Conditions: Gastroenteritis Gastritis
Keywords: Gastroenteritis Gastritis Vomiting Nausea Diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 330
Healthy volunteers: no

Brief summary:
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 (BEKINDA) (Ondansetron 24 mg Bimodal Release Tablets) for Acute Gastroenteritis.

The study will evaluate the safety and efficacy of RHB-102 (BEKINDA) in treating Acute Gastroenteritis, by comparing it to placebo.

Detailed description:
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 (BEKINDA) (Ondansetron 24 mg Bimodal Release Tablets) for Acute Gastroenteritis.

The study will evaluate the safety and efficacy of RHB-102 (BEKINDA) in treating Acute Gastroenteritis, by comparing it to placebo.

Arms:
arm 1: RHB-102, Bimodal Release Ondansetron Tablets arm 2: Placebo

Interventions: intervention 1: RHB-102 intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: RHB-102, Bimodal Release Ondansetron Tablets intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
Protocol Number RHB-102-01 
 
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-
102 (Ondansetron 24 mg Bimodal Release Tablets) for 
Presumed Acute Gastroenteritis or Gastritis 
 
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 
 
Original Protocol Date: 
7 April, 2014 
Protocol Version: 
 
Amendment 1:  6 October 2014 
 
 
 
 
Amendment 2:  9 April 2015 
 
 
 
 
Amendment 3:  14 December 2015 
 
 
 
 
Amendment 4:  13 March 2016 
 
 
 
 
Amendment 5:  9 June 2016 
 
 
 
 
 
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 Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Table of Contents 
 
Table of Contents .................................................................................................. 2 
Approvals .............................................................................................................. 5 
Protocol Synopsis ................................................................................................. 6 
List of Abbreviations ............................................................................................ 12 
1. 
Background and Rationale .......................................................................... 13 
1.1 
Acute Gastroenteritis ............................................................................ 13 
1.2 
Ondansetron for Acute Gastroenteritis ................................................. 13 
1.3 
RHB-102 ............................................................................................... 14 
1.4 
Study Rationale .................................................................................... 14 
2. 
Objectives .................................................................................................... 15 
2.1 
Primary ................................................................................................. 15 
2.2 
Secondary ............................................................................................ 15 
3. 
Study Population .......................................................................................... 16 
3.1 
Inclusion Criteria ................................................................................... 16 
3.2 
Exclusion Criteria .................................................................................. 16 
4. 
Study Design ............................................................................................... 18 
4.1 
Overview ............................................................................................... 18 
4.2 
Study Drug Administration .................................................................... 18 
4.3 
Randomization and Blinding ................................................................. 19 
4.4 
Concomitant Therapy ........................................................................... 19 
4.5 
Duration of Treatment ........................................................................... 21 
4.6 
Discontinuation of Treatment ................................................................ 22 
4.7 
Replacement of Subjects ...................................................................... 22 
5. 
Study Evaluations ........................................................................................ 23 
5.1 
Schedule of Evaluations ....................................................................... 23 
5.2 
Description of Study Procedures .......................................................... 23 
5.2.1 
Baseline procedures ...................................................................... 23 
5.2.2 
Observation while in emergency department ................................ 23 
5.2.3 
Procedures after discharge from emergency department: ............. 24 
6. 
Safety Reporting .......................................................................................... 26 


RHB-102 for Acute Gastroenteritis 
 
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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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6.1 
Terminology .......................................................................................... 26 
6.2 
Assessment of Causal Relationship ..................................................... 27 
6.3 
Adverse Event Grading and Coding ..................................................... 28 
6.4 
Handling of Serious Adverse Events .................................................... 28 
6.5 
Laboratory Test Abnormalities .............................................................. 29 
6.6 
Other Safety Considerations ................................................................. 29 
7.1 
Sample Size Considerations ................................................................. 30 
7.2 
Analysis Datasets ................................................................................. 30 
7.3 
Study Population and Demographics ................................................... 30 
7.4 
Efficacy Analyses ................................................................................. 30 
7.4.1 
Statistical Hypotheses ....................................................................... 31 
7.5 
Safety Analyses .................................................................................... 32 
7.5.1 
Adverse Events ............................................................................. 32 
7.5.2 
Other Parameters .......................................................................... 32 
7.6 
Interim Analysis .................................................................................... 32 
8. 
Study Medications ....................................................................................... 33 
9. 
Investigator Responsibilities ........................................................................ 34 
9.1 
Compliance with Declaration of Helsinki and Good Clinical Practices .. 34 
9.2   
Institutional Review Board (IRB) Review and Approval ........................ 34 
9.3   
Informed Consent ................................................................................. 34 
9.4   
Confidentiality ....................................................................................... 34 
9.5   
Source Documentation ......................................................................... 34 
9.6   
Drug Accountability ............................................................................... 35 
9.7   
Data Monitoring and Collection ............................................................. 35 
9.8   
Case Report Forms, Investigator’s Study File and Record Retention ... 35 
9.9   
Non-Protocol Research ........................................................................ 36 
10. 
Sponsor Responsibilities .......................................................................... 37 
10.1   
General ............................................................................................. 37 
10.2   
Case Report Forms ........................................................................... 37 
10.3 
Data Monitoring and Collection ............................................................. 37 
10.4   
Audit .................................................................................................. 37 
10.5   
Confidentiality ................................................................................... 37 
11. 
Protocol Modifications .............................................................................. 38 


RHB-102 for Acute Gastroenteritis 
 
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CONFIDENTIAL:  PROPRIETARY INFORMATION 
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12. 
Publication ................................................................................................ 39 
13. 
References ............................................................................................... 40 
Appendix I.  Bristol Stool Scale ........................................................................... 41 
 
 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
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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: _____________________ 
 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Protocol Synopsis 
Title 
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 (Ondansetron 24 
mg Bimodal Release Tablets) for Presumed Acute Gastroenteritis or Gastritis 
Study 
location 
US multicenter 
Study drug 
RHB-102 (Ondansetron 24 mg Bimodal Release Tablets) 
Comparator 
Placebo 
Rationale 
Ondansetron was the first 5-HT3 antagonist approved as an antiemetic.  It has 
been approved for use for prevention and treatment of nausea and vomiting 
due to cytotoxic chemotherapy and radiotherapy, as well as for prevention of 
postoperative nausea and vomiting.  Despite several clinical trials and much 
anecdotal evidence of efficacy against acute gastroenteritis, no formulation of 
ondansetron or any other 5-HT3 antagonist has ever been approved by the 
FDA for this indication. 
RHB-102 is a modified release oral tablet formulation of ondansetron.  It 
contains 6 mg ondansetron for immediate release and 18 mg in an extended 
release core.  It provides early ondansetron levels similar to a single 8 mg 
immediate release tablet and sustained release over a 24-hour period.  This 
should enable once daily dosing, so that a single dose of RHB-102 should be 
sufficient to control nausea and vomiting from acute gastroenteritis for most 
patients. 
A variety of agents are used for symptomatic treatment of acute gastritis and 
gastroenteritis.  The most commonly used non-5- HT3 antiemetics, 
prochlorperazine and promethazine, while reasonably effective may cause 
significant adverse events much more commonly than ondansetron. In recent 
published studies of patients with acute gastroenteritis, 50% or more who 
receive placebo do not vomit during the study observation period. Thus, 
patients may be exposed to potential toxicity without therapeutic benefit.  
Therefore, use of a placebo with rescue is justified in this situation. 
Ondansetron causes side effects in few patients, but gastroenteritis patients 
administered intravenous or immediate release oral ondansetron frequently 
require multiple doses to control their symptoms.  Thus, use of a modified 
release formulation may be of considerable benefit by providing rapid relief of 
symptoms and maintaining relief without need for redosing over the course of 
the illness, which is usually approximately one day. 
Objectives 
Primary: 
 
