................................................... 20 
4.2 
Study Drug Administration .................................................................................................... 20 
4.3 
Randomization and Blinding ................................................................................................. 20 
4.4 
Concomitant Therapy ........................................................................................................... 20 
4.5 
Duration of Treatment ........................................................................................................... 21 
4.6 
Dose Modification ................................................................................................................. 21 
4.7 
Discontinuation of Treatment ................................................................................................ 22 
4.8 
Replacement of Patients ....................................................................................................... 22 
5. 
Study Evaluations ........................................................................................................................ 23 
5.1 
Schedule of Evaluations ....................................................................................................... 23 
5.2 
Description of Study Procedures .......................................................................................... 23 


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5.2.1 
Baseline procedures ...................................................................................................... 23 
5.2.2 
On-study procedures ..................................................................................................... 24 
6. 
Safety Reporting .......................................................................................................................... 26 
6.1 
Terminology .......................................................................................................................... 26 
6.2 
Assessment of Causal Relationship ..................................................................................... 26 
6.3 
Adverse Event Grading and Coding ..................................................................................... 27 
6.4 
Handling of Serious Adverse Events .................................................................................... 28 
6.5 
Laboratory Test Abnormalities .............................................................................................. 29 
6.6 
Other Safety Considerations ................................................................................................. 29 
7. 
Data Analysis and Statistical Considerations ............................................................................... 30 
7.1 
Sample Size Considerations ................................................................................................. 30 
7.2 
Statistical Methods ................................................................................................................ 30 
7.2.1   General Analysis and Coding ........................................................................................... 30 
7.2.2   Analysis Populations ......................................................................................................... 31 
7.3 
Baseline Characteristics and Demographics ........................................................................ 31 
7.4 
Efficacy Analyses .................................................................................................................. 31 
7.4.1 
Primary Endpoint Analysis ............................................................................................. 31 
7.4.2 
Secondary Endpoint Analyses ....................................................................................... 32 
7.4.3 
Exploratory Endpoint Analysis ....................................................................................... 34 
7.4.4 Pharmacokinetic analyses .................................................................................................. 34 
7.4.5 
Subgroup Analyses ....................................................................................................... 34 
7.4.6 
Missing Data .................................................................................................................. 35 
7.5 
Safety Analyses .................................................................................................................... 35 
7.5.1 
Adverse Events ............................................................................................................. 35 
7.5.2 
Clinical Safety Laboratory Tests .................................................................................... 35 
7.5.3 
Other Parameters .......................................................................................................... 36 
8. 
Study Medications ....................................................................................................................... 37 
9. 
Investigator Responsibilities ........................................................................................................ 38 
9.1 
Compliance with Declaration of Helsinki and Good Clinical Practices .................................. 38 
9.2   
Institutional Review Board (IRB) Review and Approval ........................................................ 38 
9.3   
Informed Consent ................................................................................................................. 38 
9.4   
Confidentiality ....................................................................................................................... 38 
9.5   
Source Documentation ......................................................................................................... 38 


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9.6   
Drug Accountability ............................................................................................................... 39 
9.7   
Data Monitoring and Collection ............................................................................................. 39 
9.8   
Case Report Forms, Investigator’s Study File and Record Retention ................................... 39 
9.9   
Non-Protocol Research ........................................................................................................ 39 
10. Sponsor Responsibilities .............................................................................................................. 40 
10.1   General ................................................................................................................................. 40 
10.2   Case Report Forms .............................................................................................................. 40 
10.3 
Data Monitoring and Collection ............................................................................................. 40 
10.4   Audit ..................................................................................................................................... 40 
10.5   Confidentiality ....................................................................................................................... 40 
11. Protocol Modifications .................................................................................................................. 41 
12. Publication ................................................................................................................................... 42 
13. References .................................................................................................................................. 43 
Appendices ......................................................................................................................................... 44 
Appendix I.  Daily assessments ....................................................................................................... 44 
Appendix II.  Child-Pugh score ........................................................................................................ 46 
 


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Tables 
Table 1. Study Procedures.................................................................................................................. 13 
Table 2.  Pharmacokinetic sampling ................................................................................................... 24 
Table 3.  Relationship of Study Medication to Adverse Events ........................................................... 27 
 


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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Approvals 
 
The investigator agrees to conduct the trial as described in the protocol in accordance with all FDA 
regulations, and according to current ICH GCP. 
By agreement to this protocol, the investigator agrees to allow direct access to all essential 
documents, including source documents to authorized individuals representing the sponsor (including 
monitors, auditors and other personnel), to institutional review boards (IRBs) and to regulatory 
authorities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Principal Investigator: 
 
___________________________ 
 
____________ 
 
 
 
 
 
 
 
Date 
 
Name:______________________ 
 
 
 


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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Protocol Synopsis 
 
 
Title 
Randomized, Double-blind, Placebo-controlled, Phase 2 Trial of RHB-
102 (Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea 
Predominant Irritable Bowel Syndrome (IBS-D) 
Study location 
USA 
Study drug 
RHB-102, ondansetron 12 mg bimodal tablets 
Comparator 
Placebo 
Rationale 
Irritable bowel syndrome (IBS) is a functional bowel disorder in which 
abdominal pain or discomfort is associated with disordered defecation 
(Longstreth et al, 2006).  One of the major types of IBS is diarrhea 
predominant, IBS-D. 5-HT3 antagonists have been shown to slow 
intestinal transit time in animals (Clayton et al, 1999) and humans 
(Garsed et al, 2013).  In preliminary studies, ondansetron has 
demonstrated activity in IBS-D (Steadman et al, 1992; Clayton et al, 
1999; Garsed et al, 2013). Unlike alosetron, ondansetron has not been 
noted to cause ischemic colitis (FDA labeling for Lotronex [alosetron], 
2010; FDA labeling for Zofran [ondansetron], 2014). 
RHB-102 is a bimodal release formulation of ondansetron.  It provides 
an initial release similar to immediate release ondansetron and then 
extended release over 24 hours.  Because of its extended release 
properties, and once daily dosing it would appear to be an excellent 
candidate for treatment of IBS-D. 
Objectives 
Primary: 
Proportion of patients in each treatment group with response in stool 
consistency on study as compared to baseline. 
A weekly stool consistency responder is defined as a patient who 
experiences ≥50% reduction in the number of days per week with at 
least one stool with a Bristol Stool Scale score of 6 or 7 compared with 
baseline, and abdominal pain is unchanged or improved in comparison 
with baseline.  A patient will be considered a stool consistency 
responder for the study if he or she is a stool consistency responder for 
≥50% of the planned weeks of study. 
Secondary: 
Proportion of patients in each treatment group who are pain responders, 
per FDA guidance definition 
Proportion of patients in each treatment group who are overall 
responders, per FDA guidance definition 
Differences between treatment groups in  
Abdominal pain 
Abdominal discomfort 
Frequency of defecation 
Incidence and severity of adverse events 
Exploratory:  
Decrease in urgency 
 
Population 
Patients who meet Rome III criteria for IBS-D and do not have evidence 
of other gastrointestinal diseases which may be responsible for their 
symptomatology 


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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Inclusion criteria: 
1. Male and female patients age≥18 years (with a minimum of 25% 
males in the study)  
2. Patient meets FDA guidance and Rome III criteria for IBS-D: 
a. Recurrent abdominal pain or discomfort over ≥6 months, 
with frequency ≥3 days/month in the last 3 months 
associated with ≥2 of the following: 
i. Improvement with defecation 
ii. Onset associated with a change in frequency of 
stool 
iii. Onset associated with a change in the form of stool 
b. Loose or watery stools (Bristol stool form scale 6 or 7) ≥2 
days per week  
3. Average worst daily pain intensity ≥3.0  for each of the two baseline 
weeks 
4. Major laboratory parameters within the following limits (no worse 
than grade 1 abnormalities per NCI-CTCAE v4): 
a. Adequate hematologic function, as demonstrated by 
i. Hemoglobin ≥10 g/dL 
ii. ANC 1.5-10 x 109/L 
iii. Platelets ≥100 x 109/L 
b. Adequate liver and renal function as demonstrated by 
i. AST and ALT each ≤3.0 x ULN 
ii. Total bilirubin ≤1.5 x ULN 
iii. Creatinine ≤1.5 X ULN 
c. Euthyroid based on TSH and free T4 levels 
5. Patients on thyroid hormone replacement must be on a stable dose 
for at least one month prior to study entry. 
6. C-reactive protein ≤2 x upper limit of normal for lab 
7. Patients of childbearing potential and male patients with partners of 
childbearing potential must utilize effective contraceptive measures 
Women of childbearing potential are women who have menstruated 
in the past 12 months, with the exception of women who have 
undergone surgical sterilization 
8. All patients must sign informed consent. 
Exclusion criteria: 
1. Evidence of other cause for bowel disease: 
a. Relevant abnormalities seen on colonoscopy if 
previously performed or if required per this protocol 
These include but are not limited to Crohn’s disease, 
ulcerative colitis, diverticulitis, ischemic colitis, 
microscopic colitis.  
b. History of and/or positive serologic test for celiac 
disease 
c. Known or suspected lactose intolerance. 
2. History of abdominal surgery other than appendectomy or 
cholecystectomy at any time 
3. Any elective major surgery (of any organ) planned for the period of 
the study, including follow-up 
4. History of organic abnormalities of the GI tract including but not 
limited to intestinal obstruction, stricture, toxic megacolon, GI 
perforation, fecal impaction, gastric banding, adhesions or impaired 
intestinal circulation (e.g., aortoiliac disease) 
5. Current or previous diagnosis of neoplasia (except non-GI 
neoplasia in complete remission ≥5 years, squamous and basal cell 


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
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CONFIDENTIAL:  PROPRIETARY INFORMATION 
10 
 
carcinomas).  With approval of the medical monitor, patients with 
curatively treated neoplasms in complete remission <5 years may 
be entered in the study. 
6. Patients with a history of positive tests for ova or parasites or 
Clostridium difficile must be retested during the screening period 
and tests for the relevant agents must be negative 
7. Use of any 5-HT3 antagonist within 4 weeks of the start of baseline 
data collection 
8. Use of rifaximin within 4 months of the start of baseline data 
collection 
9. Use of any other agent specific for IBS (such as alosetron or 
eluxadoline) or for symptomatic treatment of IBS (such as 
antispasmotics and antidiarrheals other than loperamide) within 2 
weeks of the start of baseline data collection 
 
10. Uses of any investigational agent for any indication within 4 weeks 
of the start of baseline data collection 
 
11. Congestive heart failure, bradyarrhythmia (baseline pulse<55/min), 
known long QT syndrome 
12. Patients who have QTc prolongation>450 msec noted on screening 
ECG, or who are taking medication known to cause QT 
prolongation 
Note:  For current list of medications known to cause QT 
prolongation see: 
https://www.crediblemeds.org/healthcare-providers/drug-list/ 
There are several risk categories.  Use the list showing those drugs 
known to cause torsade de pointes (TdP). 
13. Hypersensitivity or other known intolerance to ondansetron or other 
5-HT3 antagonists 
14. Patient has taken apomorphine within 24 hours of screening 
15. Pregnant or lactating 
16. Patients with other major illnesses, either physical or psychiatric, or 
social situations which may interfere with participation in the study 
or interpretation of results 
17. Patients with severe hepatic impairment, defined as Child-Pugh 
score ≥10 at baseline. 
Design 
This is a randomized double-blind, 2-arm parallel group study. After 
qualifying for the study and signing informed consent, patients will 
undergo a two-week observation period during which stool consistency 
and frequency data and symptom data will be collected.  Patients will 
then be stratified by gender and randomized 60:40 to RHB-102 12 mg 
or placebo.  Patients will continue on treatment for 8 weeks.  Each 
medication will be given once daily. 
Group 
Treatment 
A 
RHB-102 12 mg 
B 
Placebo 
Methodology 
All patients will undergo baseline evaluation including full history and 
physical, with particular attention to gastrointestinal symptomatology 
and findings, a standard set of safety laboratory examinations (CBC and 
platelet count, biochemical profile, urinalysis, serum TSH and free T4, 
INR), and 12-lead ECG.  In addition, the following studies will be 


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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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performed to exclude other causes of gastrointestinal symptoms: 
• 
Serum testing for C-reactive protein and gluten sensitivity 
• 
Colonoscopy if required per protocol 
• 
Patients with a history of positive tests for ova, parasites or 
Clostridium difficile must undergo repeat testing, which must be 
negative, during the screening period. Starting during the baseline 
observation phase, all patients will keep diaries of symptomatology 
and stool frequency and consistency.  Stool consistency will be 
assessed according to the Bristol Stool Form scale (Lewis and 
Heaton, 1997). 
Patients will keep diaries of stool frequency and consistency, symptoms, 
study medication compliance, and use of all medications, including 
rescue medications, throughout the study. 
Serum electrolyte assays (bicarbonate, calcium, chloride, magnesium, 
potassium, and sodium) will be performed at week 3 on study. Safety 
laboratory examinations will be performed during and after the treatment 
period in accordance with the study procedures schedule below. 
Patients will be questioned periodically regarding concomitant 
medication use and the occurrence of adverse events. 
Patients must complete at least 12 days of all baseline diary 
entries within the 14 day screening period to be eligible to 
participate in the study.  Patients completing fewer than 12 days of 
diary entries may, at the investigator’s discretion, repeat the 
screening period diary.  As long as the patient can complete and 
enter the study within 6 weeks, baseline laboratory studies need 
not be repeated.  If repeating the 2 weeks’ baseline diary will result 
in a period longer than 6 weeks from consent to start of treatment, 
the medical monitor must be consulted prior to randomization. 
Endpoints 
Efficacy: 
 
Stool consistency each stool, per Bristol Stool Form scale 
Worst abdominal pain intensity per 24-hour period, on an 11-point Likert 
scale 
Frequency of bowel movements 
Worst discomfort per 24-hour period, on an 11-point Likert scale 
Interference of IBS with general functioning, on a 5-point Likert scale 
Safety: 
Occurrence of adverse events, both clinical and laboratory. 
Adverse events will be tabulated by system organ class (SOC) and 
preferred term (PT) using MedDRA version 13.1.  Adverse events will 
be graded 1-4 according to NCI-CTCAE v4 criteria. 
Statistics 
Sample size will be calculated based on expected difference in primary 
endpoint between groups using 80% power, and a significance level of 
α=0.05. 
Based on Garsed et al, 2014, the expected response rates are 80% in 
the active group and 40% in the placebo group.  To allow for a 
somewhat smaller difference, i.e., 70% response rate in active group 
and 40% in placebo group, and 60:40 rather than 1:1 randomization, a 
total of 120  patients will be randomized, 72 to RHB-102 and 48 to 
placebo. 
Safety assessments will be based on results from all patients who 
receive any study medication, either active or placebo. 
Sample size 
calculation 
 
 
 
 
 
Study populations: 
 


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Efficacy: 
Primary endpoint 
 
 
Efficacy data will be calculated, for the primary analysis, intent to treat, 
based on all patients randomized and who receive at least one dose of 
any study medication, either active or placebo.  Per protocol analysis 
will include all patients who receive ≥75% of the planned study 
medication and have at least 12 days’ baseline data and at least one full 
week (minimum 7 days of data) on study, or discontinue before that due 
to documented lack of efficacy. 
The primary endpoint in the study is stool consistency response in the 
absence of increase in pain (<10% increase in weekly average of worst 
daily pain). 
A weekly stool consistency responder is defined as a patient who 
experiences during a week ≥50% reduction in the number of days per 
week with at least one stool that has a consistency of Type 6 or 7 
compared with baseline, and abdominal pain is unchanged or improved 
in comparison with baseline. 
A patient will be characterized as an overall stool consistency responder 
if the patient was a weekly responder for ≥50% of the weeks of 
treatment. 
Secondary 
endpoints: 
 
Pain responder:  Abdominal pain intensity weekly responder:  patient 
who experiences a decrease in the weekly average of worst abdominal 
pain in the past 24 hours score ≥30% compared with baseline. 
A patient is characterized as an overall weekly responder if the patient 
meets both the stool consistency and pain response definitions for a 
given week. 
A patient is characterized as an overall study responder if the patient 
meets the criteria for overall weekly response for at least half the 
planned study weeks. 
Changes from baseline to each week on study for these parameters, as 
well as for each of the secondary efficacy parameters will be calculated 
and compared between active treatment group and placebo. 
Use of rescue medication (any and quantitatively) each week on study 
and overall across the study will be compared between each active 
treatment group and placebo. 