Comparison of the proportion of patients who are treatment successes, i.e., 
fulfill all three of the following criteria:  a) without further vomiting, b) without 
rescue medication, and c)  who were not given intravenous hydration ≥30 
minutes after the first dose of study medication through 24 hours after the first 
dose of study medication. 
Secondary: 
Comparison between ondansetron and placebo groups of 
• 
Treatment success, as defined above, through 4 days following first 
dose of study medication 
• 
Proportion of patients who experience each of the components of 
treatment failure: 
o 
Vomiting 
o 
Rescue antiemetic therapy 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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o 
Intravenous hydration  
• 
Severity of nausea 
• 
Diarrhea as reported by  
o 
Bristol Stool Scale (BSS, Appendix I):  number and distribution 
by grade of grade ≥5 stools daily throughout the study 
o 
Stool consistency, as recorded per original protocol, 
none/formed (normal)/soft/watery (diarrhea) 
• 
Incidence and severity of other symptoms of gastroenteritis 
• 
Time from first dose of study medication to discharge from ED, 
extended observation unit or hospital, whichever comes last 
• 
Time to resumption of normal activities (work/school/household) 
• 
Proportion of patients requiring hospitalization 
• 
Proportion of patients returning to emergency department for 
gastrointestinal symptoms  within 4 days of initial discharge 
• 
Adverse events 
Population 
Adults and children ≥age 12 with vomiting from presumed acute gastroenteritis 
or gastritis of ≤36 hours duration 
Inclusion criteria: 
• 
Patients must have vomited at least twice in the 4 hours preceding  
signing informed consent 
A vomiting episode is defined as an episode of forceful expulsion of 
stomach contents.  Retching if a patient has already emptied his or her 
gastric contents is also considered a vomiting episode.  A distinct 
episode is characterized by a clear break in vomiting activity of at least 
5 minutes 
• 
Emesis must have been nonbloody (streaks of blood presumed due to 
force of retching are allowed) 
• 
All patients (or a parent or guardian for patients <age 18) must sign 
informed consent.  Patients <age 18 must also sign assent. 
Exclusion criteria: 
• 
Severe dehydration 
For purposes of this study, severe dehydration is defined as two or 
more of the following criteria in the presence of decreased intake and 
increased output due to vomiting or diarrhea: 
o 
Absent or severely decreased urine output, 
o 
Weak pulse and/or low blood pressure, 
o 
Parched mucous membranes, 
o Lethargy, confusion, delirium or loss of consciousness. 
• 
Signs and symptoms severe enough to require immediate parenteral 
hydration and/or parenteral antiemetic medication 
• 
Temperature>39.0°C 
• 
Likely etiologies for acute vomiting and diarrhea other than acute 
infectious or toxic gastroenteritis or gastritis 
o 
This includes signs of an acute abdomen, which may require 
surgical intervention 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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• 
Chemically-induced gastroenteritis, e.g., from alcohol, other drugs of 
abuse or other irritant chemicals 
• 
Use within 24 hours of study entry of specific medication for treatment 
of nausea and/or vomiting, e.g., 5-HT3 antagonists or phenothiazines, 
or receipt of any IV fluid for any reason. Nonspecific gastrointestinal 
remedies, such as antacids, proton pump inhibitors and homeopathic 
remedies, are permitted. 
• 
Congestive heart failure, bradyarrhythmia (baseline pulse<55/min), 
known long QT syndrome 
• 
Patient who have known QTc prolongation>450 msec, noted on prior 
or screening ECG, or who are taking medication known to cause QT 
prolongation 
o 
Note:  For current list of medications known to cause QT 
prolongation see:  https://www.crediblemeds.org/healthcare-
providers/drug-list/  Use list showing drugs with known risk of 
TdP. 
• 
Known underlying disease which could affect assessment of hydration 
or modify outcome of treatment, e.g., renal failure, diabetes mellitus, 
liver disease, alcoholism 
o 
Patients with type 2 diabetes mellitus controlled by diet or oral 
medications and whose  baseline blood glucose is <200 may 
be entered into the study 
• 
Abdominal surgery within the past 3 months 
• 
History of bariatric surgery or bowel obstruction at any time 
• 
Hypersensitivity or other known intolerance to ondansetron or other 5-
HT3 antagonists 
• 
Patient has taken apomorphine within 24 hours of screening 
• 
Patient has previously participated in this study 
• 
Patient has participated in another interventional clinical trial, for any 
indication, in the past 30 days 
• 
For women of childbearing potential:  documented or possible 
pregnancy.  See body of protocol for detailed definition. 
Design 
Randomized, double-blind, placebo-controlled, parallel group study 
Methodology 
Patients presenting to the emergency department who fulfill entry criteria will 
be asked to participate.  Qualifying patients, once they have signed consent, 
will be stratified by age (≥ vs <age 18) and randomized 60:40 to RHB-102 or 
matching placebo. 
Patients will receive one oral dose of study medication as soon as feasible.  If 
a patient vomits within 15 minutes of the initial dose of study medication, 
he/she will receive a second dose.  If a patient vomits again, regardless of how 
long after the second dose of study medication, no further study medication 
will be administered. 
Patients vomiting ≥30 minutes after the first dose of study medication may 
receive rescue antiemetics, either parenterally or orally.  In addition, a) 
patients with severe nausea ≥30 minutes after dosing with study medication 
and who in the treating physician‘s opinion require treatment, may receive 
rescue medication.  b) These patients may receive intravenous hydration in 
addition to or in place of parenteral antiemetics if they are unable to tolerate 
oral hydration. However, only severely symptomatic patients clearly unable to 
tolerate oral hydration may receive intravenous hydration. 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
9 
Any patient receiving rescue medication or parenteral hydration will be 
deemed a treatment failure. 
Metoclopramide 0.3 mg/kg, maximum dose 10 mg, administered intravenously 
will be the default rescue medication.  Oral metoclopramide or other 
antiemetics administered either intravenously or orally may be used at the 
investigator’s discretion.  However, patients are not to receive ondansetron 
or other 5-HT3 antagonists by any route for at least 24 hours after 
administration of study medication.  The following 5-HT3 antagonists are 
available in the US:  alosetron (Lotronex), dolasetron (Anzemet), granisetron 
(Sancuso and others), ondansetron (Zofran, Zuplenz and others), palonsetron 
(Aloxi). 
Oral fluids will be administered as tolerated once a patient has not vomited for 
30 minutes after dosing with study medication (second dose for those patients 
receiving 2 doses in the ED).  Guidelines for administration of oral fluids are 
shown on page 20, section 4.4.1, of the protocol. 
Patients tolerating oral fluids will be discharged once deemed stable by the 
attending physician but not prior to 4 hours after dosing.  On discharge, 
patients will be given 3 additional doses of study medication to take once daily 
if necessary. 
Patients who do not tolerate oral fluids may receive parenteral hydration. 
Data will be collected daily for up to 4 days following study initiation (until 
symptoms have resolved) to ascertain whether the patient had further 
vomiting, other sequelae of the acute gastroenteritis or required further 
medical care for the gastroenteritis.  Data may be collected by entry by the 
patient or a caregiver into a web-based system or on paper, or by telephone 
contact daily from a study staff member.  If during the follow-up period, 
symptoms progress or worsen or new symptoms develop, the patient may be 
asked to return for further evaluation.  If by day 4 after discharge (i.e., the day 
after the last dose of study medication), the patient still notes gastroenteritis 
symptoms, he or she will be instructed to return for further evaluation. 
Endpoints 
Efficacy: 
Primary:   
Absence of vomiting without use of rescue medication or parenteral hydration 
from 30 minutes through 24 hours after the first dose of study medication.   
Secondary: 
• 
Treatment success, as defined above, through 4 days following first dose 
of study medication  
• 
Individual components of treatment failure through 4 days following first 
dose of study medication: 
o 
Vomiting 
o 
Requirement for rescue antiemetic 
o 
Treatment with intravenous hydration 
• 
Severity of nausea 
• 
Diarrhea will be reported in two ways: 
o 
Bristol Stool Scale (BSS):  number and distribution by grade of 
grade ≥5 stools daily throughout the study 
o 
Stool consistency, as recorded per prior versions of protocol, 
none/formed (normal)/soft/watery (diarrhea) 
• 
Incidence and severity of other symptoms of gastroenteritis, as recorded in 
CRF and patient diaries 
• 
Time from first dose of study medication to discharge from ED, extended 
observation unit or hospital, whichever comes last 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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• 
Time to resumption of normal activities (work/school/household) 
• 
Hospital admission 
• 
Return to emergency department for gastrointestinal symptoms 
• 
 
Safety: 
Incidence and severity of adverse events through time of last follow-up call 
Statistics 
Successful treatment is absence of further vomiting from 30 minutes through 
24 hours after initial administration of study administration without use of 
rescue antiemetic or parenteral hydration.  It is expected that 40% of the 
placebo group and 20% of the ondansetron group will fail therapy.  To 
demonstrate a statistically significant difference with two-tailed p value=0.01 
and power=90%, 320 patients will be entered into the study, 192 randomized 
to RHB-102 and 128 to placebo. 
Patients will be stratified by age (< or ≥age 18) at baseline. 
Patient demographics and disease characteristics will be summarized with 
descriptive statistics. 
Safety and efficacy analyses will be based on all patients who receive any 
study medication. 
A subgroup of patients, as defined in section 7.2 of the protocol, will also be 
evaluated for efficacy. 
The incidence of treatment failure (vomiting, use of rescue medication or 
parenteral hydration from 30 minutes through 24 hours after initial 
administration of study medication) will be compared by Mantel-Haenszel test. 
No interim analysis will be conducted. 
Study Assessments 
Day 
1 
1 
1 
2 
3 
4 
5 
Time, hours 
-1 to 0 
0 
0-T 
NA 
NA 
NA 
NA 
Baseline assessmentsa 
X 
 
 
 
 
 
 
Study drug administration 
 
Xe 
 
Xf 
Xf 
Xf 
 
Observationb 
 
 
X 
 
 
Xc 
Xc 
Patient reported eventsc 
 
 
 
X 
X 
X 
X 
Concomitant medicationsd 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Notes: 
aHistory, physical including VS (pulse, respiratory rate, blood pressure, temperature and, at 
baseline only height and weight), informed consent.  For all patients: CBC with platelet count, 
biochemical profile and ECG.  Urinalysis is required for all patients ≥age 40 and with a history of 
diabetes; it is optional for other patients.  Blood and urine specimens should be taken 
expeditiously at the beginning of assessment, but patient entry into the study and treatment need 
not wait for lab results (other than pregnancy test and fingerstick blood glucose when required) 
unless clinically indicated.  After phlebotomy, a saline lock may be placed so that the patient will 
not require an additional needle stick should he/she require intravenous fluids subsequently.  
History of present illness should include questioning regarding precipitating/causative factors, as 
well as recording of number and character of emetic and diarrheal episodes.   