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Table 1. Study Procedures 
Procedure                            Week 
-4 to -
2 
-2 and 
-1a 
1 
2b 
3 
5 
7 
9 
13 
Screening assessmentsc 
X 
 
 
 
 
 
 
 
 
Physical examination inc VSd 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
 
X 
 
 
 
 
 
 
Stool, pain and discomfort 
assessmentsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, biochemical profileg 
X 
 
X 
 
 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
 
X 
X 
Electrolytesh 
 
 
 
 
X 
 
 
 
 
Pharmacokinetic samplingi 
 
 
X 
 
X 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensing 
 
 
X 
 
 
X 
 
 
 
Review of study medication use 
 
 
 
X 
X 
X 
X 
X 
 
Notes: 
aDuring weeks -2 and -1, patients will collect baseline data, including the daily assessments, use of concomitant 
medications including those for symptoms of IBS, and occurrence of adverse events.  These data will be provided to and 
reviewed by the investigator and/or staff prior to the week 1 visit, at which time the patient will be randomized and start 
treatment. 
bWeek 2 visit may be a phone contact 
cInformed consent, history, serum TSH and free T4, urinalysis, INR, C-reactive protein, colonoscopy when required per 
protocol (see section 5.2.1, page 29, below), serology for celiac disease, stool for ova, parasites and C diff, respectively, if 
positive history for any of these, ECG. 
dPhysical examination including vital signs:  full physical examination at baseline;  interim examinations of pertinent 
systems with attention to areas of change based on symptoms at subsequent examinations.  At each visit: temperature, 
blood pressure, pulse, respiratory rate, weight.  Height to be recorded at initial screening visit only. 
eFor women of childbearing potential. 
fStool and symptom assessments:  daily Bristol chart; diaries for urgency, worst abdominal pain and worst abdominal 
discomfort during each day, using 11-point Likert scale (0-10) for each, with 0= no pain or no discomfort and 10=as bad 
as can be;  daily assessment of interference by IBS with activities of daily living on a 5-point Likert scale;  daily count of 
number of bowel movements;  adverse events also to be recorded in diary.  Diary may be given to patient at initial 
screening visit or any time thereafter. 
gSafety labs:  CBC, platelet count, biochemical profile to include at a minimum albumin, alkaline phosphatase, ALT, AST, 
bicarbonate, total bilirubin, BUN, calcium, chloride, creatinine, glucose, magnesium, potassium, total protein, sodium. 
hSerum Ca, Cl, HCO3, K, Mg, Na.  Need not be fasting or predose.  
iPharmacokinetic sampling will be performed on all patients on day 1 prior to initial dosing and on day 1 of weeks 3 and 5.  
See Table 2, page 24, for details of pharmacokinetic sampling procedure. 
 


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List of Abbreviations 
°C 
degrees Celsius 
β-HCG 
beta-human chorionic gonadotropin 
5-HT3 
5-hydroxytryptamine3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CO2 
Bicarbonate 
CRF 
case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
HIPAA 
Health Information Portability and Accountability Act 
IBS 
irritable bowel syndrome 
IBS-D 
irritable bowel syndrome – diarrhea predominant 
ICH 
International Committee on Harmonisation 
IRB 
institutional review board 
Kg 
kilogram 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
milligram 
mITT 
Modified intent-to-treat 
NCI-CTCAE v 4 
National Cancer Institute common terminology criteria 
for adverse events, version 4 
PP 
Per protocol 
SAE 
 
serious adverse event 
 
SAP 
statistical analysis plan 
SOC 
System organ class 
VS 
vital signs 
vs 
Versus 
WBC 
white blood count 
WOCBP 
women of childbearing potential 


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1. 
Background and Rationale 
1.1 
Irritable Bowel Syndrome-Diarrhea Predominant (IBS-D) 
Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain or discomfort is 
associated with disordered defecation (Longstreth et al, 2006).  Unlike inflammatory bowel diseases, 
no anatomic or biochemical abnormalities have been correlated with IBS.  The disease may cause 
substantial discomfort and morbidity, and often results in considerable reduction in quality of life 
(Canavan et al, 2014).  Over the past several decades, criteria for diagnosis and classification have 
been developed.  The Rome criteria, most recently Rome III promulgated in 2006, are the most 
commonly used for diagnosis of IBS and definition of subgroups. 
Over 10% of adults worldwide have symptoms of IBS (Canavan et al, 2014).  In most studies, 
prevalence is much greater in females than males, with ratios of 1.5-3.0 to 1 reported in various 
studies. 
Several subtypes of IBS have been defined, based on predominant stool pattern (Longstreth et al, 
2006): 
IBS-C:  IBS with constipation 
IBS-D:  IBS with diarrhea 
IBS-M:  mixed IBS, sometimes constipation, sometimes diarrhea 
Unsubtyped IBS:  not classifiable into one of the above patterns 
IBS-D is IBS with at least 25% of stools loose or watery and not more than 25% of stools hard or 
lumpy. Many different therapies, including pharmacologic, behavioral, yoga and probiotics, have been 
advocated for treatment of IBS.  A recent article reviews pharmacological interventions for IBS 
(Chang et al, 2014).  Their conclusion was that several pharmacologic interventions, including a 5-
HT3 antagonist, alosetron, had significant activity in treatment of IBS. 
1.2 
Ondansetron for IBS-D 
5-HT3 antagonists have been shown to slow intestinal transit time in animals (Clayton et al, 1999) 
and humans (Garsed et al, 2013).  One 5-HT3 antagonist, alosetron (Lotronex) has been approved 
for treatment of IBS in women with severe, chronic IBS-D which has not responded adequately to 
conventional therapy and in whom anatomic or biochemical abnormalities of the gastrointestinal tract 
had been excluded.  The drug was originally approved and then withdrawn due to the occurrence of 
ischemic colitis and other severe complications.  It was eventually reintroduced with severe 
restrictions on who can prescribe it and the patients to whom it can be administered.  
In preliminary studies, ondansetron has demonstrated activity in IBS-D (Steadman et al, 1992; 
Clayton et al, 1999; Garsed et al, 2013). Unlike alosetron, ondansetron has not been noted to cause 
ischemic colitis (FDA labeling for Lotronex [alosetron], 2010; FDA labeling for Zofran [ondansetron], 
2014).  Thus, due to its safety profile and the preliminary evidence demonstrating efficacy, 
ondansetron may be preferable to alosetron for treatment of IBS-D. 
1.3 
RHB-102 
RHB-102 is a bimodal release oral formulation of ondansetron.  It contains 12 mg of ondansetron, 3 
mg immediate release and 9 mg in an extended release matrix.  Pharmacokinetic studies in healthy 
volunteers have demonstrated rapid early release, with appearance of drug in the plasma within half 


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an hour of dosing, similarly to immediate release Zofran, but with sustained drug availability over 24 
hours.  Thus, RHB-102 should provide rapid relief, yet require only once daily dosing for a sustained 
effect.  The safety profile of RHB-102 is similar to that of Zofran 8 mg, as demonstrated in volunteer 
studies. 
1.4 
Study Rationale 
As noted above, there is preliminary evidence that ondansetron is effective in treatment of IBS-D and 
that it may be a safer alternative to alosetron.  Ondansetron has never been developed through 
rigorous phase 3 studies for this indication.   
The goal of this pilot study is to assess the efficacy of RHB-102 for treatment of IBS-D versus 
placebo.  Information from this study will be used to determine whether RHB-102 is sufficiently 
effective to warrant further assessment in a phase 3 study, and to determine the treatment and 
assessment parameters to be used in such a study. 
 
 


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2. 
Objectives 
2.1 
Primary 
Proportion of patients in each treatment group with response in stool consistency on study as 
compared to baseline. 
A weekly stool consistency responder is defined as a patient who experiences ≥50% reduction 
in the number of days per week with at least one with a Bristol Stool Scale score of 6 or 7 
compared with baseline, and abdominal pain is unchanged or improved in comparison with 
baseline.  Baseline is the 2-week period prior to the start of dosing during which stool and 
other symptom data are collected.  A patient will be considered a stool consistency responder 
for the study if he or she is a stool consistency responder for ≥50% of the planned weeks of 
study. 
2.2 
Secondary 
Efficacy:  Changes in the following assessed for each treatment group: 
• Decrease in abdominal pain 
• Decrease in abdominal discomfort 
• Decrease in frequency of defecation 
• Decrease in interference by IBS with activities of daily living 
Results of each of the secondary efficacy endpoints will be compared between each active treatment 
group and the placebo group.  In addition, a composite efficacy endpoint of stool consistency and 
abdominal pain, per FDA guidance, will be calculated for each patient. A patient is a composite 
responder (FDA endpoint) during a given week if he or she meets criteria for the primary endpoint, 
above, and meets the criteria for abdominal pain intensity response, a decrease in the weekly 
average of worst abdominal pain in the past 24 hours of ≥30% compared with baseline. 
Safety:  Incidence and severity of adverse events by treatment group 
2.3 
Exploratory 
Decrease in urgency 
This will be evaluated similarly to other secondary endpoints, above.  


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3. 
Study Population 
Approximately 
120 
patients 
who 
meet 
FDA 
guidance 
and 
Rome 
III 
criteria 
(http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf) for IBS-D and do not have 
evidence of other gastrointestinal diseases which may be responsible for their symptomatology will be 
randomized to one of the two treatment groups described below. 
3.1 
Inclusion Criteria 
1. Male and female patients age≥18 years (with a minimum of 25% males in the study)  
2. Patient meets FDA guidance and Rome III criteria for IBS-D: 
a. Recurrent abdominal pain or discomfort over ≥6 months, with frequency ≥3 
days/month in the last 3 months associated with ≥2 of the following: 
i. Improvement with defecation 
ii. Onset associated with a change in frequency of stool 
iii. Onset associated with a change in the form of stool 
b. Loose or watery stools (Bristol stool form scale 6 or 7) ≥2 days per week  
3. Average worst daily pain intensity ≥3.0  for each of the two baseline weeks 
4. Major laboratory parameters within the following limits (no worse than grade 1 abnormalities 
per NCI-CTCAE v4): 
a. Adequate hematologic function, as demonstrated by 
i. Hemoglobin ≥10 g/dL 
ii. ANC 1.5-10 x 109/L 
iii. Platelets ≥100 x 109/L 
b. Adequate liver and renal function as demonstrated by 
i. AST and ALT each ≤3.0 x ULN 
ii. Total bilirubin ≤1.5 x ULN 
iii. Creatinine ≤1.5 X ULN 
c. Euthyroid based on TSH and free T4 levels 
5. Patients on thyroid hormone replacement must be on a stable dose for at least one month prior 
to study entry. 
6. C-reactive protein ≤2 x upper limit of normal for lab 
7. Patients of childbearing potential and male partners of females of childbearing potential must 
utilize acceptable contraceptive measures 
Women of childbearing potential are women who have menstruated in the past 12 months, 
with the exception of women who have undergone surgical sterilization 
8. All patients must sign informed consent. 


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3.2 
Exclusion Criteria 
1. Evidence of other cause for bowel disease: 
a. Relevant abnormalities seen on colonoscopy if previously performed or if required per 
this protocol. These include but are not limited to Crohn’s disease, ulcerative colitis, 
diverticulitis, ischemic colitis, microscopic colitis.  
b. History of and/or positive serologic test for celiac disease 
c. Known or suspected lactose intolerance. 
2. History of abdominal surgery other than appendectomy or cholecystectomy at any time 
3. Any elective major surgery (of any organ) planned for the period of the study, including follow-
up 
4. History of organic abnormalities of the GI tract including but not limited to intestinal obstruction, 
stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, adhesions or 
impaired intestinal circulation (e.g., aortoiliac disease) 
5. Current or previous diagnosis of neoplasia (except non-GI neoplasia in complete remission ≥5 
years, squamous and basal cell carcinomas).  With approval of the medical monitor, patients 
with curatively treated neoplasms in complete remission <5 years may, be entered in the 
study.  
6. Patients with a history of positive tests for ova or parasites or Clostridium difficile must be 
retested during the screening period and tests for the relevant agents must be negative 
7. Use of any 5-HT3 antagonist within 4 weeks of the start of baseline data collection 
8. Use of rifaximin within 4 months of the start of baseline data collection 
9. Use of any other agent specific for IBS (such as alosetron or eluxadoline) or for symptomatic 
treatment of IBS (such as antispasmotics and antidiarrheals other than loperamide) within 2 
weeks of the start of baseline data collection 
10. Uses of any investigational agent for any indication within 4 weeks of the start of baseline data 
collection 
11. Congestive heart failure, bradyarrhythmia (baseline pulse<55/min), known long QT syndrome 
12. Patients who have known QTc prolongation>450 msec, noted on prior ECG, or who are taking 
medication known to cause QT prolongation 
Note:  For current list of medications known to cause QT prolongation see: 
https://www.crediblemeds.org/healthcare-providers/drug-list/ 
There are several risk categories.  Use the list showing those drugs known to cause torsade 
de pointes (TdP). 
13. Hypersensitivity or other known intolerance to ondansetron or other 5-HT3 antagonists 
14. Patient has taken apomorphine within 24 hours of screening 
15. Pregnant or lactating 
16. Patients with other major illnesses, either physical or psychiatric, or social situations which 
may interfere with participation in the study or interpretation of results 
17. Patients with severe hepatic impairment, defined as Child-Pugh score ≥10 at baseline 
 


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4. 
Study Design 
4.1 
Overview 
This is a randomized double-blind, 2-arm parallel group study. After qualifying for the study, patients 
will undergo a two-week observation period during which stool consistency and frequency data and 
symptom data (listed below and in detail in Appendix I) will be collected.  Patients will then be 
randomized 60:40 to once daily treatment with either RHB-102 12 mg or placebo.  Patients will 
continue on treatment for 8 weeks.  All medications will be given orally. 
Group 
Treatment 
A 
RHB-102 12 mg 
B 
Placebo 
4.2 
Study Drug Administration  
Once patients have consented, completed all required pretreatment tests, and found to be eligible for 
the study, they will be randomized to one of the two treatment groups.  Patients will be given a four 
week supply of drug and instructed to take it once daily, before breakfast with approximately 240 mL 
(8 oz) of water.  If a patient forgets to take the medication before breakfast, he or she can take it later 
in the day;  the time of administration should be recorded.  
Patients will also be instructed to complete a diary, including information about stool consistency 
(Bristol chart), urgency worst abdominal pain, worst abdominal discomfort, interference with daily 
activities,  concomitant medications (including rescue medications) and adverse events.   
4.3 
Randomization and Blinding 
Patients will be stratified by gender (male/female) and randomized 60:40 to treatment with one of two 
matching products: 
• RHB-102 12 mg tablets 
• Placebo 
At least 25% and not more than 65% of patients entered are to be males.  If the planned enrollment 
for either gender is reached before the end of the study, no more patients of that gender will be 
enrolled in the study. 
4.4 
Concomitant Therapy 
Patients can continue all concomitant medications, except those specifically excluded in this study, 
listed below: 
• 5-HT3 antagonists (other than study medication) 
• Other medications indicated specifically for treatment of IBS-D, e.g., eluxadoline 
• Symptomatic treatments for IBS-D such as antispasmodics and antidiarrheals (other than 
loperamide) 
• Apomorphine 
• Medications known to cause QT prolongation.  Note:  For current list of medications known to 
cause QT prolongation see:  https://www.crediblemeds.org/healthcare-providers/drug-list/ 
There are several risk categories.  Use the list showing those drugs known to cause torsade 
de pointes (TdP). 


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5-HT3 antagonists, including ondansetron, have been associated with serotonin syndrome.  When 
given as a single agent, ondansetron overdose has been associated with serotonin syndrome.  
However, most reports of serotonin syndrome have been associated with concomitant use of 
serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and 
norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, 
lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. 
Symptoms associated with serotonin syndrome may include the following combination of signs and 
symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic 
instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), 
neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, 
with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be 
warned about and monitored for the emergence of serotonin syndrome, especially with concomitant 
use of other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue RHB-102 and 
initiate supportive treatment. 
The dose of ondansetron used in this study is low.  Therefore, the risk of serotonin syndrome is 
considered extremely low, and the potential benefit of control of IBS-D considered to outweigh the 
risk of serotonin syndrome.  However, while the following classes of medications are allowed, use of 
these during the study is discouraged for patients who are not receiving these at baseline: 
• Selective serotonin reuptake inhibitors (SSRIs) 
• Serotonin and norepinephrine reuptake inhibitors (SNRIs)  
• tricyclic antidepressants 
Concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound 
hypotension and loss of consciousness when apomorphine was administered with ondansetron. 
Additional prohibited concomitant medications include systemic antibiotics (other than ≤14 days’ 
treatment for acute illnesses), drugs enhancing gastrointestinal motility, laxatives, and antidiarrheal 
agents other than loperamide. 
All medications which the patient took within the 30 days prior to the start of study therapy and those 
taken during the study and for 30 days after the last dose are to be recorded in the case report form.  
If the patient has required thyroid replacement therapy, this must be at a stable dose for at least one 
month prior to study entry. 
The only rescue medication allowed is loperamide, which may not be taken during the baseline 
assessment period.  During the treatment phase, loperamide may not be taken more often than a 
maximum daily dose of two 2 mg pills (total of 4 mg) and not more than 3 days in any given week.All 
rescue medication taken and the doses/number of pills used are to be recorded in the CRF.   
4.5 
Duration of Treatment 
Patients will be treated daily for 8 weeks.  
4.6 
Dose Modification 
Patients who develop constipation are to reduce dosing to once every other day.  When constipation 
resolves, if symptoms recur or worsen, the patient may, in consultation with the investigator, increase 
the dose back to once daily. If constipation recurs, the patient is to again decrease the dose to once 
every other day. 


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If constipation persists despite decrease in dose to once every other day, study medication is to be 
discontinued. 
Constipation is defined as no bowel movement for 48 hours or more. 
4.7 
Discontinuation of Treatment 
Patients must discontinue therapy if they require any medication prohibited in this study.  Additional 
reasons for discontinuation, at the investigator’s discretion: 
• Clinically significant adverse event, regardless of relation to study medication 
• Lack of efficacy:  worsening symptoms persisting for at least two weeks during the study 
In addition, patients may elect to discontinue study therapy at any time. 
The investigator shall attempt to obtain follow-up assessments per protocol regardless of when the 
patient discontinues therapy.  The procedures and tests required for the week 9 visit per Table 1 
should be performed at the time of early discontinuation of therapy.  The follow-up visit (week 13 in 
Table 1) should be conducted 4 weeks after the early termination visit. 
4.8 
Replacement of Patients 
Patients who are randomized but receive no study medication shall be replaced. 
Patients who receive any study medication shall not be replaced. 


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5. 
Study Evaluations 
5.1 
Schedule of Evaluations 
A flow chart of study evaluations is shown above, in Table 1.  Informed consent must be obtained 
before any study-specific procedures are performed.  However, data from procedures and 
assessments carried out prior to consent in the context of routine clinical care (e.g., endoscopies) 
may be used if they have been performed within study-required windows. 
5.2 
Description of Study Procedures 
5.2.1 Baseline procedures 
• Informed consent 
• History and physical, including vital signs. History should include detailed description of IBS 
symptomatology and therapy. 
• Physical examination should include all pertinent body systems. 
• Vital signs should include height, weight, temperature, pulse, blood pressure, respiratory rate.  All 
units should be metric. 
• Baseline laboratory studies:  CBC, biochemical profile, urinalysis, INR, serology for celiac disease 
and, for women of childbearing potential, serum or urine pregnancy test.  
• CBC to include:  total RBC, total WBC count, absolute values for individual white blood cell 
types and platelet count. 
• Biochemical profile to include:  albumin, alkaline phosphatase, ALT, AST, (total) bilirubin, BUN, 
calcium, chloride, CO2, creatinine, glucose, magnesium, potassium, sodium, total protein. 
• Urinalysis to include at a minimum:  routine:  dipstick tests for protein, glucose, ketones, blood, 
pH, specific gravity;  microscopic:  erythrocytes, leukocytes, bacteria, crystals, casts. 
• Celiac serology cascade 
• Urine or serum pregnancy test (β-HCG) for women of childbearing potential 
• Each patient’s Child-Pugh score will be calculated based on physical examination and baseline 
laboratory data.  Patients with Child-Pugh score≥10 will be disqualified and not randomized.  See 
Appendix II for calculation of Child-Pugh score. 
• 12-lead ECG 
• Colonoscopy is required for patients at least age 50 at the time of consent or if they meet any of 
the following criteria: 
a. Documented weight loss within the past 6 months, 
b. Nocturnal IBS symptoms, 
c. Familial history of colon carcinoma, or 
d. Blood mixed with stool (excluding bleeding from hemorrhoids) 
• Patients who have had a colonoscopy within 5 years of signing consent need not have a repeat 
colonoscopy unless they meet one or more of criteria a, b or d. If colonoscopy is required per 
protocol, biopsies are required. Biopsies are not mandatory for nonstudy colonoscopies.  
• Stool and symptom assessments daily for 14 days, completing not more than two weeks prior to 
planned start of treatment (see Appendix I): 
• Bristol chart for stool consistency  
• Likert scales for urgency, worst pain and worst abdominal discomfort:  11-point scales 
• Likert scale for interference by IBS with activities of daily living:  5-point scale 
• Adverse events 


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• Concomitant medications (regardless of relationship to IBS) over 30 days prior to planned start of 
treatment 
In general, colonoscopy if needed should be performed after collection of baseline stool and symptom 
data.  If performed prior to collection of baseline stool and symptom data, sufficient time should 
elapse after colonoscopy so that patient returns to his or her basal bowel movement status prior to 
collection of the stool and symptom data. 
Patients must complete at least 12 days of all baseline diary entries within the 14 day 
screening period to be eligible to participate in the study.  Patients completing fewer than 12 
days of diary entries may, at the investigator’s discretion, repeat the screening period diary.  
As long as the patient can complete and enter the study within 6 weeks, baseline laboratory 
studies need not be repeated.  If repeating the 2 weeks’ baseline diary will result in a period 
longer than 6 weeks from consent to start of treatment, the medical monitor must be 
consulted prior to randomization. 
5.2.2 On-study procedures 
Patients will be seen on day 1 of treatment, day 1 of weeks 2 and 3, every 2 weeks thereafter while 
on treatment (weeks 5, 7, 9) and 4 weeks after the end of treatment.  Assessments are to be 
performed at the times indicated in the chart of evaluations, with the following windows:   
week 1 visit:  within 6 weeks of consent; 
weeks 2, 3, 5, 7 and 9 visits:  ±2 days;   
week 13 (follow-up) visit:   ±4 days. 
All the windows are based on day 1 of treatment, rather than cumulative changes.  Thus, patients 
who adhere to the visit windows will not run out of study medication.    
At the visits indicated in Table 1: 
• Vital signs will be recorded,  
• Patients will undergo a brief physical examination of pertinent systems, 
• Study medication administration and concomitant medication use will be reviewed,  
• Adverse events recorded.   
• Completion of Bristol charts and Likert scales will be reviewed.  
• At week 3 of the study (i.e., after 2 weeks of treatment), serum electrolytes will be assayed on 
all patients. 
• CBC and biochemical profile will be repeated at weeks 5, 9 and at the end of study visit. 
Urinalysis and pregnancy test will be repeated only if clinically indicated. Where medically 
necessary, Investigators may request additional (optional) lab tests from the central lab; 
however sites will have to seek approval from the medical monitor prior to requesting these 
tests.  
• Limited pharmacokinetic sampling will be performed, as shown in the following table: 
Table 2.  Pharmacokinetic sampling 
 
Time, relative to dose 
Week/day 
Group A 
Group B 
1/1 
Predose 
Predose 


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3/1 
Predose, 1 h postdose 
6 h postdose 
5/1 
6 h postdose 
Predose, 1 h postdose 
 All patients will have a predose (blank) sample drawn prior to their first dose of study 
medication.  Patients will be randomized to give two additional samples for PK analysis either 
just prior to and one hour after the first dose of week 3 (i.e., after 2 weeks of treatment) or 
week 5 (i.e., after 4 weeks of treatment) and a fourth sample 6 h after the first dose of week 5 
or week 3. On-treatment PK sampling windows are as follows: 
• Predose:  20-28 hours after prior dose and before the dose on the day of sampling 
• One hour post-dose:  ±10 minutes 
• Six hours post-dose:  ±30 minutes  
If patient is on every other day dosing:  
•  Predose:  44 -52 hours after prior dose  
 
 
 
 


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6. 
Safety Reporting 
All patients will be assessed regularly for potential adverse events (AEs) occurring at any time after 
the patient signs the informed consent until 28 days after the last dose of study medication.  AEs 
ongoing at the end of treatment will be followed until resolution or 28 days after the last dose of study 
medication, whichever comes first.  All patients dosed will return to clinic approximately 4 weeks after 
the last dose of study medication and queried regarding the occurrence of AEs. 
6.1 
Terminology 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  An AE (may also be referred to as an 
adverse experience) can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational or marketed) product, whether or not considered related to the medicinal 
(investigational or marketed) product and from any route of administration, formulation, or dose, 
including an overdose.  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results in any of 
the following outcomes:   
death;  
is a life-threatening adverse event (defined as an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe); 
requires in-patient hospitalization or causes prolongation of existing hospitalization; 
a persistent or significant disability/incapacity incapacity or substantial disruption of the ability to 
conduct normal life functions; 
a congenital anomaly/birth defect; 
is an important medical event.  This is defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other serious outcomes listed in the definition above.  Examples of such events 
include, but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
If either the sponsor or investigator believes that the event is serious, the event must be considered 
serious and be evaluated by the Sponsor for expedited reporting. 
A suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.    
6.2 
Assessment of Causal Relationship 
The following categories and definitions for assessing the causal relationship of an event to the 
investigational product(s) are provided as a guide to be used for evaluating adverse events reported 
in this study to determine “suspected adverse reactions” that require expedited reported to regulatory 
agencies if they are unexpected.  In addition to the assessment below, the aggregate number of 


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occurrences will be considered to decide whether the event is a reportable event and requires an IND 
safety report. 
Table 3.  Relationship of Study Medication to Adverse Events 
Unrelated 
The study drug almost certainly (or certainly) did not cause the event.  Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another obvious etiology. 
Probably 
not 
related 
It is more likely that the event is due to another etiology than due to the study drug.  
Guidelines: 
There is no reasonable temporal relationship of the event to the administration of drug; 
The pattern is inconsistent with that known for the drug; and/or 
There is another more likely etiology. 
Possibly 
related 
It is approximately equally likely that the event is due to the study drug as it is due to another 
etiology.  Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The drug seems as likely as other etiologies to have caused the effect 
Probably 
related 
It is more likely that the event is due to the study drug than due to another etiology.  
Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event may be consistent with a known pattern of drug (or drug class) effects; 
The drug seems more likely than other etiologies to cause the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in 
dose; and/or 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug 
(Intentional rechallenge for the purpose of assigning causality should not be performed.) 
Definitely 
related 
The evidence is compelling that the study drug caused the adverse event.  Guidelines: 
There is a reasonable temporal relationship of the event to the study drug; 
The event is consistent with a known pattern of drug (or drug class) effects; 
The drug is far more likely than other etiologies to have caused the effect; 
The adverse event diminished upon cessation of study drug exposure or reduction in 
dose; 
The adverse event worsened or recurred upon unintentional re-exposure to the study drug 
(Intentional rechallenge for the purpose of assigning causality should not be performed.) 
Unknown 
The data are inadequate to assign any of the above causal relationship categories to the 
study drug. 
 
6.3 
Adverse Event Grading and Coding 
Adverse events will be graded according to the following criteria: 
Grade                Description 
1 
 
Mild 
2 
 
Moderate   
3                   Severe   
4                   Life-threatening or disabling  
5                 Fatal  


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AEs will be coded, grouped and tabulated by MedDRA preferred terms by body system organ class.  
MedDRA version 13.1, used previously for RHB102 studies will be used for this study as well. 
6.4 
Handling of Serious Adverse Events 
Adverse events classified as serious must be recorded on the AE page of the CRF and require 
expeditious handling and reporting to the sponsor, RedHill Biopharma, to comply with regulatory 
requirements.  These SAEs will include deaths, regardless of their causal relationship to 
investigational product.  All SAEs must be reported using the Serious Adverse Event Report form.  To 
the extent possible, the descriptive terminologies and other SAE attributes entered on the SAE report 
form should approximate similar information in the CRF.  The completed SAE report form with 
supporting documentation must be provided to the sponsor within 24 hours of the study site 
personnel’s initial notification/awareness of the event.  All telephone communication regarding 
SAE must be followed by a written report.  Duly authorized study site personnel may sign completed 
SAE report forms; however, it is recommended that the investigator sign each final SAE report. 
Collection of complete information concerning SAEs is extremely important.  Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation (e.g. 
hospital discharge summaries, additional lab and test results, autopsy reports, etc.), should be 
collected subsequently, if not available at the time of the initial report, and immediately sent to 
sponsor using the same procedure as the initial SAE report. Information on the SAE must be in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of causality. 
For ease of analysis, worldwide standardization, and regulatory reporting, the sponsor or its designee 
will code each reported adverse event or symptom to its corresponding preferred term and body 
system/organ class in the MedDRA dictionary version adopted for the study. The principal 
investigator will be responsible for assessing severity based on the intensity of the event as it 
presented using the criteria listed in section 6.3, above. 
 
 
  
   
  
 
  
In addition, the study medical monitor may be contacted directly: 
 
 
 
 
 
 
As required, all investigators will be notified of all AE reports that are determined to be serious, 
unexpected, and related (by the reporting investigator or sponsor) to the investigational product.  The 
notification will be in the form of a Safety Update (Dear Doctor Letter). 
The notification is considered an addendum to the current Investigator’s Brochure; therefore, upon 
receiving such notices, the investigator must review and immediately submit a copy to the IRB 


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according to local regulations.  The notification must be retained within the Investigator’s Brochure.  
The investigator and IRB will determine if the informed consent requires revision. 
Pregnancies will not be considered SAEs but will be handled and reported in a manner similar to 
SAEs. 
.  
6.5 
Laboratory Test Abnormalities 
All new abnormal laboratory findings and those abnormal at baseline which change significantly (i.e., 
by at least one toxicity grade as defined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] v4.03) are considered AEs.  Laboratory AEs for which there 
is no clinical intervention will be extracted from the laboratory data.  Laboratory AEs not listed in the 
NCI CTCAE v4.03 will be considered as grade 1 (mild) if there is no clinical effect or intervention.  
Laboratory values outside the normal range for certain parameters will not be considered AEs if they 
are generally not considered as indicating an abnormality; this includes such parameters as liver 
enzymes which are below the normal range.  If there is a clinical sequela or intervention, the 
laboratory abnormality is to be graded according to the criteria used for clinical AEs, described above. 
The NCI CTCAE v4.03 can be downloaded in pdf, Excel or OWL format at:  
  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
6.6 
Other Safety Considerations 
At the follow-up visit, all patients will be questioned regarding the occurrence of adverse events, 
including serious and nonserious adverse events. 
All AEs must be recorded and followed until resolution or for at least 28 days after discontinuation of 
study medication, whichever comes first. 
Any clinically significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded on the AE page of the CRF. 
 


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7. 
Data Analysis and Statistical Considerations 
7.1 
Sample Size Considerations 
Sample size is calculated based on expected results for achievement of the FDA-specified endpoint 
for stool consistency: 
A stool consistency weekly responder is defined as a patient who experiences ≥50% reduction 
in the number of days per week with at least one stool that has a consistency of type 6 or 7 
compared with baseline. 
A patient will be characterized as an overall responder if the patient was a weekly responder 
for ≥50% of the weeks of treatment. 
In addition, to be considered a responder for the week, the patient cannot have an increase in 
average abdominal pain >10% over baseline during that week.   
Based on Garsed et al, 2013, it is expected that approximately 80% of patients in the active treatment 
group and 40% of patients in the placebo group will be responder.  Using a continuity-corrected Chi-
Square test, to achieve a statistically significant difference between the active group and the placebo 
group with 80% power and significance level of α = 0.05 using 1:1 randomization, 28 patients per 
group must be treated. To allow for a smaller difference, i.e., 70% response rate in the active group 
and 40% in placebo group, and for a 3:2 randomization ratio, a total of 104 patients would be 
necessary to achieve this power.  In order to allow for some further decrease in the actual difference 
in response rates between active and placebo, e.g., early drop-outs or major protocol violations, a 
total of 120 patients will be randomized, 72 to RHB-102 and 48 to placebo. If no substantial violations 
impact the results of the study, this sample size will achieve a power of 87.5%. 
7.2 
Statistical Methods 
A detailed description of all statistical analyses to be performed for this study will be given in a 
statistical analysis plan (SAP).  Any deviations from the analysis detailed in the protocol will be 
described in the SAP. 
7.2.1   General Analysis and Coding 
The statistical analysis will be performed using the software package SAS version 9.3 or higher (SAS 
Institute Inc., Cary, NC 27513, USA).  All individual data as well as results of statistical analyses, 
whether explicitly discussed in the previous sections or not, will be presented in individual patient data 
listings and statistical summary tables. 
In general, continuous variables will be summarized using the following standard descriptive 
summary statistics: number of observations, arithmetic mean, standard deviation, minimum, median, 
maximum.  Categorical data will be described using absolute and relative frequencies.  Shift tables 
will be provided, where appropriate.  Confidence Intervals (CI) will be two-sided 95% CIs if not 
otherwise specified. If not specified otherwise, statistical tests will be two-sided with a significance 
level of α = 0.05. 
In general, if baseline values for (semi-) continuous variables are derived from the daily assessments 
during the two-week observation period preceding randomization, these will be defined as the 
average of the respective measurements over this two-week period.  
All analyses and summary tables will be displayed by treatment group. 


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Any changes in the planned statistical methods described in the SAP will be documented in the 
clinical study report. 
The following international dictionaries will be used for medical coding: 
Diagnoses: Medical Dictionary for Regulatory Activities (MedDRA), version 13.1 
Medications: World Health Organization (WHO) Drug Dictionary including ATC classification 
AEs: MedDRA, version 13.1 
7.2.2   Analysis Populations 
The following analysis populations will be defined for the statistical analyses: 
• The Safety population will include all patients who received at least 1 dose of study drug (even if 
the patient vomits immediately after drug administration). In the safety population patients will be 
analyzed by the actual treatment they received. 
• The modified Intent-to-Treat (mITT) population will include all randomized patients who received 
at least 1 dose of study drug. In the mITT population, patients will be analyzed by the treatment 
they were randomized to. 
• The Per-protocol (PP) population will include all patients from the mITT population who do not 
have a major protocol deviation that would affect treatment evaluation. Patients who discontinue 
the study due to documented lack of treatment effect will be included in the PP.  
• The Pharmacokinetic Population (PKP) will include all patients with quantifiable concentrations of 
ondansetron in plasma and sufficient and reliable dosing and sampling information to permit 
estimation of elapsed time since the prior dose. 
Major protocol deviations include but are not limited to: 
• Lack of compliance defined as having administered <75% of the planned study medication until 
discontinuation. 
• Fewer than 12 days (of planned 14 days) of baseline data. 
• Fewer than 7 days of data if not discontinued before due to lack of efficacy. 
Additional major protocol deviations will be defined in the SAP. 
7.3 
Baseline Characteristics and Demographics 
Demographic and pre-treatment patient characteristics, including disease parameters and 
comorbidities, will be summarized with descriptive statistics.   
7.4 
Efficacy Analyses 
All efficacy analyses will be conducted in the mITT and PP populations. 
7.4.1 Primary Endpoint Analysis 
The primary endpoint in the study is stool consistency response in the absence of increase in pain 
≥10%. 