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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Patients with diet-controlled type 2 diabetes mellitus are to have a finger stick blood glucose. 
For women of childbearing potential, as defined in the exclusion criteria:  urine or serum 
pregnancy test.  Negative pregnancy test result must be obtained prior to treating a patient on 
study. 
bPatients are to be observed in the emergency department for a minimum of 4 hours after initial 
dose of study medication, with VS at least once every hour and recording of intake (both oral and 
parenteral) and number of voidings.  All episodes of vomiting and diarrhea are to be recorded, 
and severity of nausea at baseline and every hour while in the ED noted.   
All patients are to have a repeat ECG 4±0.25 hours after initial dosing with study medication.  At a 
minimum of 4 hours after initial administration of study medication, after repeat ECG, patients 
may be discharged when clinically appropriate. Any patient who has an on-study ECG 
showing QTc>500 msec must have a follow-up ECG showing resolution of the QTc 
prolongation. Timing of follow-up ECG(s) at investigator discretion.   If the QTc does not 
decrease below 500 msec during follow-up, the medical monitor must be contacted to 
discuss further follow-up. 
cPrior to discharge, patients will be given diary pages to record their course after discharge.  
Patients will be contacted each day following treatment to a maximum of 4 days to determine 
whether they had further nausea and vomiting after leaving the emergency department, the 
occurrence and quality of bowel movements, including assessment using the Bristol stool scale 
(Appendix I), and the nature, occurrence and severity of other symptoms, whether they required 
further care for the acute gastroenteritis, and details regarding the continuation, if any, of the 
illness.  If symptoms persist for 3 or more days after study entry, the patient is to be instructed to 
return for further evaluation. 
dTo include all medications taken within 7 days prior to study entry, all treatments (including 
parenteral fluids) on the day of study entry, and all medication, including rescue medications, 
from the time of study entry through last follow-up. 
ePatients are to receive the first dose of study medication within one hour of signing informed 
consent. 
fPatients may take study medication daily for up to 3 days after study entry (maximum total of 4 
doses, plus one additional if patient vomits within 15 minutes of first dose) if symptoms persist.  
Patients should stop taking study medication if symptoms have resolved, though they may 
resume study medication once daily if symptoms recur after discontinuation.  Patients are not to 
take any remaining study medication after day 4.  They will be given mailers to return any unused 
study medication. 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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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 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CO2 
bicarbonate 
CRF 
case report form 
ED 
Emergency department (emergency room) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Committee on Harmonisation 
IRB 
institutional review board 
Kg 
Kilogram 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
Milligram 
NCI-CTCAE v 4 
National Cancer Institute common terminology criteria 
for adverse events, version 4 
SAE 
serious adverse event 
VS 
vital signs 
vs 
versus 
WBC 
white blood count 
WOCBP 
women of childbearing potential 
 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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1. 
Background and Rationale 
1.1 
Acute Gastroenteritis 
Acute gastroenteritis is inflammation of the stomach, small intestine or large 
intestine, leading to a combination of abdominal pain, cramping, nausea, 
vomiting and diarrhea (Graves, 2013).  Acute gastritis is inflammation of the 
stomach; patients with acute gastritis may have vomiting without diarrhea.  For 
purposes of this protocol, patients must present with at least vomiting, as 
described below, with or without other symptoms.  
Acute gastroenteritis is a major health problem worldwide.  While mortality is 
greatest in developing countries and in both the very young and old, morbidity of 
acute gastroenteritis is shared by all ages and economic strata.  In the US, most 
cases of acute gastroenteritis are viral, most commonly rotavirus and norovirus 
(Chow et al, 2010;  Graves, 2013).  In the US, there are between 15-25 million 
episodes of viral gastroenteritis annually, leading to 3-5 million office visits and 
200,000 hospitalizations.  While mortality is low, among the 17,000 people dying 
from acute gastroenteritis in the US each year, 83% are over age 65 (CDC, 
2012).   
Most cases are self-limited, resolving in one to several days.  Mild to moderate 
cases are generally treated symptomatically.  In children, there are guidelines for 
oral rehydration therapy.  More severe and prolonged cases may require 
diagnostic studies for etiologic organisms.  Depending on the severity and 
etiology, treatment varies from dietary modifications, including oral rehydration 
therapy, to intravenous fluids and antibiotics.  Antiemetics and antidiarrheals are 
often used.  Prochlorperazine and perphenazine are both approved for treatment 
of nausea and vomiting in general, i.e., including for treatment of acute 
gastroenteritis.  Several other products approved for treatment of nausea and 
vomiting in special situations, e.g., postoperatively or in association with cancer 
chemotherapy, are also used for this indication.  Ondansetron is often used in 
both children and adults with acute gastroenteritis, but has never been approved 
for this indication in any country.  
1.2 
Ondansetron for Acute Gastroenteritis  
Ondansetron has been studied in several studies in acute gastroenteritis, 
primarily in children (Chow et al, 2010.  In seven studies, either intravenous (3 
studies) or oral (4 studies) ondansetron was compared against placebo, and in 
two intravenous ondansetron was compared against active agents.  Most of the 
studies against active agents demonstrated a significant decrease in the 
proportion of patients with vomiting subsequent to dosing.  Overall, the proportion 
of patients with vomiting in the emergency department after ondansetron was 
about half that after placebo.  Only one study, comparing ondansetron with 
prochlorperazine, was entirely in adults, and one additional study, with 
ondansetron compared to placebo, was in children and adults, though most 
participants were children.  Thus, ondansetron has not been studied extensively 
in clinical trials in adults with acute gastroenteritis. 


RHB-102 for Acute Gastroenteritis 
 
April 7, 2014 
Protocol RHB-102-01 Amendment 5 
 
June 9, 2016 
CONFIDENTIAL:  PROPRIETARY INFORMATION 
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1.3 
RHB-102 
RHB-102 is a bimodal release oral formulation of ondansetron.  It contains 24 mg 
of ondansetron, 6 mg immediate release and 18 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 an hour of 
dosing, similarly to immediate release Zofran®, but with sustained drug 
availability over 24 hours.  Thus, RHB-102 should provide rapid relief from 
nausea and vomiting in patients not requiring immediate intravenous medication, 
yet require only once daily dosing for a sustained effect over the several days of 
illness.  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, ondansetron has been studied in acute gastroenteritis against 
placebo in seven clinical trials and against other agents in two studies.  While 
often used clinically, its activity in adults and adolescents with acute 
gastroenteritis has not been demonstrated.  Thus, a prospective randomized 
study of ondansetron in a major patient population will provide clear evidence of 
the efficacy of the drug, or lack thereof, in this population. 
The study will of necessity enroll only those patients who are likely to tolerate oral 
medications.  Patients with vomiting at a frequency which make it difficult for 
them to hold down a pill for half an hour are not appropriate for this study and will 
be excluded.  However, for the large population of patients with moderate 
gastroenteritis, treatment of the disease without intravenous is clearly preferable.  
In addition to being easier and more comfortable even in an emergency 
department setting, it will allow treatment of patients outside the emergency 
room, providing both patient convenience and economic benefits as compared to 
parenteral treatments in an emergency department. 
Use of a placebo control allows demonstration of activity with a reasonable 
sample size.  Ondansetron has a very benign safety profile; one of the side 
effects of ondansetron, constipation, is actually a therapeutic benefit in the 
intended indication.  In contrast, adverse events are more common with 
phenothiazines and metoclopramide, and they may be severe.  These include 
dystonia and akasthesia.  Therefore, use of a placebo control in patients with 
moderate gastroenteritis may spare some patients toxicity in a situation where 
not all patients require pharamacologic intervention.  Those patients who do 
require medication will promptly receive an active rescue intervention.  


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2. 
Objectives 
2.1 
Primary 
Comparison of the proportion of patients who are treatment successes, i.e., fulfill 
all three of the following criteria:  a) without further vomiting, b) without rescue 
medication, and c) who were not given intravenous hydration from 30 minutes 
after the first dose of study medication through 24 hours after the first dose of 
study medication. 
2.2 
Secondary 
Comparison between ondansetron and placebo groups of 
• Treatment success, as defined above, through 4 days following first 
dose of study medication 
• Proportion of patients who experience each of the components of 
treatment failure: 
o Vomiting 
o Rescue antiemetic therapy 
o Intravenous hydration  
• Severity of nausea 
• Diarrhea as reported by  
o Bristol Stool Scale (BSS):  number and distribution by grade of 
grade ≥5 stools daily throughout the study.  The Bristol Stool Scale 
is shown in Appendix I. 
o Stool consistency, as recorded per original protocol, none/formed 
(normal)/soft/watery (diarrhea) 
• Incidence and severity of other symptoms of gastroenteritis 
• Time from first dose of study medication to discharge from ED, 
extended observation unit or hospital, whichever comes last 
• Time to resumption of normal activities (work/school/household) 
• Proportion of patients requiring hospitalization 
• Proportion of patients returning to emergency department for 
gastrointestinal symptoms  within 4 days of initial discharge 
• Adverse events 
 


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3. 
Study Population 
A total of 320 adults and children ≥age 12 with vomiting from presumed acute 
gastroenteritis or gastritis of ≤36 hours duration will be enrolled in this study. 
3.1 
Inclusion Criteria 
1. Patients must have vomited at least twice in the 4 hours preceding signing 
informed consent. 
2. A vomiting episode is defined as an episode of forceful expulsion of 
stomach contents. Retching if a patient has already emptied his or her 
gastric contents is also considered a vomiting episode.  A distinct episode 
is characterized by a clear break in vomiting activity of at least 5 minutes.  
Emesis must have been nonbloody (streaks of blood presumed due to 
force of retching are allowed). 
3. All patients (or a parent or guardian for patients <age 18) must sign 
informed consent.  Patients <age 18 must also give assent to participate. 
3.2 
Exclusion Criteria 
1. Severe dehydration 
There is no generally accepted definition of severe dehydration in adults.  
As a working definition for purposes of this study, severe dehydration is 
defined as two or more of the following criteria in the presence of 
decreased intake and increased output due to vomiting or diarrhea: 
• absent or severely decreased urine output,  
• weak pulse and/or low blood pressure,  
• parched mucus membranes,  
• lethargy, confusion, delirium or loss of consciousness. 
2. Signs and symptoms severe enough to require immediate parenteral 
hydration and/or parenteral antiemetic medication 
3. Temperature>39.0°C 
4. Likely etiologies for acute vomiting and diarrhea other than acute 
infectious or toxic gastroenteritis or gastritis 
a. This includes signs of an acute abdomen, which may require 
surgical intervention 
5. Chemically-induced gastroenteritis, e.g., from alcohol,  other drugs of 
abuse or other irritant chemicals 
6. Use within 24 hours of study entry of specific medication for treatment of 
nausea and/or vomiting, e.g., 5-HT3 antagonists or phenothiazines, or 
receipt of any IV fluid for any reason.  Nonspecific gastrointestinal 
remedies, such as antacids, proton pump inhibitors and homeopathic 
remedies, are permitted 
7. Congestive heart failure, bradyarrhythmia (baseline pulse<55/min), known 
long QT syndrome 


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8. Patients who have QTc prolongation>450 msec, noted on prior or 
screening ECG (per standard algorithm used by institution), 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). 
9. Known underlying disease which could affect assessment of hydration or 
modify outcome of treatment, e.g., renal failure, diabetes mellitus, liver 
disease, alcoholism 
Patients with type 2 diabetes mellitus controlled by diet or oral medications 
and whose baseline blood glucose is <200 may be entered into the study 
10. Abdominal surgery within the past 3 months 
11. History of bariatric surgery or bowel obstruction at any time 
12. Hypersensitivity or other known intolerance to ondansetron or other 5-HT3 
antagonists 
13. Patient has taken apomorphine within 24 hours of screening 
14. Patient has previously participated in this study 
15. Patient has participated in another interventional clinical trial, for any 
indication, in the past 30 days 
16. For women of childbearing potential (WOCBP):  documented or possible 
pregnancy.  WOCBP include any female who has experienced menarche 
and who has not been surgically sterilized or is not postmenopausal 
(defined as amenorrhea ≥ 12 consecutive months).  WOCBP are excluded 
if either a) they have a positive pregnancy test on screening, or b) they 
think they may be pregnant, even if screening pregnancy test is negative.  
Time since last menstrual period is not a criterion for determining 
pregnancy status.   