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A weekly stool consistency responder is defined in the FDA guidance on IBS-D as a patient who 
experiences during a week a ≥50% reduction in the number of days with at least one stool that has a 
consistency of Type 6 or 7 on the Bristol stool scale compared with baseline. In addition, to be 
considered a responder for the week, the patient cannot have an increase in average abdominal pain 
≥10% over baseline during that week. A patient will be characterized as an overall stool consistency 
responder if the patient was a weekly responder for at least 50% of the weeks of treatment. For the 
handling of missing weekly data see section 7.4.3. 
Let pO denote the response rate under RHB-102 and pP  denote the response rate under placebo then 
the primary two-sided hypothesis to be tested is 
          H0: pO - pP  = 0  
vs the alternative 
          H1: pO - pP ≠ 0. 
A Chi-Square test with continuity correction at the significance level α = 0.05 will be employed for the 
primary (confirmatory) analysis of the primary endpoint. 
In addition, for each week the weekly response rates will also be compared between the treatment 
groups with a Chi-Square test with continuity correction. 
To assess the effect of gender on the primary endpoint, a logistic regression model with treatment 
group and gender as covariates will be applied. 
7.4.2 Secondary Endpoint Analyses 
Secondary efficacy endpoints include the following: 
• Proportion of patients in each treatment group who are pain responders, per FDA guidance 
definition 
• Proportion of patients in each treatment group who are overall responders, per FDA guidance 
definition 
• Differences between treatment groups in  
o Abdominal pain 
o Abdominal discomfort 
o Frequency of defecation 
o Interference by IBS with activities of daily living 
o Use of rescue medication 
All secondary analyses are considered as exploratory, no adjustments for multiplicity will be made. 
Pain response 
A weekly pain responder is defined as a patient who experiences a decrease in the weekly average 
of worst abdominal pain in the past 24 hours score ≥30% compared with baseline and the number of 
days per week with at least one stool with consistency of type 6 or 7 that is the same as baseline or 
decreased and the number of stools of Type 6 or 7 on those days remains unchanged or decreased. 
An overall pain responder is defined as patient who was a weekly pain responder for at least 50% of 
the weeks of treatment. 
A Chi-Square test with continuity correction at the significance level α = 0.05 will be employed for the 
comparison of the treatment groups regarding overall and weekly pain response. 


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To assess the effect of gender on the overall pain response, a logistic regression model with 
treatment group and gender as covariates will be applied. 
Overall response 
A patient is characterized as a weekly responder if the patient meets both the stool consistency and 
pain response definitions for a given week. 
A patient is characterized as an overall study responder if the patient meets the criteria for both 
weekly stool consistency and pain response for at least for at least 50% of the weeks of treatment. 
A Chi-Square test with continuity correction at the significance level α = 0.05 will be employed for the 
comparison of the treatment groups regarding overall and weekly study response. 
To assess the effect of gender on the overall study response, a logistic regression model with 
treatment group and gender as covariates will be applied. 
Abdominal pain 
Abdominal pain is measured as the worst abdominal pain during a 24-hour period, on an 11-point 
Likert scale ranging from 0 (no pain) to 10 (as bad as can be imagined). For each treatment week the 
change in the weekly average of worst abdominal pain from baseline will be compared between the 
treatment groups with an Analysis of Covariance (ANCOVA) model including treatment group, study 
site and gender as independent variables and baseline abdominal pain (see section 7.2.1) as 
covariate.  To assess the impact of time a Repeated Measurement Model will be applied with the 
weekly changes from baseline as dependent variables, treatment group, study site, gender, week and 
treatment x week interaction as independent variables and baseline abdominal pain as covariate. 
Abdominal discomfort 
Abdominal discomfort is measured on an 11-point Likert scale ranging from 0 (no discomfort) to 10 
(as bad as can be imagined).  For each treatment week the change in the weekly average of 
abdominal discomfort from baseline will be compared between the treatment groups with an Analysis 
of Covariance (ANCOVA) model including treatment group, study site and gender as independent 
variables and baseline abdominal discomfort (see section 7.2.1) as covariate.  To assess the impact 
of time a Repeated Measurement Model will be applied with the weekly changes from baseline as 
dependent variables, treatment group, study site, gender, week and treatment x week interaction as 
independent variables and baseline abdominal discomfort as covariate. 
Interference by IBS with activities of daily living  
Interference with daily activities is measured on a 5-point Likert scale ranging from 0 (no interference) 
to 4 (unable to carry out activities of daily living).  For each treatment week the change in the weekly 
average of interference from baseline will be compared between the treatment groups with an 
Analysis of Covariance (ANCOVA) model including treatment group, study site and gender as 
independent variables and baseline interference score (see section 7.2.1) as covariate.  To assess 
the impact of time a Repeated Measurement Model will be applied with the weekly changes from 
baseline as dependent variables, treatment group, study site, gender, week and treatment x week 
interaction as independent variables and baseline interference score as covariate 
Frequency of defecation 
For each treatment week the change in average daily frequency of defecation from baseline will be 
will be compared between the treatment groups with an Analysis of Covariance (ANCOVA) model 
including treatment group, study site and gender as independent variables and baseline daily 


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frequency of defecation (see section 7.2.1) as covariate.  To assess the impact of time a Repeated 
Measurement Model will be applied with the weekly changes from baseline as dependent variable, 
treatment group, study site, gender, week and treatment x week interaction as independent variables 
and baseline daily frequency of defecation as covariate. 
Use of rescue medication  
Use of rescue medication will be analyzed qualitatively and quantitatively. For each treatment week 
and overall across the treatment phase the number of patients using any rescue medication will be 
compared between the treatment groups using a continuity corrected Chi-Square test. The number of 
days  rescue medication is used in each week of treatment and overall will be compared between the 
treatment groups using the Wilcoxon Rank-Sum test.  
7.4.3 Exploratory Endpoint Analysis 
Urgency 
Urgency is the feeling of a need to defecate and inability to control or incomplete control over 
defecation.  Urgency over the course of the day, is measured on an 11-point Likert scale ranging from 
0 (no urgency) to 10 (as bad as can be imagined).  For each treatment week the change in the 
weekly average of urgency from baseline will be compared between the treatment groups with an 
Analysis of Covariance (ANCOVA) model including treatment group, study site and gender as 
independent variables and baseline urgency (see section 7.2.1) as covariate.  To assess the impact 
of time a Repeated Measurement Model will be applied with the weekly changes from baseline as 
dependent variables, treatment group, study site, gender, week and treatment x week interaction as 
independent variables and baseline urgency as covariate. 
 
7.4.4 Pharmacokinetic analyses 
Nonlinear mixed-effects methods will be used to develop a population-based pharmacokinetic 
(PopPK) model of ondansetron concentrations in plasma after administration of RHB-102. Individual 
post hoc Bayesian estimates of pharmacokinetic (PK) model parameters will be used to estimate the 
steady-state peak (Cmax) and trough (Cτ) concentrations and the area under the curve of 
concentration versus time over the dosing interval (AUCτ). Cmax, Cτ, and AUCτ will serve as 
exposure metrics in exploratory plots of exposure versus relevant efficacy and safety endpoints. 
Exposure-response (ER) models may be developed to describe emerging trends. PopPK and ER 
modeling may be described in a separate modeling and simulation analysis plan and reported 
separately from the clinical study report. The date and time will be recorded for the dose of RHB-102 
(or placebo) taken prior to blood sampling to determine ondansetron concentration in plasma. This is 
the dose of the prior day for pre-dose PK samples. 
 
7.4.5 Subgroup Analyses 
The primary endpoint, improvement in stool consistency, and the secondary endpoints pain response 
and overall response will be analyzed for all patients and by gender.  To evaluate the differences in 
effect by gender, additional efficacy endpoints may be analyzed by gender if trends towards 
differences (p-value from logistic regression ≤ 0.1) are seen in the endpoints initially analyzed by 
gender. 


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Further sub-group analyses may be performed as ad-hoc analyses after the protocol-defined 
analyses if this is suggested by the data. 
7.4.6 Missing Data 
If a patient fails to provide any assessments after baseline (e.g. if the diary is missing completely) 
he/she will be counted as a non-responder in any of the overall responder analyses (overall stool 
consistency response, overall pain response, overall study response).  To be included in one of the 
weekly analyses for the primary or any of the secondary endpoints a patient has to provide data for 
this endpoint at least on 4 days of the respective week, otherwise the patient will be excluded from 
the analysis. If a patient fails to be included in more than two of the weekly responder analyses, 
he/she will also be counted as non-responder in any of the overall responder analyses. Otherwise 
missing values will not be imputed.  
7.5 
Safety Analyses 
The safety and tolerability of RHB-102 will be determined by reported AEs, physical examinations, 
vital signs, and laboratory tests. All analyses of safety will be performed in the Safety population. 
7.5.1 Adverse Events 
The incidence of treatment-emergent AEs will be summarized for each treatment group by MedDRA 
system organ class (SOC) and preferred term. An AE is defined as treatment-emergent if its onset 
date/time is on or after the date/time of the first intake of study drug or if a pre-existing condition 
becomes worse after the date/time of first intake of study drug. An AE is defined as pre-treatment if its 
onset date/time is before the date/time of the first intake of study drug. AEs will be summarized 
according to the following:  
• 
An overview of the absolute and relative frequencies of patients with at least one AE will be given 
for the categories pre-treatment and treatment-emergent by seriousness, severity, and causality. 
• 
Further tables will present the absolute and relative frequencies of patients with at least one 
treatment-emergent AE classified by SOC and preferred term and, in addition, by severity and 
causality. 
• 
The absolute and relative frequencies of patients with at least one SAE will be summarized by 
SOC and preferred term and, in addition, by severity and causality. 
• 
Individual patient data listings will be provided for all deaths and discontinuation of study 
medication due to AEs. 
Regarding the summaries by severity and causality, the following rule will be applied: if a patient 
experiences more than one AE within the same SOC or with the same preferred term, the AE with the 
highest severity or closest relationship to study drug will be used for the analysis. 
7.5.2 Clinical Safety Laboratory Tests 
Key laboratory data will be subjected to both a quantitative analysis (descriptive summary statistics) 
and qualitative analysis where frequencies of normal, abnormal low, and abnormal high values will be 
computed. Specific analytes to be evaluated will be listed in the SAP. 
The following analyses will be performed: 
• 
Standard descriptive summary statistics will be calculated at each scheduled measuring time 
point and the last individual measuring time point. 


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• 
Standard descriptive summary statistics will be calculated for the absolute change from baseline 
to each scheduled measuring time point after baseline and the last individual measuring time 
point. 
• 
Shift tables displaying changes with respect to the normal range between baseline and each 
scheduled measuring time point after baseline and the last individual measuring time point will be 
provided.  Shift tables will show changes by grade for analytes graded in the NCI CTCAE v 4.03 
criteria. 
• 
A listing of all patients with abnormal values at any time point will be given. 
No inferential testing will be performed to compare the differences between the treatment groups; a 
paired-sample t-test may be provided for each group for change from baseline if data warrant. 
7.5.3 Other Parameters 
The results from physical examination, including vital signs, will be presented in the patient data 
listings.  Findings on physical examination, including vital signs, which constitute clinically significant 
changes will be listed as adverse events. 


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8. 
Study Medications 
Patients will receive a bottle containing 30 tablets of RHB102 12 mg or matching placebo.  Thirty 
tablets will give the patient enough medication for 4 weeks treatment plus 2 days, to allow for minor 
delays in return to clinic on the assigned date. 
Patients will be instructed to take one tablet daily, at the same time, preferably in the morning on 
arising.  The tablets should be taken with water.   Patients are to keep a diary of medication 
administration, noting the time of administration each day.  At each visit, patients should bring their 
bottle of pills for a count.  At week 5, remaining medication will be collected and the patient given a 
new bottle of study medication. 
Medication should be stored at room temperature, 15-25°C. 
 


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9. 
Investigator Responsibilities 
9.1 
Compliance with Declaration of Helsinki and Good Clinical Practices 
The study will be performed in accordance with the Declaration of Helsinki (1964) as revised, most 
recently in Fortaleza, Brazil (2013), US FDA regulations and the ICH Guideline for Good Clinical 
Practice, E6(R1).  The investigator will ensure that all those concerned with conducting the study 
(such as pharmacists, research nurses and co-investigators) are provided with copies of the protocol 
and all safety information prior to the start of the study. 
9.2   Institutional Review Board (IRB) Review and Approval 
The investigator is responsible for obtaining IRB approval to conduct this study (including IRB 
approval of the Informed Consent form) and for ensuring continuing review as required by the IRB.  
Written confirmation of this approval and periodic review must be provided to the sponsor prior to the 
start of the study and at appropriate intervals. 
9.3   Informed Consent 
The investigator will inform patients as to the nature, expected duration and purpose of the study, the 
administration of the study medication, and the hazards involved, as well as the potential benefits that 
may come from treatment with this investigational drug.  Informed consent must be obtained in 
accordance with US Code of Federal Regulations (21 CFR Part 50).   
The patient will be informed that his/her medical records will be patient to review by the sponsor and 
possibly by a representative of the Food and Drug Administration.  Patients will be informed that they 
are free to refuse participation in this clinical investigation, and if they should participate, it will be 
made clear to them that they may withdraw from this study at any time without prejudicing further 
care.  Signed written informed consent must be obtained from every patient prior to study entry.  The 
original will be kept by the investigator and will be patient to review by the sponsor; a copy will be 
given to the patient. 
9.4   Confidentiality 
All information provided to the investigator relevant to the study medication, as well as information 
obtained during the course of the study, will be regarded as confidential.  The investigator and 
members of his/her research team agree not to disclose or publish such information in any way to any 
third-party without prior written permission from the sponsor, except as required by law. 
9.5   Source Documentation 
The investigator will allow inspections of the study site and documentation by clinical research and 
audit personnel from the sponsor, external auditors or representatives of regulatory authorities.   The 
purpose of these inspections is to verify and corroborate the data collected on the case report forms.  
In order to do this direct access to the patients’ medical or clinic records is necessary.  The 
investigator will ensure that certain information is contained in the medical or clinic records of the 
patient and that the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories; 
• a note on the day the patient entered the study describing the study number, the drug being 
evaluated, the study number assigned to that patient and a statement that consent was obtained; 


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• a note of each subsequent study visit including any concerns about adverse events or abnormal 
laboratory data and their resolution; 
• notes of all concomitant medication taken by the patient including start and stop dates; 
• a note of when the patient terminated from the study, the reason for termination and the patient’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each patient 
during the clinical phase of the study (thereafter it will be archived with the study file). 
9.6   Drug Accountability 
The investigator agrees to supervise the maintenance of records of the receipt, dispensing and return 
or destruction of study material supplied by the sponsor.  Destruction of any material must be 
witnessed and documented in writing.  The dispensing record must make it clear which patient 
received which material. 
9.7   Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the study center at 
regular intervals during the study for monitoring purposes and to assist the research staff with any 
queries they may have. 
9.8   Case Report Forms, Investigator’s Study File and Record Retention 
All case report forms and supporting source documentation must be available to the sponsor during 
monitoring visits. 
Prior to review of the case report forms by the sponsor’s representative and forwarding of the case 
report forms to the sponsor, they should be reviewed for completeness and legibility by the 
investigator or a member of the research team. 
The investigator will maintain all records relating to the study (including copies of case report forms) 
for at least 2 years after written notification by the sponsor that the investigational drug program has 
been either completed or terminated, or that a New Drug Application (NDA) has been approved by 
the FDA.  Should the investigator retire, relocate, or for other reasons withdraw from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept that 
responsibility, and the sponsor must be notified in writing of the name and address of said person. 
9.9   Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
patients in this study without the prior written permission of the patient, the sponsor and the IRB. 


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10. 
Sponsor Responsibilities 
10.1   General 
The sponsor agrees to adhere to US FDA Guidelines on Good Clinical (Research) Practices and with 
the ICH Guideline for Good Clinical Practice, E6(R1).  The sponsor has a legal responsibility to report 
fully to regulatory authorities the results of this study.  It is the sponsor’s responsibility to obtain 
appropriate regulatory approval to perform the study. 
10.2   Case Report Forms 
Case report forms will be provided by the sponsor or, upon agreement with the sponsor, forms 
generated by the investigative site may be used.  If an electronic data collection system is used, the 
system will be compliant with applicable aspects of 21 CRF Part 11, ICH guidelines, GCP and HIPAA. 
10.3 Data Monitoring and Collection 
Suitably qualified and trained clinical research personnel of the sponsor will visit the study center at 
regular intervals during the study for monitoring purposes and to assist the research staff with any 
queries they may have. Case report forms and source documentation will be available for review 
during monitoring visits to the center.  The function of this monitoring is to ensure compliance with the 
protocol, adherence to regulatory and good clinical (research) practice obligations, proper 
maintenance of records including drug accountability records, correct administration of study 
medications including storage conditions and accurate reporting of adverse events.   
10.4   Audit 
The sponsor has an obligation to audit a proportion of studies; this is usually undertaken by a 
department other than the clinical research department.  Therefore the sponsor, an independent 
auditor or a regulatory authority may wish to audit the study site and documentation and these audits 
may take place as the study is running or up to several years later. 
10.5   Confidentiality 
The sponsor will not keep any material on file bearing any patient’s name, and the patient’s 
confidentiality will be maintained at all times. 
 
 


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11. 
Protocol Modifications 
If necessary during the course of the study, the protocol may be modified by the sponsor in 
consultation with the investigator.  Except in the case of modifications to resolve an imminent safety 
issue, any protocol modification or revision must be reviewed and approved by the investigator’s IRB 
prior to implementation. 
 


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12. 
Publication 
The sponsor reserves the right of decision regarding publication or presentation.  If deemed 
necessary by the sponsor for protection of proprietary information prior to patent filing, the 
investigator agrees to delay for 60 days before any presentation or publication is submitted. 
 


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
    16 February 2017 
 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
43 
 
13. 
References 
Canavan C, West J, Card T.  The economic impact of the irritable bowel syndrome.  Alimentary 
Pharmacol Ther 2014;40:1023-34. 
Canavan C, West J, Card T.  The epidemiology of irritable bowel syndrome.  Clin Epidemiol 
2014;6:71-80. 
Chang L, Lembo A, Sultan S.  American Gastroenterological Association Institute Technical Review 
of the Pharmacological Management of Irritable Bowel Sndrome.  Gastroneterol 2014;147:1149-72. 
Clayton NM, Sargent R, Butler A, Gale J, Maxwell MP, Hunt AAE, Barrett VJ, Cambridge D, Bountra 
C, Humphrey PPA.  The pharmacological properties of the novel selective 5-HT3 receptor antagonist, 
alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat.  
Neurogastroenterol Mot 1999;11:207-17. 
FDA Guidance for Industry:  Irritable bowel syndrome:  clinical evaluation of drugs for treatment.  
May, 2012. 
Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller 
R.  A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhea.  Gut 
2014;63:1617-25. 
Hod K, Ringel-Kulka T, Martin CF, Mahrashak N, Ringel Y.  High-sensitive C-reactive protein as a 
marker for inflmammation in irritable bowel syndrome.  J Clin Gastroenterol 2016;50:227-32. 
Lewis SJ, Heaton KW.  Stool form scale as a useful guide to intestinal transit time.  Scand J 
Gastroenterol 1997;32:920-4. 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC.  Functional bowel 
disorders.  Gastroenterol 2006;130;1480-91. 
Steadman CJ, Talley NJ, Phillips S, Zinsmeister AR.  Selective 5-hydroxytryptamine type 3 receptor 
antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome:  A pilot 
study.  Mayo Clin Proc 1992;67:732-8. 


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
    16 February 2017 
 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
44 
 
Appendices 
Appendix I.  Daily assessments 
A. Stool consistency:  Bristol scale 
 
B. Likert scale for abdominal pain 
How bad was your worst abdominal pain over the past 24 hours? 
0 
No pain 
1 
Barely felt pain 
2 
 
3 
Mild 
4 
 
5 
Moderate 
6 
 
7 
Severe 
8 
 
9 
Excruciating 
10 
As bad as can be imagined 


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
    16 February 2017 
 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
45 
 
 
C. Likert scale for urgency 
How bad was your urgency over the past 24 hours? 
0 
No urgency 
1 
Barely noticed urgency over the course of the day 
2 
 
3 
Mild 
4 
 
5 
Moderate 
6 
 
7 
Severe 
8 
 
9 
Excruciating 
10 
As bad as can be imagined 
 
D. Likert scale for abdominal discomfort 
 
How much abdominal discomfort did you have over the past 24 hours? 
 
0. No discomfort 
1. Barely felt discomfort 
2.  
3. Mild 
4.  
5. Moderate 
6.  
7. Severe 
8.  
9. Excruciating 
10. As bad as can be imagined 
 
E. Likert scale for interference in daily activities 
How much did your IBS interfere with your daily activities over the past 24 hours? 
0 
No interference 
1 
Mild interference 
2 
Moderate interference 
3 
Severe interference  
4 
Unable to carry out activities of daily living 
 
 
 


RHB-102 for IBS-D:  Protocol RHB-102-02   Amendment 4 
    16 February 2017 
 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
46 
 
Appendix II.  Child-Pugh score 
Measure 
1 
point 
2 points 
3 points 
Total bilirubin, mg/dl 
<2 
2-3 
>3 
Serum albumin, g/dl 
>3.5 
2.8-3.5 
<2.8 
INR 
<1.7 
1.7-2.2 
>2.2 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic 
encephalopathy 
None 
Grade I-II (or suppressed with 
medication) 
Grade III-IV (or 
refractory) 
 
Score: 5-6:  C-P A, mild 
7-9:  C-P B, moderate 
10-15:  C-P C, severe 
 

SAP_001.pdf: 
Sponsor: RedHill Biopharma Ltd. 
SAP Final  28 Jun 2017 
Study: RHB-102-02 
 
Redhill 
Page 1 of 35 
 
 
 
 
STATISTICAL ANALYSIS PLAN   
 
 
Final 1.0 dated 28
th June 2017 
 
Randomized, Double-blind, Placebo-controlled, Phase 2 Trial of RHB-102 
(Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea Predominant Irritable 
Bowel Syndrome (IBS-D) 
 
 
 
Protocol number: RHB-102-02 
 
Protocol Date: Amendment 4 dated 16th February 2017 
 
 
 
 
Sponsor: 
RedHill Biopharma Ltd.  
21 Ha’arba’a St.  
Tel-Aviv 64739, Israel 
 
 
 
 
 
 
 
 
 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor. 
 
2
 


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1 
REVISION HISTORY 
Date 
Version 
Description  
Author  
28th June 2017 
Final 1.0 
Final Version 
 
 
 
 
 
 
 
 
 
4
 


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Table of Contents 
SIGNATURES 
································································································ 2 
1 
REVISION HISTORY ············································································ 3 
2 
LIST OF ABBREVIATIONS AND KEY TERMS 
··········································· 7 
3 
INTRODUCTION 
·················································································· 9 
4 
STUDY OBJECTIVES 
············································································ 9 
4.1 
Primary Objective 
·············································································· 9 
4.2 
Secondary Objectives 
·········································································· 9 
4.2.1 
Efficacy 
···················································································· 9 
4.2.2 
Safety ······················································································ 9 
4.2.3 
Exploratory ··············································································· 10 
5 
STUDY DESIGN ·················································································· 10 
5.1 
Description of the Disease ··································································· 10 
5.2 
Study Design Overview and Drug Administration 
········································ 10 
5.3 
Flow Chart ····················································································· 11 
5.4 
Randomization and Blinding ································································ 12 
5.5 
Duration of Treatment 
········································································ 
12 
5.6 
Dose Modification ············································································ 12 
5.7 
Discontinuation of Treatment 
································································ 12 
5.8 
Replacement of Patients 
······································································ 13 
5.9 
Sample Size Justification 
····································································· 13 
6 
ANALYSIS SETS/POPULATIONS ··························································· 13 
6.1 
Modified Intent-to-Treat (mITT) population ·············································· 14 
6.2 
Per-Protocol (PP) Population ································································ 14 
6.3 
Safety Population (SAF) ····································································· 
14 
6.4 
Pharmacokinetic Population (PKP) ························································· 14 
7 
ENDPOINTS & ANALYSIS VARIABLES ·················································· 15 
7.1 
Efficacy Endpoints 
············································································ 
15 
7.1.1 
Primary Efficacy Endpoint 
····························································· 15 
7.1.2 
Secondary Efficacy Endpoints 
························································· 15 
7.1.3 
Exploratory Efficacy Endpoints ······················································· 15 
7.2 
Efficacy Variables ············································································ 15
5
 


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7.2.1 
Primary Efficacy Variable 
······························································ 15 
7.2.2 
Secondary Efficacy Variables 
·························································· 15 
7.2.3 
Exploratory Efficacy Variables 
························································ 16 
7.3 
Safety Endpoints ·············································································· 16 
7.4 
Safety Variables 
··············································································· 16 
7.5 
Other Variables 
················································································ 17 
7.5.1 
Duration of Exposure ··································································· 17 
7.5.2 
Percent Compliance ····································································· 17 
7.5.3 
Prior, Concomitant, and Follow-up Medication ····································· 17 
7.5.4 
Demographics 
············································································ 18 
8 
STATISTICAL METHODOLOGY ··························································· 18 
8.1 
General Considerations ······································································· 18 
8.1.1 
Model Structure or SAS Codes ························································ 19 
8.2 
Study Population ·············································································· 21 
8.2.1 
Disposition of Patients ································································· 21 
8.2.2 
Protocol Deviations ····································································· 21 
8.2.3 
Demographic and Other Baseline Characteristics 
··································· 22 
8.2.4 
Prior and Concomitant Medications 
··················································· 22 
8.3 
Study Drugs ···················································································· 23 
8.3.1 
Exposure ·················································································· 23 
8.3.2 
Treatment Compliance 
·································································· 23 
8.4 
Analysis of Efficacy ·········································································· 23 
8.4.1 
Analysis of Primary Endpoint ························································· 23 
8.4.2 
Analysis of Secondary Endpoints ····················································· 
24 
8.4.3 
Analysis of Exploratory Endpoints 
···················································· 26 
8.4.4 
Sub-group Analyses 
····································································· 27 
8.5 
Analysis of Safety 
············································································· 27 
8.5.1 
Adverse Events ·········································································· 27 
8.5.2 
Clinical Safety Laboratory Tests ······················································ 28 
8.5.3 
Other Parameters ········································································ 29 
8.6 
Analysis of Pharmacokinetics (PK) 
························································· 30 
8.7 
Analysis of Pharmacodynamics (PD) 
······················································· 30 
8.8 
Subgroups of Interest ········································································· 30 
8.9 
Other Analyses ················································································ 31
6
 


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8.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 31 
8.10.1 
Missing Data 
············································································· 31 
8.10.2 
Outliers ··················································································· 31 
8.10.3 
Visit Windows ··········································································· 31 
9 
INTERIM ANALYSIS ··········································································· 32 
10 
CHANGES TO PLANNED ANALYSES 
····················································· 32 
11 
REFERENCES ···················································································· 33 
12 
APPENDICES ····················································································· 34 
 
 
7
 


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2 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviation 
Description of abbreviations         
AE 
Adverse Event          
ALT 
Alanine Aminotransferase  
ANCOVA  
Analysis of Covariance  
AST  
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under Curve 
BUN  
Blood Urea Nitrogen  
CBC  
Complete Blood Count  
CO2  
Bicarbonate  
CRF  
Case Report Form  
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
ER 
Exposure-response 
FDA  
Food and Drug Administration  
IBS  
Irritable Bowel Syndrome  
IBS-D  
Irritable Bowel Syndrome – Diarrhea predominant  
ICH  
International Committee on Harmonisation  
kg  
kilogram  
LS 
Least Square          
MedDRA  
Medical dictionary for regulatory activities  
mg  
Milligram  
mITT  
Modified Intent-To-Treat  
MMRM 
Mixed Model Repeated Measures 
NCI-CTCAE v 4  National Cancer Institute common terminology criteria for adverse 
events, version 4  
OR 
Odds Ratio 
oz 
US Fluid Ounce 
PD 
Protocol Deviation 
PK 
Pharmacokinetics 
PP 
Per Protocol  
PT 
Preferred Term 
SAE  
Serious Adverse Event  
SAF 
Safety Analysis  
SAP  
Statistical Analysis Plan  
SAS 
Statistical Analysis System 
SD 
Standard Deviation          
SE 
Standard Error          
SOC  
System Organ Class  
TLF 
Tables, Listings, and Figures 
TSH 
Thyroid Stimulating Hormone 
USA 
United States of America 
vs  
Versus  
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Abbreviation 
Description of abbreviations         
WBC  
White Blood Cells 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 
List of Key Terms 
Terms 
Definition of terms 
Adverse Event 
An adverse event is as any untoward medical occurrence in a patient 
administered a study drug and that does not necessarily have a causal 
relationship with this treatment. 
Baseline 
The baseline value is defined as the measurement before the first dose 
of double-blind study drug.  
Discontinuation 
The act of concluding participation, prior to completion of all 
protocol required elements, in a trial by an enrolled patient. 
End of Study 
The time of the last patient’s last protocol-defined assessment. 
Enrolled 
A screened patient who has received the study medication. 
Randomization 
The process of assigning trial patients to treatment or control groups 
using an element of chance to determine assignments in order to 
reduce bias. 
Screened 
A patient who has signed informed consent and has performed the 
screening visit. 
Serious Adverse 
Event 
An adverse event is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
results in death, is life threatening, results in persistent or significant 
disability/incapacity or substantial disruption of the ability to conduct 
normal life functions, results in congenital anomaly, or birth defect, 
requires inpatient hospitalization or leads to prolongation of 
hospitalization, or a medically important event. 
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3 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.  
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock. For operational efficiency an earlier time is usually targeted. If needed, revisions 
to the approved SAP may be made prior to database hard lock. Revisions will be version 
controlled.  If conflicts arise between the SAP and protocol, the SAP will supersede the 
protocol. 
 
4 
STUDY OBJECTIVES  
4.1 Primary Objective 
Proportion of patients in each treatment group with response in stool consistency on study as 
compared to baseline. The primary endpoint is based on overall stool response, as defined in 
section 7.2.1.1.  In addition, the proportion of patients in each treatment group who are 
weekly responders will be summarized over time. 
4.2 Secondary Objectives 
4.2.1 Efficacy 
Changes in the following assessed for each treatment group: 
• Decrease in worst abdominal pain  
• Decrease in discomfort  
• Decrease in frequency of defecation  
• Decrease in interference by irritable bowel syndrome (IBS) with activities of daily 
living  
Results of each of the secondary efficacy endpoints will be compared between the active 
treatment group and the placebo group. In addition, a composite efficacy endpoint of stool 
consistency and worst abdominal pain, per FDA guidance, will be calculated for each patient. 
An abdominal pain response per FDA guidance will be calculated separately. A patient is a 
composite responder (FDA endpoint) during a given week if he or she meets criteria for the 
primary endpoint, above, and meets the criteria for abdominal pain response, a decrease in 
the weekly average of worst abdominal pain in the past 24 hours of ≥30% compared with 
baseline.  
4.2.2 Safety 
10
Incidence and severity of adverse events by treatment group 


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4.2.3 Exploratory 
• Decrease in urgency 
• Use of rescue medication 
This will be evaluated similarly to other secondary endpoints, above. 
5 
STUDY DESIGN 
5.1 Description of the Disease 
Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain or 
discomfort is associated with disordered defecation (Longstreth et al, 2006). Unlike 
inflammatory bowel diseases, no anatomic or biochemical abnormalities have been correlated 
with IBS. The disease may cause substantial discomfort and morbidity, and often results in 
considerable reduction in quality of life (Canavan et al, 2014).  
Over 10% of adults worldwide have symptoms of IBS (Canavan et al, 2014). In most studies, 
prevalence is much greater in females than males, with ratios of 1.5-3.0 to 1 reported in 
various studies. 
IBS-D (IBS with diarrhea) is IBS with at least 25% of stools loose or watery and not more 
than 25% of stools hard or lumpy. 
5.2 Study Design Overview and Drug Administration 
This is a randomized, double-blind, 2-arm parallel group study conducted in USA.  
After qualifying for the study, patients will undergo a two-week observation period during 
which stool consistency and frequency data and symptom data (refer section 12) will be 
collected. Patients will then be randomized 60:40 to once daily treatment with either RHB-
102 12 mg (Group A) or placebo (Group B). Patients will continue on treatment for 8 weeks. 
All medications will be given orally. 
After randomization, patients will be given a four week supply of drug and instructed to take 
it once daily, before breakfast with approximately 240 mL (8 oz) of water. If a patient forgets 
to take the medication before breakfast, he or she can take it later in the day; the time of 
administration should be recorded.  
Patients will also be instructed to complete a diary, including information about stool 
consistency (Bristol chart), worst abdominal pain, discomfort, interference with daily 
activities, concomitant medications (including rescue medications) and adverse events. 
 
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5.3 Flow Chart  
A flow chart of study evaluations or procedures is shown below in Table 1.  
Table 1 
Study procedures 
Week 
Procedure 
-4 to -2 -2 and -1
a 
1 
2b 3 
5 
7 
9 
13 
Screening assessmentsc  
X 
 
 
 
 
 
 
 
 
Physical examination inc VS
d  
X 
 
X 
 
X X X X X 
Pregnancy teste  
 
X 
 
X 
 
 
 
 
 
 
Stool, pain and discomfort 
assessments
f  
 
 
X 
X 
X X X X X X 
CBC, biochemical profileg  
 
X 
 
X 
 
 
X  X X 
Urinalysis  
 
X 
 
 
 
 
X  X X 
Electrolytesh 
 
 
 
 
X 
 
  
 
Pharmacokinetic samplingi 
 
 
X 
 
X X   
 
Concomitant medications  
 
X 
X 
X 
X X X X X X 
Adverse events  
 
X 
X 
X 
X X X X X X 
Study medication dispensing  
 
 
 
X 
 
 
X  
 
 
Review of study medication use  
 
 
 
 
X X X X X 
 
a. During weeks -2 and -1, patients will collect baseline data, including the daily assessments, use of 
concomitant medications including those for symptoms of IBS, and occurrence of adverse events. These 
data will be provided to and reviewed by the investigator and/or staff prior to the week 1 visit, at which 
time the patient will be randomized and start treatment.  
b. Week 2 visit may be a phone contact 
c. Informed consent, history, serum TSH and free T
4, urinalysis, INR, C-reactive protein, colonoscopy if not 
performed within 24 months of start of screening, fecal calprotectin if colonoscopy >3 months prior to 
consent, serology for celiac disease, stool for ova, parasites and C diff, respectively, if positive history for 
any of these, ECG.  
d. Physical examination including vital signs: full physical examination at baseline; interim examinations of 
pertinent systems with attention to areas of change based on symptoms at subsequent examinations. At each 
visit: temperature, blood pressure, pulse, respiratory rate, weight. Height to be recorded at initial screening 
visit only.  
e. For women of childbearing potential. 
f. Stool and symptom assessments: daily Bristol chart; diaries for urgency, worst abdominal pain and worst 
abdominal discomfort during each day, using 11-point Likert scale (0-10) for each, with 0= no pain or no 
discomfort and 10= as bad as can be; daily assessment of interference by IBS with activities of daily living 
on a 5-point Likert scale; daily count of number of bowel movements; adverse events also to be recorded in 
diary. Diary may be given to patient at initial screening visit or any time thereafter. 
g. Safety labs: CBC, platelet count, biochemical profile to include at a minimum albumin, alkaline 
phosphatase, ALT, AST, bicarbonate, total bilirubin, BUN, calcium, chloride, creatinine, glucose, 
magnesium, potassium, total protein, sodium. 
h. Serum Ca, Cl, HCO3, K, Mg, Na.  Need not be fasting or predose. 
i. Pharmacokinetic sampling will be performed on all patients on day 1 prior to initial dosing and on day 1 of 
weeks 3 and 5. See Table 2 
12
for details of pharmacokinetic sampling procedure. 