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4. 
Study Design 
4.1 
Overview 
Patients presenting to the emergency department who fulfill entry criteria will be 
asked to participate.  A screening log will be kept listing all patients considered 
with reasons for patients not entering the study.  Any patient whose information is 
reviewed in consideration for the study, even if not actually approached, is to be 
included in the screening log.  The screening log will differentiate between those 
who are prescreened, i.e., who are reviewed but never progress to request for 
consent, from those who are screened, i.e., who  are approached for consent, 
whether or not they actually sign consent or eventually participate in the study.    
Qualifying patients, once they have signed consent, will be stratified by age (≥ vs 
<age 18) and randomized 60:40 to RHB-102 or matching placebo.  All patients 
will undergo laboratory testing and ECG, as specified below, once they have 
signed consent.  However, only results of the pregnancy test (for women of 
childbearing potential) and a finger stick blood glucose (for patients with type 2 
diabetes mellitus controlled by diet or oral medications) are required prior to 
treatment. 
Patients will be started on oral fluids ≥30 minutes after taking study medication 
(second dose for patients who receive 2 doses in ED) if they have not vomited 
during that period.  Intravenous hydration should not be administered unless the 
patient has vomited or is clearly unable, after a reasonable period of time has 
elapsed since administration of study medication, to tolerate oral fluids. 
At 4±0.25 hours after initial dosing, all patients are to have a repeat 12-lead 
ECG.  Once stable, but not less than 4 hours after initial dosing, patients may be 
discharged from the emergency department.  If a patient leaves the ED less than 
4 hours after dosing, an ECG should be obtained if at all possible, even if the 
patient is leaving against protocol requirements. 
On discharge, patients will be given an additional 3 doses of study medication to 
take at 24-hour intervals if nausea persists.  Patients will be contacted daily for 4 
days after discharge to determine their condition.  Those patients who have 
persistent, worsening or recurrent nausea and/or vomiting during the follow-up 
period may be asked to come in for follow-up assessment by study personnel.   
4.2 
Study Drug Administration  
After results of the pregnancy test and/or blood glucose (when required) are 
obtained and determined to be negative/within acceptable limits and the patient 
is randomized, the investigator or a designate will administer the first dose of 
study medication under observation.  If the patient vomits within 15 minutes, 
regardless of whether pill fragments are seen, a second dose of study medication 
will be administered by the investigator or a designate.  If a patient retches but 
does not actually vomit any gastric contents, no second dose will be 
administered.  If a patient vomits again, regardless of how long after the second 
dose of study medication, no further study medication will be administered. 
Patients vomiting ≥30 minutes after the first dose of study medication may 
receive rescue antiemetics, either parenterally or orally.  In addition, patients with 


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severe nausea ≥30 minutes after dosing with study medication and which in the 
investigator‘s opinion requires treatment may receive rescue medication.  
Metoclopramide 0.3 mg/kg, maximum dose 10 mg, administered intravenously 
will be the default rescue medication.  Oral metoclopramide or other antiemetics 
administered either intravenously or orally may be used at the investigator’s 
discretion.  However, patients are not to receive ondansetron or other 5-HT3 
antagonists by any route for at least 24 hours after administration of study 
medication either in the ED or after discharge.  The following 5-HT3 
antagonists are available in the US:  alosetron (Lotronex), dolasetron (Anzemet), 
granisetron (Sancuso and others), ondansetron (Zofran, Zuplenz and others), 
palonsetron (Aloxi). 
Oral fluids will be administered as tolerated once a patient has not vomited for 30 
minutes after dosing with study medication (second dose for those patients 
receiving 2 doses in the ED).  Only patients who do not tolerate oral fluids after 
an adequate attempt at oral hydration may receive parenteral hydration.  Patients 
are not to receive intravenous hydration until it is clear to the treating physician 
that the patient is clearly in need of parenteral hydration. 
Patients tolerating oral fluids will be discharged once deemed stable by the 
attending physician but not prior to 4 hours after dosing and repeat ECG.   
Patients who do not tolerate oral fluids will receive parenteral hydration. 
Patients who are admitted but have not vomited or received antiemetics other 
than study medication may, at the investigator’s discretion, continue treatment 
with study medication. 
4.3 
Randomization and Blinding 
As noted above, patients will be stratified by age and randomized 60:40 to 
receive either RHB-102 or matching placebo.  Medication will be provided in kits 
of 5 pills:  one for initial administration, one if repeat dosing is required in the 
emergency department (and which will be retained by the investigator if not 
required), and three which the patient will take home. 
4.4 
Concomitant Therapy 
If deemed necessary by the investigator, patients may take rescue antiemetics, 
either orally or intravenously, as described in section 4.2, above.  Also, if deemed 
necessary by the investigator, patients may receive parenteral hydration.  
However, every effort should be made to avoid both rescue medications and 
parenteral hydration, and to proceed with oral hydration, unless it is clear that the 
patient will not be able to tolerate oral hydration. 
From the time a patient takes any antiemetic other than study medication, 
whether while in or after leaving the emergency department, or receives 
parenteral hydration, he or she will be deemed a treatment failure, even in 
the absence of vomiting. 
Patients may take antipyretic and antidiarrheal medication as needed prior to or 
after initial dosing with study medication.  Patients may also take medications for 
gastrointestinal symptoms as long as they are not specifically antiemetics.  For 


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example, they may use proton pump inhibitors or antacids.  Once vomiting is 
controlled, patients should resume any medications they routinely take. 
Patients for whom an intravenous medication (other than antiemetic) is indicated 
once on study may receive that medication in up to 100 mL fluid.  This will not be 
considered parenteral hydration.  For example, if a patient has a urinalysis 
suggesting infection and the investigator or other physician wish to give the 
patient an intravenous antibiotic dose, that will not be considered treatment 
failure as long as the drug is given in ≤100 mL fluid.  
If once on study, a patient requires a medication which may prolong the QTc 
interval, he or she should not receive further study medication.  However, 
evaluation of the patient should continue per protocol. 
4.4.1 Oral hydration guidelines 
The following are guidelines for oral rehydration.  These are suggested but not 
required; investigators may follow institutional procedures and should use clinical 
judgment in determining when and how much oral fluid to administer. 
1. After ingestion of the study drug along with small amount of fluids, nothing 
else by mouth for the first 30 minutes. 
2. At approximately 30 minutes after study drug administration, gently 
encourage drinking of approximately 8 ounces (240 mL) of fluid over the 
next 30 minutes. 
3. At approximately 60 minutes after study drug administration, further 
encourage oral hydration according to patient symptoms, as follows:  
a. The overall goal is for the patient to ingest approximately one liter 
over 1-2 hours after study drug administration.  One liter is 
common, although as much as 2 liters may be taken, depending on 
the patient’s volume status and symptom of nausea.  
b. Alternatively, a patient may ingest 600-700 mL, indicate feeling 
better and want to be discharged.  If, based on improvement in 
symptoms, the investigator feels confident the patient will do well at 
home, the discharge takes place.  
Please note the following:  
• Too much fluid given too quickly may increase symptoms of nausea.  
• Too little fluid:  in the absence of at least some ED rehydration, it is difficult 
to be confident the patient will further tolerate reasonable amounts of fluid 
at home (or to determine if the patient is failing hydration in the ED).  
From the time a patient takes any antiemetic other than study medication, 
whether while in or after leaving the emergency department, or receives 
any parenteral hydration, he or she will be deemed a treatment failure. 
4.4.2 Serotonin syndrome 


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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. 
All medications taken in the 7 days prior to study entry and from the time the 
patient arrives in the emergency room until he or she completes the study will be 
recorded in the case report form (CRF).  
4.5 
Duration of Treatment 
On discharge, patients who have not had further vomiting and have not required 
rescue medication in the emergency department will be given 3 additional doses 
of study medication to take once daily if necessary.  Patients will be instructed to 
take additional study medication if they are nauseated (whether persistent or 
recurrent) or have any vomiting.  However, patients are not to take study 
medication more than 3 days after study entry.  Thus, if a patient receives an 
initial dose of study medication in the emergency department, feels well the next 
day and does not take study medication, but subsequently has a recurrence of 
symptoms, that patient may not take the remaining dose of study medication on 
day 5.  Rather, the patient should return for reassessment during the follow-up 
period. 
Patients or their caregivers are to complete a diary each day for 4 days, 
recording episodes of vomiting, diarrhea, presence and severity of nausea, 
presence/development of other signs or symptoms related to the gastroenteritis, 
and occurrence of adverse events.  This diary may be completed either on paper 
or through a web-based system.  Alternatively, patients or their caregivers will be 
contacted daily for up to 4 days following study initiation (until symptoms have 
resolved) to ascertain whether the patient had further vomiting, other sequelae of 
the acute gastroenteritis or required further medical care for the gastroenteritis.  If 
symptoms persist for 3 days after study entry, the patient will be instructed to 
return for further evaluation on the third or fourth day. 


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For patients discharged prior to 8:00 pm, the ED day diary page is to be 
completed.  The ED day diary page is to include only information regarding 
events after discharge from the ED; information on events during the patient’s ED 
stay is not to be repeated in the diary.  For those discharged 8:00 pm to midnight, 
or later, diary information is to be recorded only on the follow-up diaries.  But 
vomiting episodes and adverse events occurring between 8:00 pm and midnight 
the preceding day should be included in the information captured. 
4.6 
Discontinuation of Treatment 
Patients may take study medication daily for up to 4 days (day 1 medication is 
the one or two tablets administered in the emergency department).   
• If a patient vomits or otherwise receives rescue medication in the 
emergency department, he or she is not to receive additional study 
medication, even if nausea and/or vomiting is controlled with rescue 
medication. 
• If the QTc interval at 4 hours after initial dose of study medication is >500 
msec, study medication is to be discontinued. 
• Patients experiencing recurrent nausea or vomiting after discharge from 
the emergency department and initial discontinuation of study medication 
due to resolution of symptoms may opt to resume study medication. 
If a patient experiences an adverse event, regardless of relationship to study 
medication, which, in the investigator’s opinion endangers or makes it difficult to 
evaluate the patient, the investigator may elect to have the patient stop study 
medication. 
If once on study, a patient requires a medication which may prolong the QTc 
interval, he or she should not receive further study medication.  However, 
evaluation of the patient should continue per protocol. 
Patients may elect to discontinue treatment at any time. 
4.7 
Replacement of Subjects 
Patients who are randomized but do not receive study medication will be 
replaced.  Patients who receive any study medication, even if they vomit 
immediately thereafter or cannot swallow the medication, will not be replaced. 