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Table 2 
Pharmacokinetic sampling 
 
Time, relative to dose 
Week/day 
Group A 
Group B 
1/1 
Predose 
Predose 
3/1 
Predose, 1 h postdose 
6 h postdose 
5/1 
6 h postdose 
Predose, 1 h postdose 
 
5.4 Randomization and Blinding 
Patients will be stratified by gender (male/female) and randomized 60:40 to treatment with 
one of two matching products: 
• RHB-102 12 mg tablets  
• Placebo 
At least 25% and not more than 65% of patients entered are to be males. If the planned 
enrollment for either gender is reached before the end of the study, no more patients of that 
gender will be enrolled in the study. 
5.5 Duration of Treatment  
Patients will be treated daily for 8 weeks. 
5.6 Dose Modification  
Patients who develop constipation are to reduce dosing to once every other day. When 
constipation resolves, if symptoms recur or worsen, the patient may, in consultation with the 
investigator, increase the dose back to once daily. If constipation recurs, the patient is to 
again decrease the dose to once every other day.  
If constipation persists despite decrease in dose to once every other day, study medication is 
to be discontinued.  
Constipation is defined as no bowel movement for 48 hours or more. 
5.7 Discontinuation of Treatment  
Patients must discontinue therapy if they require any medication prohibited in this study. 
Additional reasons for discontinuation, at the investigator’s discretion: 
• Clinically significant adverse event, regardless of relation to study medication  
• 
13
Lack of efficacy: worsening symptoms persisting for at least two weeks during the 
study  


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In addition, patients may elect to discontinue study therapy at any time.  
The investigator shall attempt to obtain follow-up assessments per protocol regardless of 
when the patient discontinues therapy. The procedures and tests required for the week 9 visit 
per Table 1 should be performed at the time of early discontinuation of therapy. The follow-
up visit (week 13 in Table 1) should be conducted 4 weeks after the early termination visit. 
5.8 Replacement of Patients  
Patients who are randomized but receive no study medication shall be replaced.  
Patients who receive any study medication shall not be replaced. 
5.9 Sample Size Justification 
Sample size is calculated based on expected results for achievement of the FDA-specified 
endpoint for stool consistency:  
A stool consistency weekly responder is defined as a patient who experiences ≥50% 
reduction in the number of days per week with at least one stool that has a consistency of 
type 6 or 7 compared with baseline.  
 
A patient will be characterized as an overall responder if the patient was a weekly 
responder for ≥50% of the planned weeks of treatment.  
In addition, to be considered a responder for the week, the patient cannot have an increase in 
average abdominal pain >10% over baseline during that week. Based on Garsed et al, 2013, it 
is expected that approximately 80% of patients in the active treatment group and 40% of 
patients in the placebo group will be responder. Using a continuity-corrected Chi-Square test, 
to achieve a statistically significant difference between the active group and the placebo 
group with 80% power and significance level of α = 0.05 using 1:1 randomization, 28 
patients per group must be treated. To allow for a smaller difference, i.e., 70% response rate 
in the active group and 40% in placebo group, and for a 3:2 randomization ratio, a total of 
104 patients would be necessary to achieve this power. In order to allow for some further 
decrease in the actual difference in response rates between active and placebo, e.g., 
unexpectedly high early drop-out rate or variability in study data, a total of 120 patients will 
be randomized, 72 to RHB-102 and 48 to placebo. If no substantial violations impact the 
results of the study, this sample size will achieve a power of 87.5%. 
6 
ANALYSIS SETS/POPULATIONS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
14
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of  patients to analysis sets will be determined prior to database hard lock.  


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6.1 Modified Intent-to-Treat (mITT) population  
The mITT population will include all patients who took at least 1 dose of double-blinded 
study drug after randomization. 
In the mITT population, patients will be analyzed by the treatment they were randomized to.  
The population will be used for the summary of all baseline characteristics, including 
demographics, disease state data, prior medications, prior medical history and a statistical 
analysis of efficacy endpoints. 
6.2 Per-Protocol (PP) Population 
The PP population will include all patients from the mITT population who do not have a 
major protocol deviation (PD) that would affect treatment evaluation. Patients who 
discontinue the study due to documented lack of treatment effect will be included in the PP.  
Major PD include but are not limited to:  
• Lack of compliance defined as having administered <75% of the planned study 
medication until discontinuation.  
• Fewer than 12 days (of planned 14 days) of baseline data.  
• Fewer than 7 days of data if not discontinued before due to lack of efficacy.  
• Use of forbidden IBS medications*. 
• Failure to fulfill inclusion/exclusion criteria defining IBS-D. 
*includes the specific medications (e.g. eluxadoline) or non-specific medications (e.g. 
usage of loperamide more than 4 mg per day). 
All efficacy analyses will be conducted in the mITT and PP populations. 
6.3 Safety Population (SAF) 
The SAF will include all patients who received at least 1 dose of study drug (even if the 
patient vomits immediately after drug administration).  
In the SAF, patients will be analyzed by the actual treatment they received.  
The SAF will be used for summarizing demographic and safety data. 
6.4 Pharmacokinetic Population (PKP) 
The PKP will include all patients treated with RHB-102 with quantifiable concentrations of 
ondansetron in plasma and sufficient and reliable dosing and sampling information to permit 
estimation of elapsed time since the prior dose.  
15
All Pharmacokinetic (PK) analyses will be conducted in the PKP. 


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7 
ENDPOINTS & ANALYSIS VARIABLES    
7.1 Efficacy Endpoints 
7.1.1 Primary Efficacy Endpoint 
• Stool consistency each stool, per Bristol Stool Form scale  
7.1.2 Secondary Efficacy Endpoints 
• Worst abdominal pain intensity per 24-hour period, on an 11-point Likert scale  
• Combined endpoint of stool consistency and worst abdominal pain (FDA endpoint) 
• Frequency of bowel movements  
• Worst discomfort per 24-hour period, on an 11-point Likert scale  
• Interference of IBS with general functioning, on a 5-point Likert scale  
7.1.3 Exploratory Efficacy Endpoints 
• Urgency, on a 11-point Likert scale 
• Use of rescue medication 
7.2 Efficacy Variables 
7.2.1 Primary Efficacy Variable  
7.2.1.1  Stool Consistency  
A weekly stool consistency responder is defined in the FDA guidance on IBS-D as a patient 
who experiences during a week a ≥50% reduction in the number of days with at least one 
stool that has a consistency of Type 6 or 7 on the Bristol stool scale (refer Appendix 1) 
compared with baseline. In addition, to be considered a responder for the week, the patient 
cannot have an increase in average abdominal pain >10% over baseline during that week. A 
patient will be characterized as an overall stool consistency responder if the patient was a 
weekly responder for at least 50% of the planned weeks of treatment. 
In case a patient took rescue medication on a day this day will be counted as “failed day”, i.e. 
it will be treated as if the patient had at least one stool that has a consistency of Type 6 or 7 
on the Bristol stool scale on this day.  
7.2.2 Secondary Efficacy Variables  
7.2.2.1 Pain Response  
A weekly pain responder is defined as a patient who experiences a decrease in the weekly 
average of worst abdominal pain in the past 24 hours score ≥30% compared with baseline 
and no increase in the number of days per week with stools with consistency of Type 6 or 7.  
16
An overall pain responder is defined as patient who was a weekly pain responder for at least 
50% of the planned weeks of treatment. 


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7.2.2.2 Overall Response 
A patient is characterized as a weekly responder if the patient meets both the stool 
consistency and pain response definitions for a given week.  
A patient is characterized as an overall study responder if the patient meets the criteria for 
both weekly stool consistency and pain response for at least 50% of the planned weeks of 
treatment. 
7.2.2.3 Abdominal Pain  
Abdominal pain is measured as the worst abdominal pain during a 24-hour period, on an 11-
point Likert scale ranging from 0 (no pain) to 10 (as bad as can be imagined).  
7.2.2.4 Discomfort  
Discomfort is measured on an 11-point Likert scale ranging from 0 (no discomfort) to 10 (as 
bad as can be imagined). 
7.2.2.5 Interference by IBS with Activities of Daily Living  
Interference with daily activities is measured on a 5-point Likert scale ranging from 0 (no 
interference) to 4 (unable to carry out activities of daily living). 
Refer Appendix 2 for sample diary card for abdominal pain, discomfort and IBS interference 
with daily activities.  
7.2.3 Exploratory Efficacy Variables  
7.2.3.1 Urgency 
Urgency is the feeling of a need to defecate and inability to control or incomplete control 
over defecation. Urgency over the course of the day, is measured on an 11-point Likert scale 
ranging from 0 (no urgency) to 10 (as bad as can be imagined). 
7.2.3.2 Use of Rescue Medication 
Use of rescue medication is the use of any IBS-D related medication after start of randomized 
treatment, including allowed rescue medication loperamide. 
7.3 Safety Endpoints  
• Occurrence of adverse events, both clinical and laboratory.  
Adverse events will be tabulated by system organ class (SOC) and preferred term (PT) using 
Medical Dictionary for Regulatory Activities (MedDRA) version 13.1. Adverse events will 
be graded 1-5 according to NCI-CTCAE v4 criteria. 
7.4 Safety Variables 
Safety will be assessed by evaluation of the following variables: 
• 
17
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug). 


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• Vital signs  
• Physical Examination 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory variables (CBC, serum chemistry including liver function tests, 
and urinalysis) 
7.5 Other Variables 
7.5.1 Duration of Exposure 
For each patient the duration of exposure on double-blind treatment will be calculated in days 
using the following formula: 
(Date of last dose of study drug – Date of first dose of study drug) + 1 
where the dates of the first and last known double-blind treatment are recorded on the study 
drug dosing eCRF pages. If they are missing, then no imputed dates will be used. Any gaps 
in dosing will be included in the total number of days on double-blind treatment.  
7.5.2 Percent Compliance 
Percent compliance for the study medication (either RHB102 12 mg or matching placebo) 
during treatment period is defined for each patient as the number of tablets taken, divided by 
the number of tablets that should have been taken times 100. 
The number of tablets that should have been taken is calculated as 1 + (date of last intake of 
study medication – date of first intake of study medication) times the prescribed daily dose 
(i.e. 1 tablet per day). In case a patient has to reduce the dose due to constipation to once 
every other day, the number of days that should have been without dosing will be subtracted 
from the calculated number. The number of tablets taken is the total number of tablets 
recorded as taken based on the CRF, summed over the days counted when calculating the 
number of tablets that should have been taken, including the day of the last study treatment 
dose. 
7.5.3 Prior, Concomitant, and Follow-up Medication 
7.5.3.1 Prior Medication 
Prior medication is defined as medication that stopped before the date of the first dose of 
treatment (i.e. last medication intake is prior to first dose of treatment date (exclusive)). All 
prior medications (includes IBS-D related or non- IBS-D related), regardless of when they 
were taken, will be collected on the eCRF.   
7.5.3.2 Concomitant Medication 
Concomitant medication (includes IBS-D related or non-IBS-D related) is defined as a 
medication with either 
• 
18
a recorded medication start date falling within the treatment period, or 


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• a recorded medication start date prior to the first day of study medication during the 
randomized treatment period without any recorded medication stop date prior to the 
start of the randomized treatment period. 
This means that concomitant medications will be any medication taken from start of the 
randomized treatment period up to the end of the randomized treatment period. Medications 
with incomplete start or stop dates will be considered concomitant medications if it is possible 
that they could have been concomitant medications. 
7.5.3.3 Follow-up Medication 
Follow-up medication (includes IBS-D related or non-IBS-D related) is defined as any 
medication starting after the week 9 visit date. 
7.5.4 Demographics 
The patient’s year of birth, sex, race, ethnicity, height, and weight will be recorded at 
Screening Visit. 
8 
STATISTICAL METHODOLOGY 
8.1 General Considerations 
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher. Specifications for table, figures, and data listing formats can be found in the TLF 
specifications for this study. 
Continuous variables will be summarized using the standard descriptive statistics which 
includes number of patients (n), arithmetic mean, standard deviation (SD), minimum, median, 
and maximum. When needed, the use of other percentiles (e.g. 10%, 25%, 75% and 90%) 
will be mentioned in the relevant section. Categorical variables will be described using 
absolute and relative frequencies (n & %’s). Percentages by categories will be based on the 
number of patients with no missing data, i.e. will add up to 100%. Shift tables will be 
provided, where appropriate. Confidence Intervals (CI) will be two-sided 95% Cis if not 
otherwise specified. If not specified otherwise, statistical tests will be two-sided with a 
significance level of α = 0.05.  
In general, baseline is defined as the last measurement before the first dose of double-blind 
study drug. In this study, if baseline values for (semi-) continuous variables are derived from 
the daily assessments during the two-week observation period preceding randomization, 
these will be defined as the average of the respective measurements over this two-week 
period. 
All analyses and summary tables will be displayed by treatment group. Primary and few key 
secondary endpoints will be analyzed by subgroups. For the definition of subgroups of 
interest please refer to section 8.8.
19
 


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8.1.1 Model Structure or SAS Codes 
8.1.1.1 Chi-Square Test with Continuity Correction 
The following SAS statements will be used for the primary and secondary endpoint analyses: 
PROC  FREQ data=<dataset name>; 
TABLES response variable*grouping variable/CHISQ OUT=< output dataset name> 
 OUTPUT OUT=stats; 
RUN; 
Note: In case the assumption of Chi-square test is not met (e.g. expected cell frequencies < 5), 
a Fisher’s exact test will also be carried out as supportive analysis for the primary and binary 
secondary endpoints. The SAS code is similar but with “FISHER” option in the “TABLES” 
statement above. 
8.1.1.2 Logistic Regression  
For the primary secondary and secondary endpoint analyses, a logistic regression model for the 
response rate (RR) will be modeled with the logit link as follows: 
      logit(E(RR
ij))  =  β0  +   Trti  +  Genderj  
where (E(RR
ij)) is the probability that a patient s from treatment group i, and gender j 
demonstrates a response. 
The odds ratio (OR) as well as its two-sided Wald 95% CIs and p-value for Treatment vs 
placebo will be derived. 
The SAS code used to implement this test will be similar to that shown below: 
PROC GENMOD DATA =<dataset name> 
order=data; 
CLASS Trt Gender; 
MODEL Responder(event='1') = Trt Gender/ DIST=bin LINK=logit 
LRCI type3 wald; 
ESTIMATE ‘Treatment versus placebo’ 
Trt 1 -1 / EXP; 
LSMEANS Trt / DIFF CL CORR PDIFF; 
RUN; 
8.1.1.3 Analysis of Covariance 
Changes from baseline to a post-baseline visit (in every treatment week for worst abdominal 
pain discomfort, Interference by IBS, frequency of defecation, and urgency) will be analyzed 
using the following Analysis of Covariance  (ANCOVA) model: 
      Chijks  =  β0  +  β
1Baseijks  +  Trti  +  Sitej  +  Genderk  +  ∈ijks
20
 


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where Chijks is the change from baseline for patient s from treatment group i, study site j, and 
gender k. β
0 and β
1 are the intercept and the slope of Chijks as a function of the baseline value 
and ∈ijks is the residual for each patient. 
The ANCOVA model results will be presented with least squares (LS) means and two-sided 
95% confidence intervals (CIs) for mean changes from baseline within each treatment group. 
Differences in LS means between treatment vs placebo will be derived together with two-
sided 95% CIs and p-values.  
The SAS code used to implement this test will be similar to that shown below: 
PROC MIXED DATA=dataset COVTEST NOCLPRINT; 
CLASS Trt Site Gender; 
MODEL Ch=Base Trt Site Gender / SOLUTION CL; 
LSMEANS Trt / CL OM AT MEANS PDIFF; 
ESTIMATE ‘Treatment versus placebo’ Trt 1 -1 /EST CL; 
RUN; 
8.1.1.4 Mixed Model Repeated Measures (MMRM) 
To assess the impact of time, weekly changes from baseline to each post-baseline visit  “t” 
(e.g. in mean values in worst abdominal pain, discomfort, interference by IBS with activities 
of daily life, and frequency of defecation etc.,) will be analyzed using the following MMRM 
model: 
 Chijkst =  β0  +  β
1Baseijks  +  Trti  +  Sitej  +  Genderk  +  Weekt + Trt*Weekit + ∈ijkst 
where Chijkst is the change from baseline (i.e. time = 0 week) for patient s from treatment 
group i, Study site group j, Gender k and for given week t (t= 1,…,8). β
0 and β1 are the 
intercept and the slope of Chijks as a function of the baseline value and ∈ijkst is the residual 
for each patient. Trt*Weekit is the time-by-treatment interaction effect. The unstructured co-
variance matrix will be used to adjust for the within-patient error variance co-variance. 
The MMRM model results will be presented with LS means, standard errors and two-sided 
95% CIs for mean change from baseline overall and at all time points (weeks 1 to 8) within 
each treatment group. The denominator degrees of freedom will be calculated according to 
the Kenward-Roger method. 
The SAS code used to implement this test will be similar to that shown below: 
PROC MIXED DATA=dataset COVTEST NOCLPRINT METHOD=REML; 
CLASS ID Trt Time Site Gender; 
MODEL ch=Base Trt Site Gender Time Time*Trt / 
SOLUTION CL DDFM=KenwardRoger; 
REPEATED Time /SUBJECT = ID TYPE = UN R RCORR; 
LSMEANS
21
 Trt / CL PDIFF; 