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5. 
Study Evaluations 
5.1 
Schedule of Evaluations 
A flow chart of study evaluations is shown above, on page 10. 
5.2 
Description of Study Procedures 
5.2.1 Baseline procedures 
• History and physical, including vital signs. History should include detailed 
history of present illness, including questioning about similarity of this episode 
with prior episodes, exposures to similar illnesses, and questioning about 
etiologies if not obvious. 
• Physical examination should include all pertinent body symptoms. 
• Vital signs should include height, weight, temperature, pulse, blood pressure, 
respiratory rate.  All units should be metric. 
• Baseline laboratory studies:   
o Required of all patients:  CBC, biochemical profile, ECG 
 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. 
 Standard 12-lead ECG 
o All patients ≥40 years of age and those with type 2 diabetes regardless 
of age:  urinalysis, to include at a minimum:  routine:  dipstick tests for 
protein, glucose, ketones, blood, pH, specific gravity;  microscopic:  
erythrocytes, leukocytes, bacteria, crystals, casts.   Urinalysis is 
optional for patients <age 40. 
o For patients with diet-controlled type 2 diabetes mellitus:  finger stick 
blood glucose 
o For women of childbearing potential, serum or urine pregnancy test (β-
HCG) 
• When drawing blood, a saline lock may be placed so that if the patient 
requires subsequent intravenous medications or hydration, he or she will not 
have to be stuck again.  
Treatment can start once the urinary pregnancy test results are obtained and 
determined to be negative, and, for type 2 diabetics, finger stick results obtained 
and blood glucose is <200 mg/dL.  Results of chemistries, CBC and urinalysis do 
not have to be available prior to start of study medication. 
5.2.2 Observation while in emergency department  
To start immediately after administration of study medication: 
• Intake and output hourly:   
o all oral and parenteral intake  


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o urination:  number of voidings 
o vomiting:  number of episodes  
o stool output:  number, consistency (per scale in original protocol and per 
Bristol Stool Scale, Appendix I) 
• Vital signs at least hourly and just prior to discharge:  temperature, blood 
pressure, pulse, respiratory rate 
• Questioning regarding adverse events: hourly and just prior to discharge 
• Assessments of nausea: on signing informed consent, just prior to first dose 
of study medication, hourly, just prior to discharge from emergency 
department.  A 5-point Likert scale will be used: 
0 
No nausea 
1 
Mild nausea 
2 
Moderate nausea 
3 
Severe nausea 
4 
Nausea as bad as can be 
• 12-lead ECG 4±0.25 hours after initial dose of study medication (regardless of 
whether dose was repeated in ED).  If patient leaves ED <4 hours after 
dosing, an ECG should still be obtained just prior to discharge. 
• Brief physical examination of pertinent systems prior to discharge 
If a patient vomits ≥30 minutes after taking the first dose of study medication, 
requires rescue antiemetic or parenteral hydration, he or she will be considered a 
treatment failure.  The patient will be followed according to the schedule above 
for a total of 4 hours from the time of first administration of study medication or 
until discharged home, whichever comes first.  After that, for patients still in the 
emergency department or hospital, the patient will be followed per standard 
protocol, according to the patient’s condition. 
5.2.3 Procedures after discharge from emergency department: 
Any patient who has a post-dosing ECG showing QTc>500 msec must have a 
follow-up ECG within 72 hours of initial dosing showing resolution of the QTc 
prolongation.  This may be performed on an inpatient or outpatient basis at the 
investigator’s discretion.  If the QTc does not decrease below 500 msec during 
initial follow-up, the medical monitor must be contacted to discuss further follow-
up. 
If a patient vomits from 30 minutes after taking the first dose of study medication 
until 24 hours after the first dose of study medication or requires rescue 
antiemetic or parenteral hydration during that period, even without vomiting, he or 
she will be considered a treatment failure.  In that case, the only post-emergency 
department follow-up will be a call 72-96 hours after discharge from the 
emergency department to ascertain whether the patient’s symptoms have 


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resolved, whether any adverse events occurred, and whether the patient required 
further medical follow-up, either in an emergency department or other medical 
facility. 
Prior to discharge, patients who are treatment successes (i.e., no vomiting, no 
rescue medication and no parenteral hydration while in emergency department) 
will be given a diary card to record: 
• all episodes of vomiting and bowel movements, with description of each 
bowel movement 
• severity of nausea (on a 5-point Likert scale) three times a day: before 
breakfast or the time at which the patient usually eats breakfast, between 
1:00-2:00 pm, and at bedtime 
• any symptoms the patient may have related to gastroenteritis, such as chills, 
fever, abdominal pain 
• adverse events 
• medications taken, either for gastroenteritis (study medication and others) or 
other conditions 
Patients will be contacted at least once daily for 4 days after discharge from the 
emergency department to question them about the presence of gastroenteritis 
symptoms and adverse events, to ask if and when they took study medication, 
and to ask whether they have returned to normal daily activities.  The information 
recorded by the patient on his/her diary card will form the basis for data collected 
in the follow-up calls.  If during the follow-up period, symptoms progress or 
worsen or new symptoms develop, the patient may be asked to return for further 
evaluation.  If by day four after discharge (i.e., the day after the last dose of study 
medication), the patient still notes gastroenteritis symptoms, he or she will be 
instructed to return to see the investigator or his/her designate for further 
assessment.  In addition, if the investigator is concerned that a patient may not 
be entering the data promptly and appropriately or as an added stimulus to data 
entry by the patient, the investigator may also contact the patient. 
For patients returning due to persistent gastroenteritis 3 days after discharge 
from the ED, an interim history and physical examination will be performed.  
Laboratory studies may be performed if clinically indicated, and results of these 
studies will be entered into the CRF. 


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6. 
Safety Reporting 
All subjects will be assessed regularly for potential adverse events (AEs) 
occurring at any time after the subject signs the informed consent, until discharge 
after the last dose of study medication.  AEs ongoing at the time of last dose of 
study medication will be followed until resolution or until 30 days after the last 
dose of study medication, whichever comes first.  Post-study follow-up will be by 
telephone or e-mail after subjects are discharged.  All subjects dosed will be 
contacted per the schedule above and queried regarding the occurrence of AEs 
and serious adverse events (SAEs). 
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 subject 
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 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 
subject 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. 


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Admission for gastroenteritis is not a serious adverse event, as the 
gastroenteritis is a preexisting condition, not an adverse event.  Admission for 
gastroenteritis will be considered lack of efficacy, and is recorded as such as a 
secondary efficacy outcome. 
If, however, a patient develops new symptoms in the ED, such as findings 
leading to a diagnosis of an acute abdomen, and is admitted, that would be 
considered a serious adverse event.  
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 
occurrences will be considered to decide whether the event is a reportable event 
and requires an IND safety report. 
Table 1.  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.) 


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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 NCI-CTCAE v 4.  These criteria 
can be accessed at:  http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
For AEs not included in the NCI-CTCAE v 4, the following criteria will apply: 
Grade                Description 
1 
 
Mild 
2 
 
Moderate   
3                   Severe   
4                   Life-threatening or disabling  
5                 Fatal  
AEs will be coded, grouped and tabulated by MedDRA preferred terms by body 
system organ class.  MedDRA version 13.1 will be used for the entire study. 
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. 
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 


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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 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. 
All SAE reports must be e-mailed or faxed directly to 
 
 
 
 
 
 
 
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 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. 
6.5 
Laboratory Test Abnormalities 
If any laboratory tests are performed on study, all new abnormal laboratory 
findings after initial administration of study medication 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] v4.0) are considered AEs.  Laboratory AEs for which there 
is no clinical intervention will be recorded only on the laboratory data pages of 
the eCRF.  Laboratory AEs not listed in the NCI CTCAE v4.0 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. 
6.6 
Other Safety Considerations 
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 
The primary endpoint is a composite of the following three parameters from 30 
minutes until 24 hours after the first dose of study medication: 
• absence of vomiting  
• no use of rescue medication, and 
• no intravenous hydration 
If all of the above three criteria are fulfilled, the patient is considered a treatment 
success for the primary analysis.  If one or more of the above three criteria are 
not fulfilled, i.e., the patient either experiences vomiting, receives rescue 
medication or receives intravenous hydration from 30 minutes through 24 hours 
after the first dose of study medication, the patient is considered a treatment 
failure. 
It is expected that approximately 40% of the placebo group will fail treatment 
during the 24 hours after initial dosing and that RHB-102 will reduce the 
incidence of treatment failure by approximately 50%, i.e., to an incidence of 20% 
in the active treatment group.  Patients will be stratified by age (<18, ≥18 years of 
age) and randomized 60:40 to active versus placebo.  To demonstrate a 
statistically significant decrease in the incidence of vomiting with a 2-tailed p-
value=0.01 and power=90%, 320 patients will be entered into the study, 192 
randomized to RHB-102 and 128 to placebo. 
7.2 
Analysis Datasets 
Safety and efficacy analyses will be based on all patients who receive any study 
medication, even if they vomit shortly after administration or are unable to 
swallow the medication. 
Primary and selected secondary efficacy analyses will also be performed on a 
predefined subgroup of patients defined as follows: 
1. 
Meet all inclusion/exclusion criteria 
2. 
If they vomit within 15 minutes of receiving the first dose of study 
medication, receive a second dose 
3. 
Do not have a primary diagnosis on discharge from the ED (or, if 
admitted, on discharge from the hospital) other than acute 
gastroenteritis or gastritis 
7.3 
Study Population and Demographics 
Demographic and pretreatment patient characteristics, including disease 
parameters and comorbidities, will be summarized with descriptive statistics.  
The descriptive statistics will include sample size, mean, standard deviation, 
median, minimum, and maximum for continuous variables and number and 
percentages for discrete variables.   
7.4 
Efficacy Analyses 
The primary endpoint is described above.   