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ESTIMATE ‘Ondansetron versus placebo’ Trt 1 -1 /EST 
CL; 
RUN; 
In case of non-convergence of the above model,  the same model but with AutoRegressive-1 
(AR(1) covariance matrix) will be preferred. If the problem is still not resolved, the model 
could be fitted by removing study site from the list of covariates.  
8.2 Study Population 
8.2.1 Disposition of Patient
Patients 
The following patient data will be presented: 
• Number of patients with informed consent, discontinued before randomization,
randomized (overall only);
• Number and percentage of patients randomized in each analysis set/population, by
treatment group and overall;
• Number and percentage of patients completed and discontinued treatment, by
primary reason for treatment discontinuation for randomized patients, by treatment
group;
• Number and percentage of patients completed and discontinued the study (as defined
by investigator’s assessment per End of Study page of the CRF), by primary reason
for study discontinuation for randomized patients and by treatment group;
• Number and percentage of patients who completed the study according to the
following objective definition: A patient is defined as a completer if the following
conditions are fulfilled: (i) completion of at least 7.6 calendar weeks of treatment
(with or without treatment gaps), (ii) attendance of an end-of-study visit 28 ± 11 days
after the last date of study medication intake.
• Number and percentage of patients excluded from PP population by reason for
exclusion defined in section 6.2, by treatment group for mITT.
8.2.2 Protocol Deviations 
Major protocol deviations as defined in the study protocol (Section 7.2.2 Protocol 
Deviations) will be assessed for all randomized patients. The number and percentage of 
patients meeting any criteria will be summarized for each criterion and overall, by treatment 
group and total as well as by study site. Patients deviating from a major criterion more than 
once will be counted once for the corresponding criterion. Any patients who have more than 
one major protocol deviation will be counted once in the overall summary. A data listing will 
be provided by site and patient for all the major and minor protocol deviations. 
22
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows: 


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Protocol Deviation (PD)1 - Lack of compliance defined as having administered <75% 
of the planned study medication until discontinuation,  
PD2 - Fewer than 12 days (of planned 14 days) of baseline data, 
PD3 - Fewer than 7 days of data if not discontinued before due to lack of efficacy, 
PD4 - Use of forbidden IBS medications*, 
PD5 – Failure to fulfill inclusion/exclusion criteria defining IBS-D, 
PD6 – Presence of excluded conditions at baseline. 
*includes specific medications (e.g. eluxadoline) or non-specific medications (e.g. 
loperamide over allowed amount). 
Note: Failure to fulfill the other entry criteria such as laboratory parameters outside the limits 
will be considered as minor protocol deviations.  
8.2.3 Demographic and Other Baseline Characteristics 
Demographic and pre-treatment patient characteristics, including disease parameters and 
comorbidities, will be summarized with descriptive statistics by treatment group. 
Descriptive statistics for age (in years), baseline weight (in kg), body mass index (BMI), 
body surface area (BSA)  and height (in cm) at study entry will be presented.  Frequency 
tabulations for sex, ethnicity, age group (< 65, ≥ 65 years), race, Irritable Bowel Syndrome 
Symptomatology as collected in the eCRF will be presented. This will be done for the SAF, 
mITT and PP Populations by treatment group. 
BMI is calculated as BMI (kg/m2) = weight (kg) / height
2 (m).   
BSA is calculated as BSA (m²) = weight0.5 (kg) x height
0.5 (m) / 6 (Mosteller formula). 
Medical history is coded in MedDRA v 13.1, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group for the SAF.  
8.2.4 Prior and Concomitant Medications 
Prior medications (IBS-D related or non-IBS-D related) are coded with World Health 
Organization – Drug Dictionary (WHO-DD) March 2015 Enhanced, and will be summarized 
by therapeutic subgroup (Anatomical Therapeutic Chemical (ATC) 2
nd level) and chemical 
subgroup (ATC 4
th level) and preferred World Health Organization (WHO) name by 
treatment group for the SAF.  
As with prior medications, concomitant medications (includes IBS-D related or non- IBS-D 
related) will be summarized for each treatment group by therapeutic subgroup (ATC 2
nd 
level) and chemical subgroup (ATC 4
th level) and preferred WHO name for the SAF. 
Patients taking the same medication multiple times will be counted once per medication and 
investigational period.  
Please refer section 7.5.3 
23
for case definitions.  


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8.3 Study Drugs 
8.3.1 Exposure 
The following information on drug exposure will be presented for each treatment group for 
the SAF: 
• Descriptive statistics for number of days treatment was received will be presented by 
treatment group 
• Descriptive statistics will be presented for the duration of exposure by treatment 
group. 
8.3.2 Treatment Compliance 
Overall compliance will be examined for patients in the SAF whose total study drug count 
and first and last days of treatment are known. 
Percent overall compliance will be summarized in two ways for the SAF: 
• Descriptive statistics will be presented by treatment group. 
• Percent compliance will be categorized according to the following categories by 
treatment group: 
○ less than 50% 
○ at least 50%, less than 75% 
○ at least 75%, less than 90% 
○ at least 90%, less than 110% 
○ greater than 110% 
○ unknown. 
8.4 Analysis of Efficacy  
All efficacy analyses will be conducted in the mITT and PP populations. 
8.4.1 Analysis of Primary Endpoint 
8.4.1.1 Primary Analysis  
The primary endpoint in the study is stool consistency response in the absence of increase in 
pain ≥10%. 
Hypotheses: 
Let pO denote the response rate under RHB-102 and p
P denote the response rate under 
placebo then the primary two-sided hypothesis to be tested is  
H0: p
O - p
P = 0  
vs the alternative  
H1: pO - p
P
24
 ≠ 0.  


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A Chi-Square test with continuity correction at the significance level α = 0.05 will be 
employed for the primary (confirmatory) analysis of the primary endpoint.  
In case the assumptions of Chi-square test is not met (e.g. expected cell frequencies < 5), a 
Fisher’s exact test in addition to Chi-square test with continuity correction will be carried out 
as supportive analysis. This analysis holds also for the other binary endpoints. 
8.4.1.2 Secondary Analysis  
The weekly response rates will also be compared for each week between the treatment groups 
with a Chi-Square test with continuity correction.  
For each treatment week the change in average daily stool consistency (as measured on the 
Bristol Stool Form scale) from baseline will be compared between the treatment groups with 
an ANCOVA model including treatment group, study site and gender as independent 
variables and baseline daily stool consistency (see section 8.1) as covariate. If on a day no 
stool was confirmed, a value of 0 will be assigned for this day.  
To assess the impact of time a Repeated Measurement Model will be applied with the weekly 
changes from baseline as dependent variable, treatment group, study site, gender, week and 
treatment x week interaction as independent variables and baseline daily stool consistency as 
covariate. Study site could be removed from the covariates in case of convergence issues.    
To assess the effect of gender on the primary endpoint, a logistic regression model with 
treatment group and gender as covariates will be modeled.  
8.4.2 Analysis of Secondary Endpoints  
Secondary efficacy endpoints include the following:  
• Proportion of patients in each treatment group who are pain responders, per FDA 
guidance definition  
• Proportion of patients in each treatment group who are overall responders, per FDA 
guidance definition  
• Differences between treatment groups in  
o Abdominal pain  
o Discomfort  
o Frequency of defecation  
o Interference by IBS with activities of daily living  
All secondary analyses are considered as exploratory, no adjustments for multiplicity will be 
made. 
8.4.2.1 Pain Response  
Refer section 7.2.2.1 
25
to understand the derived pain response variable.  


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A Chi-Square test with continuity correction at the significance level α = 0.05 will be 
employed for the comparison of the treatment groups regarding overall and weekly pain 
response.  
To assess the effect of gender on the overall pain response, a logistic regression model with 
treatment group and gender as covariates will be applied.  
8.4.2.2 Overall Response 
Refer section 7.2.2.2 to understand the derived overall response variable.  
 A Chi-Square test with continuity correction at the significance level α = 0.05 will be 
employed for the comparison of the treatment groups regarding overall and weekly study 
response.  
To assess the effect of gender on the overall study response, a logistic regression model with 
treatment group and gender as covariates will be applied. 
8.4.2.3 Abdominal Pain  
Refer section 7.2.2.3 to understand the abdominal pain variable.  
For each treatment week the change in the weekly average of worst abdominal pain from 
baseline will be compared between the treatment groups with an ANCOVA model including 
treatment group, study site and gender as independent variables and baseline worst 
abdominal pain (see section 8.1) as covariate.  
To assess the impact of time, a Repeated Measurement Model will be applied with the 
weekly changes from baseline as dependent variables, treatment group, study site, gender, 
week and treatment x week interaction as independent variables and baseline worst 
abdominal pain as covariate. Study site could be removed from the covariates in case of 
convergence issues.    
8.4.2.4 Discomfort  
Refer section 7.2.2.4 to understand the discomfort variable.  
For each treatment week the change in the weekly average of discomfort from baseline will 
be compared between the treatment groups with an ANCOVA model including treatment 
group, study site and gender as independent variables and baseline discomfort (see section 
8.1) as covariate.  
To assess the impact of time, a Repeated Measurement Model will be applied with the 
weekly changes from baseline as dependent variables, treatment group, study site, gender, 
week and treatment x week interaction as independent variables and baseline discomfort as 
covariate. Study site could be removed from the covariates in case of convergence issues.    
8.4.2.5 Interference by IBS with Activities of Daily Living  
Refer section 7.2.2.5 
26
to understand the interference by IBS with activities of daily living 
variable.  


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For each treatment week the change in the weekly average of interference from baseline will 
be compared between the treatment groups with an ANCOVA model including treatment 
group, study site and gender as independent variables and baseline interference score (see 
section 8.1) as covariate.  
To assess the impact of time, a Repeated Measurement Model will be applied with the 
weekly changes from baseline as dependent variables, treatment group, study site, gender, 
week and treatment x week interaction as independent variables and baseline interference 
score as covariate. Study site could be removed from the covariates in case of convergence 
issues.     
8.4.2.6 Frequency of Defecation  
For each treatment week the change in average daily frequency of defecation from baseline 
will be compared between the treatment groups with an ANCOVA model including 
treatment group, study site and gender as independent variables and baseline daily frequency 
of defecation (see section 8.1) as covariate.  
To assess the impact of time a Repeated Measurement Model will be applied with the weekly 
changes from baseline as dependent variable, treatment group, study site, gender, week and 
treatment x week interaction as independent variables and baseline daily frequency of 
defecation as covariate. Study site could be removed from the covariates in case of 
convergence issues.    
8.4.3 Analysis of Exploratory Endpoints  
8.4.3.1 Urgency 
For each treatment week the change in the weekly average of urgency from baseline will be 
compared between the treatment groups with an ANCOVA model including treatment group, 
study site and gender as independent variables and baseline urgency (see section 8.1) as 
covariate. To assess the impact of time, a Repeated Measurement Model will be applied with 
the weekly changes from baseline as dependent variables, treatment group, study site, gender, 
week and treatment x week interaction as independent variables and baseline urgency as 
covariate. 
8.4.3.2 Use of Rescue Medication 
Use of rescue medication will be analyzed qualitatively and quantitatively. The number of 
patients using any rescue medication (any dosage) during the complete treatment phase will 
be compared between the treatment groups using a continuity corrected Chi-Square test.  
27
The only rescue medication allowed as per protocol is loperamide, which may not be taken 
more often than package insert instructions, i.e., maximum daily dose two 2 mg pills (total of 
4 mg) or equivalent in other dosage forms. The number of patients using loperamide (any 
dosage) during the complete treatment phase will be compared between the treatment groups 
using a continuity corrected Chi-Square test. The average weekly dosage (mg/week) of 
loperamide for each treatment week and overall will be summarized by descriptive statistics 
and compared between the treatment groups using a two-sided t-test. 


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8.4.4 Sub-group Analyses 
The primary endpoint, improvement in stool consistency, and the secondary endpoints pain 
response and overall response will be analyzed for all patients and by gender, CRP value at 
baseline (≤ or > median CRP, the median value in the mITT population will be used for 
defining the subgroups)  and use of rescue medication after start of randomized treatment, i.e. 
Chi-square test with continuity correction will be repeated by gender, CRP value at baseline 
and use of rescue medication as described under the sections 8.4.1.1, 8.4.2.1 and 8.4.2.2. 
To evaluate the differences in effect by gender, additional efficacy endpoints may be 
analyzed by gender if trends towards differences (p-value from logistic regression ≤ 0.1) are 
seen in the endpoints initially analyzed by gender.  
Further sub-group analyses may be performed as ad-hoc analyses after the protocol-defined 
analyses if this is suggested by the data. 
8.5 Analysis of Safety 
The safety and tolerability of RHB-102 will be determined by reported AEs, physical 
examinations, vital signs, and laboratory tests. All analyses of safety will be performed in the 
Safety population. 
No inferential comparison between treatment groups will be performed for the safety analysis 
in this study. 
8.5.1 Adverse Events 
The incidence of treatment-emergent AEs will be summarized for each treatment group by 
MedDRA v 13.1 SOC and PT. An AE is defined as treatment-emergent if its onset date/time 
is on or after the date/time of the first intake of study drug or if a pre-existing condition 
becomes worse after the date/time of first intake of study drug. An AE is defined as pre-
treatment if its onset date/time is before the date/time of the first intake of study drug. If it is 
not possible to determine whether an AE is treatment–emergent, due to a missing or 
incomplete start date, the AE will be regarded as treatment–emergent unless the stop date 
definitely indicates that the event was prior to first dose of study drug.  
All new abnormal laboratory findings and those abnormal at baseline which change 
significantly (i.e., by at least one toxicity grade as defined in the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) are considered AEs. 
Laboratory AEs for which there is no clinical intervention will be extracted from the 
laboratory data programmatically. Laboratory AEs not listed in the NCI CTCAE v4.03 will 
be considered as grade 1 (mild) if there is no clinical effect or intervention. Laboratory values 
outside the normal range for certain parameters will not be considered AEs if they are 
generally not considered as indicating an abnormality; this includes such parameters as liver 
enzymes which are below the normal range. If there is a clinical sequela or intervention, the 
laboratory abnormality is to be graded according to the criteria used for clinical AEs.  
28
The NCI CTCAE v4.03 can be downloaded in pdf, Excel or OWL format at:  


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http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
AEs will be summarized according to the following:  
• An overview of the absolute and relative frequencies of patients with at least one AE 
will be given for the categories pre-treatment and treatment-emergent by seriousness, 
severity, and causality.  
• Further tables will present the absolute and relative frequencies of patients with at 
least one treatment-emergent AE classified by SOC and PT and, in addition, by 
severity and causality.  
• The absolute and relative frequencies of patients with at least one SAE will be 
summarized by SOC and PT. 
• Individual patient data listings will be provided for all discontinuation of study 
medication due to AEs.  
Regarding the summaries by severity and causality, the following rule will be applied: 
If a patient experiences more than one AE within the same SOC or with the same PT, the AE 
with the highest severity or closest relationship to study drug will be used for the analysis. 
8.5.2 Clinical Safety Laboratory Tests 
Key laboratory data (biochemistry, hematology, and urinalysis) will be subjected to both a 
quantitative analysis (descriptive summary statistics such as mean, standard deviation, 
minimum, maximum, and median) and qualitative analysis where frequencies of normal, 
abnormal low, and abnormal high values will be computed.  
The following parameter will be analyzed: 
Complete blood count (CBC) including: 
• hemoglobin,  
• total white blood cells (WBC) count, 
• absolute values for individual white blood cell types (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)  
• platelet count. 
Biochemical profile including: 
• albumin,  
• alkaline phosphatase,  
• alanine transaminase (ALT),  
• aspartate transaminase (AST),  
• (total) bilirubin,  
• 
29
blood urea nitrogen (BUN),  


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• calcium, 
• chloride, 
• CO2, 
• creatinine,  
• glucose,  
• magnesium,  
• potassium,  
• sodium,  
• total protein. 
Urinalysis including: 
• routine:  dipstick tests for protein, glucose, ketones, blood, pH, specific gravity; 
• microscopic:  erythrocytes, leukocytes, bacteria, crystals, casts. 
At screening only also the following parameters will be evaluated: INR (at baseline only), 
serum TSH and free T
4, INR, and C-reactive protein. 
The following analyses will be performed for CBC and biochemical profile, results for 
urinalysis will be listed only:  
• Standard descriptive summary statistics will be calculated at each scheduled 
measuring time point and the last individual measuring time point.  
• Standard descriptive summary statistics will be calculated for the absolute change 
from baseline to each scheduled measuring time point after baseline and the last 
individual measuring time point.  
• Shift tables displaying changes with respect to the normal range between baseline and 
the worst value measured after baseline will be provided. Shift tables will show 
changes by grade for analytes graded in the NCI CTCAE v 4.03 criteria.  
• A listing of all patients with abnormal values at any time point will be given.  
For the summary tables laboratory parameter will be reported using US conventional units. 
No inferential testing will be performed to compare the differences between the treatment 
groups; a paired-sample t-test may be provided for each group for change from baseline if 
data warrant. 
8.5.3 Other Parameters 
30
The results from physical examination, including vital signs, will be presented in the patient 
data listings. Findings on physical examination, including vital signs, which constitute 
clinically significant changes will be listed as adverse events. 