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7.4.1 Statistical Hypotheses 
The primary objective for the study is to test for superiority of RHB-102 vs 
placebo for the proportion of the primary endpoint.   
The null hypothesis is that the odds ratio between two treatment groups is one, 
i.e. there is no treatment difference in the proportions of the primary endpoint.  
Cochran Mantel Haenszel (CMH) test stratified by age will be used to test the null 
hypothesis.  The hypothesis will be tested at an overall level of 0.05 (2-sided).    
7.4.2 Primary Analysis 
The study primary endpoint will be tested by Cochran Mantel Haenszel (CMH) 
test stratified by age.  Common odds ratio and its 95% confidence interval will be 
provided. If the observed 2-sided p-value from the CMH test is less than 0.05, 
statistical significance will be declared.  Point estimates of the proportions for 
each treatment arm will be provided along with the corresponding 2-sided 95% 
confidence intervals.  The point estimate of the difference of the proportions 
between treatment arms will also be provided along with corresponding 2-sided 
95% confidence intervals.   
In addition, subgroup analyses by each age group (<18, ≥18 years of age) will be 
conducted for the primary and selected secondary endpoints.   For a given age 
group, unstratified CMH test will be performed. 
An additional subgroup analysis will be performed which will exclude those 
patients determined during the course of their treatment and study follow-up to 
have a diagnosis other than acute gastroenteritis or gastritis. 
7.4.3 Handing of Missing Values  
Every effort will be made to collect all vomiting-related information.   In the ED, 
patients will be under observation, complete efficacy data is expected.  Rare 
cases may occur in which a patient leaves the ED before any observations can 
be made.  In addition, some patients may not report events between the time 
they leave the ED and 24 hours after first dose of study medication.  It is 
expected that >90% of patients will provide data until at least 24 hours after initial 
dosing.  Patients who drop out of the study will be imputed as failures/non-
responders for the primary analysis.  Sensitivity analyses using different 
imputations for missing values will be specified in the SAP.  
7.4.4 Secondary Analyses 
Additional analyses will be done comparing the following parameters between 
treatment groups: 
• Proportion of patients who experience or require each of the components 
of treatment failure: 
o Vomiting 
o Rescue antiemetic therapy 
o Intravenous hydration  
• Severity of nausea 


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• Incidence and severity of diarrhea 
• Incidence and severity of other symptoms of gastroenteritis 
• Time from first dose of study medication to discharge from ED, extended 
observation unit or hospital, whichever comes last 
• Time to resumption of normal activities (work/school/household) 
• Proportion of patients requiring hospitalization 
• Proportion of patients returning to emergency department for 
gastrointestinal symptoms  within 4 days of initial discharge 
7.5 
Safety Analyses 
The safety and tolerability of RHB-102 will be determined by reported AEs, 
physical examinations, vital signs, and, if performed on study, laboratory tests. 
Subjects who receive any RHB-102 (even if they vomit shortly after 
administration) are considered evaluable for safety. 
ECGs of patients who undergo paired ECGs on the study will be analyzed for 
shifts in QTcF. 
7.5.1 Adverse Events 
The NCI-CTCAE v4.0 system will be used to grade new or worsening laboratory 
abnormalities.  New laboratory abnormalities for which there are no CTCAE v4.0 
criteria will be assigned grade 1 if there were no clinical effects or interventions, 
and according to the criteria in section 6.3 if there were clinical effects and/or 
interventions. AEs will be grouped and tabulated by MedDRA preferred terms by 
system organ class.  
The Medical Dictionary for Regulated Activities (MedDRA) version 13.1 will be 
used to classify all AEs with respect to system organ class and preferred term. 
Summary tables of AEs and SAEs will be prepared by system organ class, 
preferred term and severity for each treatment group. AEs that lead to premature 
discontinuation from the study or to death will be listed separately via data 
listings.   
7.5.2 Other Parameters 
Findings on physical examination, including vital signs, which constitute clinically 
significant changes will be listed as adverse events.  The incidence of 
hospitalization will be compared between treatment groups as an efficacy 
parameter.  The causes for hospitalization, other than for gastroenteritis, will be 
listed as SAEs. 
7.6 
Interim Analysis   
No interim analysis will be conducted. 


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8. 
Study Medications 
Study medication, either RHB-102 or matching placebo, will be provided by the 
sponsor in kits of 5, labeled with a randomization code and required drug 
information. 
Study medication is to be stored at 15-30°C. 
Each RHB-102 tablet contains a total of 24 mg of ondansetron.  Matching 
placebo containing no active drug will also be provided. 
On randomization, the appropriate bottle of study medication will be provided by 
ED pharmacist.  The investigator or a designate will administer the first dose of 
study medication under observation.   
If the patient vomits within 15 minutes, regardless of whether pill fragments are 
seen, a second dose of study medication will be administered by the investigator 
or a designate.  If the patient experiences no vomiting in the ED after 
administration of the first dose of study medication, the second tablet will be 
retained for audit purposes.  Patients who have not failed therapy before ED 
discharge will take the bottle containing the remaining 3 tablets home on 
discharge. 
After each patient completes the study, he or she will send any remaining study 
medication back to the investigator in a prepaid, addressed mailer to be 
provided. 


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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 subjects 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 subject will be informed that his/her medical records will be subject to review 
by the sponsor and possibly by a representative of the Food and Drug 
Administration.  Subjects 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 
subject prior to study entry.  The original will be kept by the investigator and will 
be subject to review by the sponsor; a copy will be given to the subject. 
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 subjects’ medical or clinic records is necessary.  The 
investigator will ensure that certain information is contained in the medical or 
clinic records of the subject and that the entries are signed and dated, as follows: 


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• 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 subject entered the study describing the study number, 
the drug being evaluated, the study number assigned to that subject and a 
statement that consent was obtained; 
• 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 subject including start and 
stop dates; 
• a note of when the subject terminated from the study, the reason for 
termination and the subject’s general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical 
records of each subject 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 of study material supplied by the sponsor.  All unused 
study medication, both individual tablets and unused kits, must be returned to the 
sponsor’s designated agent.  The dispensing record must make it clear which 
subject 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, they 
should be reviewed for completeness and accuracy 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. 


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9.9   Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be 
undertaken on the subjects in this study without the prior written permission of 
the subject, 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 subject’s name, and 
the subject’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 
Redhill has agreed to provide unblended data to a publications committee for 
publication of the results of this study once completed and all data have been 
cleaned and the blind broken.  The publications committee will be constituted 
according to the guidelines set out in the letter to investigators dated September 
17, 2015.  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. 
 


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13. 
References 
Chow CM, Leung AKC, Hon KL.  Acute gastroenteritis:  from guidelines to real 
life.  Clin Exp Gastroenterol 2010;3:97-112. 
Deaths from gastroenteritis double. CDC press release 14 March 2012.  
http://www.cdc.gov/media/releases/2012/p0314_gastroenteritis.html?s_cid=ccu0
32612_013  Downloaded 24 Feb 2014. 
Graves NS.  Acute gastroenteritis.  Primary Care Clin Office Pract 2013;40:727-
41. 


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Appendix I.  Bristol Stool Scale 
 
 

SAP_001.pdf: 
RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number RHB-102-01 
 
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 
(Ondansetron 24 mg Bimodal Release Tablets) for Presumed Acute 
Gastroenteritis or Gastritis  
 
 
 
 
 
SAP Version: 4.0 
 
SAP Date: May 29, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
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RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
TABLE OF CONTENTS  
1. REVIEW AND APPROVAL ................................................................................................3 
2. REVISION HISTORY...........................................................................................................4 
3. INTRODUCTION .................................................................................................................5 
3.1. Study Design .............................................................................................................5 
3.2. Study Objectives .......................................................................................................6 
1.2.1 Primary Objective ...................................................................................................6 
1.2.2 Secondary Objectives .............................................................................................6 
4. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ..................................6 
5. HYPOTHESES AND DECISION RULES ...........................................................................7 
5.1. Statistical Hypotheses ...............................................................................................7 
5.2. Statistical Decision Rules ..........................................................................................7 
6. ANALYSIS SETS .................................................................................................................7 
6.1. Full Analysis Set .......................................................................................................7 
6.2. Subgroup Analysis Sets .............................................................................................7 
6.2.1. Subgroup Population 1 .......................................................................................7 
6.2.2. Subgroup Population 2 .......................................................................................7 
6.3. Safety Analysis Set ....................................................................................................8 
6.4. Treatment Misallocations ..........................................................................................8 
6.5. Protocol Deviations ...................................................................................................8 
7. ENDPOINTS AND COVARIATES .....................................................................................8 
7.1. Efficacy Endpoint(s) .................................................................................................8 
7.2. Safety Endpoints .......................................................................................................9 
7.3. Covariates ................................................................................................................10 
8. HANDLING OF MISSING VALUES ................................................................................10 
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................10 
9.1. Study Population and Demographics ......................................................................10 
9.2. Analyses of Primary Endpoint ................................................................................10 
9.3. Efficacy Analyses for Secondary and Tertiary Endpoints ......................................11 
9.4. Safety Analyses .......................................................................................................12 
10. REFERENCES ..................................................................................................................12 
 
 
 
Confidential 
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RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
1. REVIEW AND APPROVAL 
 
Prepared by: 
 
 
 
 
 
Date 
 
 
 
Review and Approval:  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
i
T
D


RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
2. REVISION HISTORY 
SAP Version  
SAP Version Date 
Which version of Protocol or Protocol Amendment is 
the SAP based on? Rationales for Changes if 
applicable 
Version 1.0 
April 16, 2015 
First SAP based on Protocol Amendment 2 dated  
April 9, 2015.   
Version 2.0  
September 22, 
2016 
Amended based on Protocol Amendment 5 dated 
June 9, 2016.  Major changes included: 
• Extended primary endpoint timeframe to 24 
hours 
• Updated the secondary endpoint list per 
Protocol Amendment 3 
• Added sensitivity analyses for the primary 
endpoint, per FDA’s request 
• Added analysis of Bristol Stool Scale (BSS) 
and concordance assessment between BSS 
and Stool Consistency, as recorded per 
original protocol 
• Additional subgroup analyses 
• 12-lead ECG analyses 
Version 3.0 
May 18, 2017 
Three changes: 
• Added adjudication process in primary 
endpoint section 7.1 
• Added diary date imputation in handing of 
missing values section 8. 
• Updated project manager’s name in SAP 
review and approval section 
Version 4.0 
May 29, 2017 
Four changes or updates: 
• Added a subgroup definition in subgroup 
analysis set section 6.2. 
• Updated adjudication process in primary 
endpoint section 7.1 
• Clarified missing imputation when the 
primary endpoint is unknown in handing of 
missing values section 8. 
• Clarified sensitivity analyses when the 
primary endpoint is unknown and added a 
subgroup analysis in analysis of primary 
endpoint section 9.2 
 
 
 
Confidential 
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RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
3. INTRODUCTION 
This document describes the planned data summaries and statistical analyses for Protocol RHB-
102-01, entitled “Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 (Ondansetron 24 
mg Bimodal Release Tablets) for Presumed Acute Gastroenteritis or Gastritis”.  It is meant to 
supplement the study protocol which should be referred to for details regarding the objectives 
and design of the study.  Any deviation to this analysis plan will be described in the Clinical 
Study Report.  
Based on feedback from telephone conferences with the FDA on 
 
  preteleconference memos and postteleconference minutes, and on subsequent discussions 
with investigators, this SAP has been revised.  No unblinding took place prior to this revision. 
3.1. Study Design 
Patients presenting to the emergency department who fulfill entry criteria will be asked to 
participate.  A screening log will be kept listing all patients considered with reasons for patients 
not entering the study.  Any patient whose information is reviewed in consideration for the study, 
even if not actually approached, is to be included in the screening log.  The screening log will 
differentiate between those who are prescreened, i.e., who are reviewed but never progress to 
request for consent, from those who are screened, i.e., who  are approached for consent, whether 
or not they actually sign consent or eventually participate in the study. Qualifying patients, once 
they have signed consent, will be stratified by age (≥ vs <age 18) and randomized 60:40 to RHB-
102 or matching placebo.  All patients will undergo laboratory testing and ECG, as specified 
below, once they have signed consent.  Of the blood and urine tests, only results of the 
pregnancy test (for women of childbearing potential) and a finger stick blood glucose (for 
patients with type 2 diabetes mellitus controlled by diet or oral medications) are required prior to 
treatment.  The pretreatment ECG results are available immediately and are to be used to qualify 
patients. 
Patients will be started on oral fluids ≥30 minutes after taking study medication (second dose for 
patients who receive 2 doses in ED) if they have not vomited during that period.  Intravenous 
hydration should not be administered unless the patient has vomited or is clearly unable, after a 
reasonable period of time has elapsed since administration of study medication, to tolerate oral 
fluids. 
At 4±0.25 hours after initial dosing, all patients are to have a repeat 12-lead ECG.  Once stable, 
but not less than 4 hours after initial dosing, patients may be discharged from the emergency 
department.   On discharge, patients who are not treatment failures will be given an additional 3 
doses of study medication to take at 24-hour intervals if nausea persists.  Patients will be 
contacted daily for 4 days after discharge to determine their condition.  Those patients who have 
persistent, worsening or recurrent nausea and/or vomiting during the follow-up period may be 
asked to come in for follow-up assessment by study personnel. 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
3.2. Study Objectives 
1.2.1 Primary Objective 
Comparison of the proportion of patients who are treatment successes, i.e., fulfill all three of the 
following criteria:   
a) without further vomiting,  
b) without rescue medication, and  
c) who were not given intravenous hydration from 30 minutes after the first dose of study 
medication through 24 hours after the first dose of study medication. 
 
1.2.2 Secondary Objectives 
Comparison between ondansetron and placebo groups of  
• Treatment success, as defined above, through 4 days following first dose of study 
medication 
• Proportion of patients who experience each of the components of treatment failure: 
o Vomiting 
o Rescue antiemetic therapy 
o Intravenous hydration  
• Severity of nausea 
• Diarrhea as reported by  
o Bristol Stool Scale (BSS):  number and distribution by grade of grade ≥5 stools 
daily throughout the study 
o Stool consistency, as recorded per original protocol, none/formed 
(normal)/soft/watery (diarrhea) 
• Incidence and severity of other symptoms of gastroenteritis 
• Time from first dose of study medication to discharge from ED, extended observation 
unit or hospital, whichever comes last 
• Time to resumption of normal activities (work/school/household) 
• Proportion of patients requiring hospitalization 
• Proportion of patients returning to emergency department for gastrointestinal 
symptoms  within 4 days of initial discharge 
• Adverse events 
 
4. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No interim analysis will be conducted. 
 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
5. HYPOTHESES AND DECISION RULES 
5.1. Statistical Hypotheses 
The primary objective for the study is to test for superiority of RHB-102 vs placebo for the 
proportion of the primary endpoint.   
The null hypothesis is that the odds ratio between the two treatment groups is one, i.e. there is no 
treatment difference in the proportions of the primary endpoint.  Cochran Mantel Haenszel 
(CMH) test stratified by age will be used to test the null hypothesis.  The hypothesis will be 
tested at an overall level of 0.05 (2-sided).    
5.2. Statistical Decision Rules 
If the observed 2-sided pvalue is less than 0.05, then statistical significance will be declared.  If 
the proportions are in favor of RHB-102 treatment arm, then “proportion of patients with success 
with RHB-102 is statistically significant better than proportion of patients with success with 
placebo” will be declared. 
6. ANALYSIS SETS 
6.1. Full Analysis Set 
The intent-to-treat population (ITT) will consist of all patients who receive any study medication, 
even if they vomit shortly after administration or are unable to swallow the medication.  The 
primary efficacy analysis will be conducted using ITT population.  
6.2. Subgroup Analysis Sets 
6.2.1. Subgroup Population 1 
Primary and selected secondary efficacy analyses will also be performed on a predefined 
subgroup of patients defined as follows: 
1. 
Meet all inclusion/exclusion criteria  
2. 
If they vomit within 15 minutes of receiving the first dose of study medication, receive a 
second dose  
3. 
Do not have a primary diagnosis on discharge from the ED (or, if admitted, on discharge 
from the hospital) other than acute gastroenteritis or gastritis 
6.2.2. Subgroup Population 2 
Another subgroup analysis set will include subjects from sites who enroll 5 or more patients.   
Analyses of the primary and the first secondary endpoint (treatment success through 4 days) will 
be performed.  Nine of the 21 sites which enrolled patients enrolled fewer than 5 each;  this 
group comprised 7% of total patients treated on study.  Patients from these sites had a 
disproportionately high incidence of major protocol deviations, 42% versus 6% for patients from 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
sites which enrolled at least 5 patients.  Several of these sites appeared to have significant 
difficulty not only enrolling but also in following protocol procedures.  Accordingly, analyzing 
results excluding these sites is another sensitivity analysis, akin to a per protocol analysis. 
 
6.3. Safety Analysis Set 
The safety analysis set will include all patients who receive any study medication, even if they 
vomit shortly after administration or are unable to swallow the medication. 
6.4. Treatment Misallocations  
If a subject is randomized but took incorrect treatment, then they will be reported under their 
randomized treatment group for all efficacy analyses, but will reported under the treatment they 
actually received for all safety analyses. 
6.5. Protocol Deviations 
Significant protocol deviations may include, but not limited to:  
 
• Failure to meet significant inclusion/exclusion criteria 
• No evidence of adequate compliance to study medication   
• Receiving excluded concomitant medication, including additional doses of study 
medication not administered per protocol 
• Failure to obtain required efficacy data: 
o While in ER:  patients who sign out AMA or who are otherwise uncooperative in 
providing protocol-specified efficacy or safety data, including failure to stay in 
ED for 4 hours following dosing for a follow-up ECG 
o After discharge:  patients who fail to provide protocol-specified follow-up data, 
including data on drug compliance and efficacy assessments  
 
7. ENDPOINTS AND COVARIATES 
7.1. Efficacy Endpoint(s) 
1) Primary Efficacy Endpoint:  the proportion of patients who fulfill all the following 3 
criteria from 30 minutes after first administration of study medication until 24 hours after 
the first dose of study medication: 
a. absence of vomiting  
b. no use of rescue medication, and 
c. no intravenous hydration 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
If all of the above three criteria are fulfilled, the patient is considered a treatment success for 
the primary analysis.  If one or more of the above three criteria are not fulfilled, i.e., the 
patient either experiences vomiting, receives rescue  medication or receives intravenous 
hydration from 30 minutes through 24 hours after the first dose of study medication, the 
patient is considered a treatment failure. 
Based on the 2nd blinded dry run conducted on 
, there were 28 subjects who did 
not have all the information needed to determine per the algorithm used if they met the 
primary endpoint successfully.  For 17 patients, all treated under amendment 1 or 2, in which 
the primary endpoint was treatment success on emergency department discharge, the reason 
for not having complete information was the lack of an ER day diary.  For these patients, 
based on all follow up data available, no treatment failure events occurred.  Therefore, these 
patients are considered treatment successes.  Among the other eleven, data were reviewed 
and several queries issued.  Based on this review, patients were assessed by the medical 
monitor to be treatment successes (n=4), failures (n=1) or unknown (n=6).  The adjudicated 
primary endpoint outcomes will be used for the primary analyses.  
  
2) Secondary and Tertiary Efficacy Endpoints:   
• Treatment success, as defined above, through 4 days following first dose of study 
medication 
• Proportion of patients who experience or require each of the components of treatment 
failure: 
o Vomiting 
o Rescue antiemetic therapy 
o Intravenous hydration  
• Severity of nausea  
• Incidence and severity of diarrhea 
• Incidence and severity of other symptoms of gastroenteritis 
• Time from first dose of study medication to discharge from ED, extended observation 
unit or hospital, whichever comes last 
• Days to resumption of normal activities (work/school/household) 
• Proportion of patients requiring hospitalization 
• Proportion of patients returning to emergency department for gastrointestinal 
symptoms  within 4 days of initial discharge 
 
7.2. Safety Endpoints 
• Adverse Events (AE) graded by NCI-CTCAE v4.0 system 
• Serious AE (SAE) 
• Death, if any 
• Vital signs 
• Laboratory tests 
• Physical examination 
• 12-lead ECG 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
 