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8.5.3.1 Electrocardiograms (ECGs) 
ECG variables (heart rate, PR interval, RR interval, QRS interval, QT interval, and QTcF 
interval) will be summarized using descriptive statistics or frequencies and percentages for 
each treatment group at baseline. 
Number and percent of patients with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by local investigator for the 12 lead ECG 
will be tabulated by treatment group at baseline.  
8.5.3.2 Pregnancy Test Results 
By-patients listing of pregnancy test results will be provided using Safety population. 
8.6 Analysis of Pharmacokinetics (PK) 
Ondansetron concentrations will be listed and summarized by visit and PK randomization group. 
In the listing, the date and time will be recorded for the dose of RHB-102 (or placebo) taken prior 
to blood sampling to determine ondansetron concentration in plasma. This is the dose of the prior 
day for pre-dose PK samples. 
Nonlinear mixed-effects methods will be used to develop a population-based pharmacokinetic 
(PopPK) model of ondansetron concentrations in plasma after administration of RHB-102. 
Individual post hoc Bayesian estimates of pharmacokinetic (PK) model parameters will be used 
to estimate the steady-state peak (Cmax) and trough (Cτ) concentrations and the area under the 
curve of concentration versus time over the dosing interval (AUCτ). PopPK modeling will be 
described in a separate modeling and simulation analysis plan.  
8.7 Analysis of Pharmacodynamics (PD) 
Cmax, Cτ, and AUCτ will serve as exposure metrics in exploratory plots of exposure versus 
relevant efficacy and safety endpoints. Exposure-response (ER) models may be developed to 
describe emerging trends. 
ER modeling will be described in a separate modeling and simulation analysis plan. 
8.8 Subgroups of Interest 
Primary efficacy endpoint and few secondary endpoints will be summarized by treatment 
group for the subgroups defined on the basis of the categorized variables listed below: 
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Grouping variable 
Subgroups 
Gender 
Male 
Female 
Use of rescue medication after start of 
randomized treatment 
Yes 
No 
CRP value at baseline 
≤ median CRP 
> median CRP 
 
8.9 Other Analyses 
Not applicable 
8.10 Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
8.10.1 Missing Data 
If a patient fails to provide any assessments after baseline (e.g. if the diary is missing 
completely) he/she will be counted as a non-responder in any of the overall responder analyses 
(overall stool consistency response, overall pain response, overall study response). To be 
included in one of the weekly analyses for the primary or any of the secondary endpoints a 
patient has to provide data for this endpoint at least on 4 days of the respective week, otherwise 
the patient will be considered a non-responder for that week for the weekly response analyses 
or will be excluded from the analysis for the quantitative analyses. If a patient fails to be 
included in more than two of the weekly responder analyses, he/she will also be counted as 
non-responder in any of the overall responder analyses. Otherwise missing values will not be 
imputed. For the treatment of missing/incomplete start and stop dates of adverse events and 
medications refer to the corresponding sections. 
8.10.2 Outliers 
No outlier detection will be performed.  
8.10.3 Visit Windows 
Day 1 for the randomized study treatment period is the start date of study medication. The 
following visit windows will apply for the measurements (vital signs and laboratory data) 
collected in the eCRF . 
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Analysis visit 
Protocol defined 
visit window 
Actual assessment window (Study Days) 
Screening 
-4 to -2 weeks 
 
Baseline 
-2 to -1 week 
 
Week 1 
Within 6 weeks of 
consent 
 
Week 2 
Week 2 ± 2 days 
5 - 9 
Week 3 
Week 3 ± 2 days 
12 - 16 
Week 5 
Week 5 ± 2 days 
26 - 30 
Week 7 
Week 7 ± 2 days 
40 - 44 
Week 9/End of Treatment 
Week 9 ± 2 days 
54 - 58 
Week 13/Follow-up  
Week 13 ± 4 days 
80 - 88 
NOTE: visit windows/study days will be calculated based on the Week 1 date. 
 
Values falling outside of the visit windows will be listed only but will not contribute to any 
summary statistics except for the laboratory shift tables to worst value after baseline. 
For laboratory and non-laboratory parameters, if a patient has more than one measurement 
included within a window, the assessment closest to the target day will be used. In case of ties 
between observations located on different sides of the target day, the earlier assessment will be 
used. 
9 
INTERIM ANALYSIS  
No interim analyses or safety data monitoring reports are planned for this study.  
10 
CHANGES TO PLANNED ANALYSES 
The following analyses have been added/clarified in the SAP. 
• An objective definition of study completion has been added in section 8.2.1. 
• Fisher’s exact test in case the expected cell frequency is < 5 for Chi-square test with 
continuity correction.  
• For MMRM, proposal to remove study site as one of the covariates in case of issues 
with convergence.  
• Subgroup analyses with subgroups defined by the use of rescue medication and the 
baseline CRP value (≤ or > median)  have been added. 
• An analysis of weekly mean daily stool consistency was added. 
• The analysis of rescue medication use was clarified. The following summaries will be 
presented 
o Overall Use of Rescue Medication  
o Overall Use of loperamide 
o Overall Mean Weekly Dosage (mg/week) of loperamide 
o 
33
Mean Weekly Dosage (mg/week) of loperamide 


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Use of rescue medication was now defined as an exploratory endpoint in this study. 
• No summaries of SAEs by severity and causality and no patient listing for cases of  
death will be generated. 
11 
REFERENCES 
Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol 
2014;6:71-80. 
Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, 
Spiller R.  A randomised trial of ondansetron for the treatment of irritable bowel syndrome 
with diarrhea.  Gut 2014;63:1617-25.  
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterol 2006;130;1480-91. 
 
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12 
APPENDICES 
Appendix 1: Bristol Stool Form Scale 
 
 
 
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Appendix 2: Diary card for abdominal pain, discomfort and IBS interfere with daily 
activities 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 
Addendum 1.0 dated 28
th November 2017 
 
Randomized, Double-blind, Placebo-controlled, Phase 2 Trial of RHB-102 
(Ondansetron 12 mg Bimodal Release Tablets) for Diarrhea Predominant Irritable 
Bowel Syndrome (IBS-D) 
 
 
 
Protocol number: RHB-102-02 
 
Protocol Date: Amendment 4 dated 16th February 2017 
 
SAP Date: Version 1.0 dated 28th June 2017 
 
 
 
 
Sponsor: 
RedHill Biopharma Ltd.  
21 Ha’arba’a St.  
Tel-Aviv 64739, Israel 
 
 
 
 
 
 
 
 
 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor. 
 
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Signatures 
 
 
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1 
REVISION HISTORY 
Date 
Version 
Description  
Author  
28th June 2017 
Final 1.0 
Final Version 
 
28th November 2017 Addendum 1.0 
Addendum to the 
Final Version 
 
 
 
 
 
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Table of Contents 
SIGNATURES 
································································································ 2 
1 
REVISION HISTORY ············································································ 3 
2 
INTRODUCTION 
·················································································· 5 
3 
GENERAL CONSIDERATIONS 
······························································· 5 
3.1 
Study Populations ·············································································· 5 
3.2 
Use of Rescue Medication ···································································· 5 
4 
ADDITIONAL ANALYSES 
······································································ 6 
4.1 
Patient Disposition 
············································································· 6 
4.2 
Reasons for Screening Failures 
······························································· 6 
4.3 
Baseline Characteristics 
······································································· 6 
4.4 
Efficacy Analyses 
·············································································· 7 
4.4.1 
Analyses in the PPKP and Non-PPKP Populationse ································· 7 
4.4.2 
Previous Use of IBS-D Related Medications as Covariate 
·························· 7 
4.4.3 
Sensitivity Analysis Regarding Use of Rescue Medication 
························· 7 
4.4.4 
Figures for Weekly and Overall Response Variables 
································ 7 
4.4.5 
Figures for Baseline CRP versus Efficacy Parameter 
································ 7 
4.5 
PK analyses 
····················································································· 8 
4.6 
Safety Analyses ················································································ 8 
4.6.1 
Adverse Events ··········································································· 8 
4.6.2 
Laboratory Parameter 
···································································· 8 
 
 
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2 
INTRODUCTION 
This Addendum to the Statistical Analysis Plan (SAP), Final 1.0, June 28th 2017, contains a 
description of the additional analyses requested to support the final TFLs. These analyses are 
ad-hoc analyses which were requested after the study was unblinded. The analyses described 
in this document do not replace the analyses conducted according to the final version of the 
SAP. 
3 
GENERAL CONSIDERATIONS 
3.1 Study Populations 
As the mITT and Safety population are identical in this study, the tables for the latter 
population will be not generated for the final report when the same table is also to be 
generated for the mITT population. A footnote will be added to the table in the mITT 
population indicating the reason for omitting the table in the safety population. 
To assess the impact of the results of the PK analysis on the study outcomes two further 
study populations will be defined in addition to those defined in the study protocol and SAP: 
Per Protocol Pharmacokinetic Population (PPPK population) 
The PPPK population will include all patients from the PK population whose PK results are 
appropriate to the treatment that they have received. 
For patients treated with RHB-102: 
• Positive values not below the level of quantification (BLQ) and not greater than 100 
ng/mL for ondensatron concentrations measured 1 hour or 6 hours after dosing at the 
week 3 and the week 5 visits. 
• Pre-dose values of ondensatron concentrations BLQ at the week 1 visit. 
• Pre-dose values of ondensatron concentrations at the week 3 and week 5 visit may be 
positive, but not greater than 100 ng/mL, or BLQ. 
For patients treated with placebo all measured concentrations of ondensatron must be BLQ 
for inclusion in the PPPK population. 
Non-Per Protocol Pharmacokinetic Population (Non-PPPK population) 
All patients in the PK population that do not fulfill the conditions to be included in the PPPK 
population will be included in the Non-PPPK population. 
These two new analysis populations are introduced to show that the efficacy results in these 
populations are similar to the results in the mITT populations and to each other. 
3.2 Use of Rescue Medication 
41
For classifications regarding the use of rescue medication the analyses so far utilized the 
information from the patient diary and the eCRF page for IBS-D related medications. For the 
final analysis the information from the diary will not be used anymore (except in the special 


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case outlined below). Especially for the calculation of the primary and two key secondary 
efficacy endpoints - stool consistency response, pain response and study response as defined 
in section 7.2 of the SAP - “failed days” due to the intake of rescue medication will not be 
defined by the corresponding entries in the diary but according to the recoded medication use 
in the eCRF. 
• If the dose of an IBS-D related medication is not denoted as per need (PRN) a day 
will be counted as “failed day” regarding the consistency if it is in the interval 
between start date and end date (both dates inclusive) of the recorded medication. If 
the medication is ongoing then all days on or after the start date will be counted as 
“failed days”.  
• If the dose of an IBS-D related medication is denoted as per need (PRN), then and 
only then also the entries in the patient diary will be taken into account. A day will be 
counted as “failed day” if it lies between the start and the end date (both dates 
inclusive) of the pertaining medication and if the use of rescue medication for this day 
is answered with yes in the diary. If for a day between start and the end date of the 
pertaining medication use of rescue medication is not supported in the diary this day 
will be categorized according to the recorded values of the Bristol Stool Scale. If the 
medication is ongoing then this rule will be applied to all days after the medication 
start date.  
For the subgroup analyses by use of rescue medication the two groups (use of rescue 
mediation/ no use of rescue medication) will solely be defined by the records from the eCRF. 
4 
ADDITIONAL ANALYSES 
4.1 Patient Disposition 
In Table 14.1.1.1 the reasons for discontinuation of study medication will be added. Further 
three additional categories will be displayed:  
(1) Patients in the PPPK population 
(2) Patients in the Non-PPPK population 
(3) Patients who completed treatment with study medication but discontinued the study 
A listing will be generated that includes patients with different outcomes recorded on the end 
of treatment and end of study page from the eCRF. 
4.2 Reasons for Screening Failures 
An analysis will be added that summarizes the reason for screening failures (violated 
inclusion and met exclusion criteria). Patients who failed screening without documented 
violation of an entry criterion will be summarized under “Unknown reason”. 
4.3 Baseline Characteristics 
42
In addition to the Irritable Bowel Syndrome Symptomatology as collected in the eCRF, the 
number and frequency of patients will be presented who have: 


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(1) at least one symptom rated as moderate or severe. 
(2) at least one symptom rated as severe. 
This will be done for the mITT and PP Populations by treatment group. 
4.4 Efficacy Analyses 
4.4.1 Analyses in the PPPK and Non-PPPK Populations 
The primary efficacy variable (overall stool response) and the two key secondary efficacy 
variables (overall pain response and overall study response) will also be analyzed in the 
PPPK population and Non-PPPK population as defined in Section 3.1 of this Addendum. 
4.4.2 Previous Use of IBS-D Related Medications as Covariate 
The summary of previous use of IBS-D related medications showed an imbalance between 
subjects later randomized to RHB-102 12 mg and placebo (32% in RHB-102 vs. 22% in 
placebo group). To investigate a possible effect, a logistic regression model will be applied to 
the primary efficacy variable (overall stool response) and the two key secondary efficacy 
variables (overall pain response and overall study response). This logistic regression model 
will include treatment group and previous use of IBS-D related medications (yes/no) as 
covariates. The same modelling will be used as has been applied in the SAP defined analysis 
for gender (see section 8.1.1.2 of the SAP). The analyses will be performed for the mITT 
population.  
4.4.3 Sensitivity Analysis Regarding Use of Rescue Medication 
According to the SAP (Section 7.2.1.1) in case a patient took rescue medication on a day this 
day will be counted as “failed day”, i.e. it will be treated as if the patient had at least one 
stool that has a consistency of Type 6 or 7 on the Bristol stool scale on this day. To assess the 
impact of this imputation rule on the primary and key secondary efficacy parameters a 
sensitivity analysis will be performed where the values of the Bristol stool scale as recorded 
in the diary, and not the imputed values, will be used. 
This analysis will be performed in the mITT population for weekly and overall stool 
consistency response and for weekly and overall study response. 
4.4.4 Figures for Weekly and Overall Response Variables 
In addition to the bar charts for weekly and overall stool consistency response, bar charts for 
weekly and overall pain response and weekly and overall study response will be generated 
for the mITT population. The p-values for the weekly and overall comparisons between 
RHB-102 and placebo will be added to the graphical presentations. 
4.4.5 Figures for Baseline CRP versus Efficacy Parameter 
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The subgroup analysis by baseline CRP showed quite different results for the subgroup with 
baseline CRP ≤ median and baseline CRP > median. For the first subgroup there were no 
significant differences between RHB-102 and placebo whereas for the second subgroup 
RHB-102 was superior to placebo for overall stool consistency response and overall study 


Sponsor: RedHill Biopharma Ltd. 
SAP Addendum  28 Nov 2017 
Study: RHB-102-02 
 
Redhill 
Page 8 of 8 
response and nearly so for overall pain response. To visualize the effect of baseline CRP 
different plots will be generated for the primary efficacy variable overall stool consistency 
response and the two key secondary efficacy variables overall pain and overall study 
response: 
(1) Scatterplots of baseline CRP against the response (horizontal lines intersecting the y-
axis for response and non-response, respectively, and baseline CRP on the x-axis). 
(2) “ROC-curves” with use of a different cut-off value for definition of the subgroups 
(cut-off value plotted against the response probabilities in the RHB-102 and placebo 
groups for patients with baseline CRP exceeding the cut-off value and not exceeding 
the cut-off value).  
4.5 PK analyses 
Table 14.2.19 – Summary of Ondansetron Plasma Concentrations (ng/mL) - will also be 
generated for the PPPK Population. 
4.6 Safety Analyses 
4.6.1 Adverse Events 
The following summaries of Adverse Events (AEs) will be generated in addition to those 
contained in the SAP defined analysis: 
(1) Treatment emergent AEs by System Organ Class (SOC) and Preferred Term by 
gender. Restricted to SOCs Gastrointestinal Disorders, Investigations and Nervous 
System Disorders. 
(2) Treatment emergent AEs by System Organ Class (SOC), Preferred Term and 
Intensity by gender. Restricted to AEs of moderate and severe intensity in the SOC 
Gastrointestinal Disorders and AEs with Preferred Term Constipation (all intensities) 
(3) Treatment emergent AEs by System Organ Class (SOC) and Preferred Term by onset 
of AE (onset during treatment with RHB-102/placebo vs. onset during follow-up). 
(4) Summary of patients with AE of either increase in ALT or increase in AST. 
Further a listing of laboratory adverse events with a CTCAE grade of 3 or higher will be 
generated including the following parameter: ALT, AST, glucose and potassium. 
4.6.2  Laboratory Parameter 
As there is a discrepancy between laboratory adverse events concerning creatinine and the 
laboratory shift table with respect to CTCAE grades the CTCAE criteria for creatinine will 
be modified to include grading only for values above the normal limit but not for values that 
increased compared to the baseline value. 
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