7.3. Covariates  
The analyses of the primary and secondary endpoints will be performed using the following 
randomization stratification factor as covariate:  
• Age (<18, ≥18 years of age)  
Analyses of a given continue endpoint will also include its corresponding baseline as a covariate. 
8. HANDLING OF MISSING VALUES   
Every effort will be made to collect all vomiting-related information.   In the ED, patients will be 
under observation, complete efficacy data is expected.  Rare cases may occur in which a patient 
leaves the ED before any observations can be made.  In addition, some patients may not report 
events between the time they leave the ED and 24 hours after first dose of study medication.  It is 
expected that >90% of patients will provide data until at least 24 hours after initial dosing.  
Patients who drop out of the study and patients who have unknown primary endpoint will be 
imputed as failures/non-responders for the primary analysis.  
Diary dates will be imputed based on nominal date.  For example, a subject’s first dose in ED is 
18May2017, his/her ER day diary date will be 18May2017 and his/her Day 1 diary date will be 
19May2017. 
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
9.1. Study Population and Demographics 
Demographic and pretreatment patient characteristics, including disease parameters and 
comorbidities, will be summarized with descriptive statistics.  The descriptive statistics will 
include sample size, mean, standard deviation, median, minimum, and maximum for continuous 
variables and number and percentages for discrete variables. 
Baseline chemistry, CBC and urinalyses were performed on selected patients prior to amendment 
4.  Beginning with amendment 4, instituted in March, 2016, all patients were required to have 
chemistry and CBC performed; urinalysis remained optional.  In addition beginning with 
amendment 4, pre- and 4 hr post-treatment ECGs were required of all patients. 
Data for chemistry, CBC and urinalysis parameters are analyzed by treatment group, as 
described above.  ECGs, which are performed pre- and post-treatment, are analyzed in greater 
detail, as described below. 
9.2. Analyses of Primary Endpoint 
Primary efficacy analysis will be based on the ITT population.  The primary endpoint will be 
tested by Cochran Mantel Haenszel (CMH) test stratified by age.  Common odds ratio and its 
95% confidence interval will be provided.  If the observed 2-sided p-value from the CMH test is 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
less than 0.05, statistical significance will be declared. Point estimates of the proportions for each 
treatment arm will be provided along with the corresponding 2-sided 95% confidence intervals.  
The point estimate of the difference of the proportions between treatment arms will also be 
provided along with corresponding 2-sided 95% confidence intervals.   
For the above primary analysis, Patients who drop out of the study and patients who have 
unknown primary endpoint will be imputed as failures/non-responders, as stated in the handing 
of missing value section above. 
As a sensitivity analysis, patients who drop out of the study and patients who have unknown 
primary endpoint will be imputed as responders.  The primary analysis of CHM by age will be 
repeated. 
One additional sensitivity analysis, the most conservative approach, will have following 
imputations:  
• patients who drop out of the study and patients who have unknown primary endpoint in 
active arm will be imputed as failures/non-responders  
• patients who drop out of the study and patients who have unknown primary endpoint in 
placebo arm will be imputed as responders 
 In addition, subgroup analyses by each age group (<18, ≥18 years of age) will be conducted.   
For a given age group, unstratified CMH test will be performed.  Furthermore, subgroup 
analyses by baseline nausea severity will also be conducted.   None and mild severity will be 
combined as one group.  For a given severity group, unstratified CMH test will be performed.   
Primary analysis will also be performed on Subgroup Population 1 and Subgroup Population 2.  
9.3. Efficacy Analyses for Secondary and Tertiary Endpoints 
ITT population will be used for the analyses of all secondary and tertiary endpoints.   
1) Analyses of Binary/Proportion Endpoint 
Same statistical test as for the analyses of the primary endpoint, as stated in Section 9.2, will be 
used for analyzing other proportion endpoints. 
2) Analyses of Time-to-Event Endpoints 
Time to event endpoints will be compared between the treatment arms using stratified log-rank 
test adjusting the age stratification factor.  The endpoints will also be summarized using the 
Kaplan-Meier method and displayed graphically when appropriate. Median event times and 2-
sided 95% confidence interval for each median will be provided. 
3) Analyses of Continuous Endpoints 
Descriptive statistics, including the mean, standard deviation, median, minimum, and maximum 
values, will be provided for continuous endpoints. 
4) Analyses of Ordinal Categorical Endpoints 
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Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 4.0  
The number and percentage of patients in each category will be provided for categorical 
endpoints.  Bristol Stool Scale (BSS), added in the Protocol Amendment 3, is an 8 point ordinal 
categorical variable.  Wilcoxon rank sum test will be used to compare the two treatment groups. 
5) Concordance Assessment of Bristol Stool Scale and Stool consistency 
Stool consistency, as recorded per original protocol, none/formed (normal)/soft/watery 
(diarrhea), is a 4 point ordinal categorical variable.  Cross-tabulation of stool consistency and 
BSS among all the patients who have both assessments at a given time point will be created to 
evaluate the concordance of the two scales.  Cohen’s Weighted Kappa Coefficient and 95% 
confidence interval will be provided. 
 
9.4. Safety Analyses  
The safety and tolerability of RHB-102 will be determined by reported AEs, physical 
examinations, vital signs, and, if performed on study, laboratory tests. Subjects who receive any 
RHB-102 (even if they vomit shortly after administration) are considered evaluable for safety.  
Physical exam findings will not be analyzed separately. Rather, new and worsening 
abnormalities will be considered AEs and analyzed with those data. 
1) Adverse Events 
The NCI-CTCAE v4.0 system will be used to grade new or worsening laboratory abnormalities.  
New laboratory abnormalities for which there are no CTCAE v4.0 criteria will be assigned grade 
1 if there were no clinical effects or interventions, and according to the criteria in protocol 
section 6.3 if there were clinical effects and/or interventions. AEs will be grouped and tabulated 
by MedDRA preferred terms by system organ class.  
The Medical Dictionary for Regulated Activities (MedDRA) version 13.1 will be used to classify 
all AEs with respect to system organ class and preferred term. 
Summary tables of AEs and SAEs will be prepared by system organ class, preferred term and 
severity for each treatment group. AEs that lead to premature discontinuation from the study or 
to death will be listed separately via data listings.   
2) Other Parameters 
Findings on physical examination, including vital signs, which constitute clinically significant 
changes, will be listed as adverse events.  The incidence of hospitalization will be compared 
between treatment groups as an efficacy parameter.  The causes for hospitalization, other than for 
gastroenteritis, will be listed as SAEs. 
ECGs of patients who undergo paired ECGs on the study will be analyzed for shifts in QTcF and 
QTcB. 
10. REFERENCES 
None. 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
 
 
 
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN 
 
Protocol Number RHB-102-01 
 
Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 
(Ondansetron 24 mg Bimodal Release Tablets) for Presumed Acute 
Gastroenteritis or Gastritis  
 
 
 
 
 
Supplemental SAP Version: 1.0 
 
SAP Date: June 23, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
TABLE OF CONTENTS  
1. REVIEW AND APPROVAL ................................................................................................3 
2. REVISION HISTORY...........................................................................................................4 
3. INTRODUCTION .................................................................................................................5 
4. COVARIATES ......................................................................................................................5 
5. SENSITIVITY ANALYSIS (SAFETY POPULATION) .....................................................5 
6. PRIMARY ENDPOINT UNTIL DISCHARGE FROM THE ED ........................................6 
7. PRIMARY ENDPOINT ANALYSIS (SUBGROUP POPULATION 1) BY AGE ..............6 
8. PRIMARY ENDPOINT ANALYSIS BY AGE TERCILE GROUPS .................................6 
9. LOGISTIC REGRESSIONS .................................................................................................6 
9.1. Primary endpoint analysis by logistic regression ......................................................6 
9.2. Primary endpoint analysis by logistic regression adjusted by age as continuous 
variable ...................................................................................................................7 
9.3. Primary endpoint analysis by logistic regression adjusted by baseline nausea severity
 ................................................................................................................................7 
9.4. Primary endpoint analysis by logistic regression adjusted by age and baseline nausea 
severity ....................................................................................................................7 
10. SUCCESS AND FAILURE BY INVESTIGATIVE SITE .................................................7 
11. HIERARCHICAL ANALYSIS OF REASON FOR TREATMENT FAILURE ................7 
12. ANALYSIS OF VOMITTING ............................................................................................8 
13. ANALYSIS OF NAUSEA ..................................................................................................8 
14. CORRELATION BETWEEN AGE AND BASELINE SEVERITY NAUSEA ................8 
15. LISTING OF REDOSED SUBJECTS DUE TO VOMITTING .........................................8 
16. LISTING OF SUBJECTS EXCLUDED FROM SUBGROUP POPULATION 1 .............9 
 
 
 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
     Version 1.0 
1. REVIEW AND APPROVAL
Prepared by: 
 
 
Date 
Review and Approval: 
 
Date 
  
 
 
Date 
Date 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
     Version 1.0 
2. REVISION HISTORY
SAP Version 
SAP Version Date 
Which version of Protocol or Protocol Amendment is 
the SAP based on? Rationales for Changes if 
applicable 
Version 1.0 
June 23, 2017, 
Supplemental SAP to final SAP Version 4.0 dated on 
May 29, 2017 and signed on June 1, 2017 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
3. INTRODUCTION 
This is a Supplemental SAP to final SAP Version 4.0 dated on May 29, 2017 and signed on June 
1, 2017.  Study was unblinded on June 3, 2017.   This document describes supplemental analyses 
beyond the original planned analyses.   For detail of study design, please refer to Protocol RHB-
102-01, entitled “Randomized, Placebo-Controlled, Phase 3 Trial of RHB-102 (Ondansetron 24 
mg Bimodal Release Tablets) for Presumed Acute Gastroenteritis or Gastritis”.  For details of 
main study analyses, please refer to the final SAP Version 4.0.     
 
4. COVARIATES  
The final SAP defined randomization stratification factor as covariate:  
• Age (<18, ≥18 years of age)  
In this supplemental SAP, two additional covariates will be defined.   Subjects who are ≥18 years 
of age will be grouped by age terciles.  Actual cut-point will be derived based on the distribution 
of age.  Covariate variable Age will be coded as below: 
Age 
<18 
1st 1/3 group of 
≥18 years of age 
2nd 1/3 group of 
≥18 years of age 
3rd 1/3 group of 
≥18 years of age 
Coding 
1 
2 
3 
4 
 
Another covariate is Baseline Nausea Severity.   Baseline nausea severity will be coded as 
below: 
Baseline 
nausea 
severity 
No Nausea 
Mild Nausea 
Moderate 
Nausea 
Severe 
Nausea 
Nausea as bad 
as can be 
Coding 
1 
2 
3 
4 
5 
 
 
5. SENSITIVITY ANALYSIS (SAFETY POPULATION)  
Subject 23-001 was randomized to Placebo treatment but received RHB-102 treatment. This 
subject is classified as Placebo subject in ITT Population but RHB-102 subject in Safety 
Population.   
 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
A sensitivity analysis of primary endpoint will be performed based on actual treatment received 
(Safety Population).    
 
6. PRIMARY ENDPOINT UNTIL DISCHARGE FROM THE ED 
Primary endpoint 2 will be defined as the same as primary endpoint in main SAP except the 
timeframe will be from 30 minutes of first study dose administration to discharge from ED. 
 
Based on both ITT and Subgroup Population 1, primary endpoint 2 will be analyzed as the same 
as the primary endpoint, as described in the final SAP.   
 
7. PRIMARY ENDPOINT ANALYSIS (SUBGROUP POPULATION 1) BY AGE  
Based on Subgroup Population 1, perform Primary Analysis Table 14.2.1.3 by Age (<18, ≥18 
years of age). 
 
8. PRIMARY ENDPOINT ANALYSIS BY AGE TERCILE GROUPS 
Based on both ITT and Subgroup Population 1, perform Primary Analysis Table 14.2.1.3 by 3 
age tercile groups (as defined in covariate section).   
 
9. LOGISTIC REGRESSIONS 
Per final SAP, the primary endpoint was analyzed and tested by using Cochran Mantel Haenszel 
(CMH) test stratified by age.   In order to adjust for covariates, logistic regressions will be used 
in this supplemental SAP.    
In this section, all logistical regression analyses will be performed for both ITT population and 
Subgroup Population 1.  
 
9.1. Primary endpoint analysis by logistic regression 
Primary endpoint will be analyzed using logistic regression with treatment as a factor and age 
(<18, ≥18 years of age) as a covariate.   Pvalues and odds ratios of treatment and age from the 
logistic regression will be presented.   This analysis is to mimic the CMH analysis performed in 
the final SAP.  
 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
9.2. Primary endpoint analysis by logistic regression adjusted by age as continuous variable  
Primary endpoint will be analyzed using logistic regression with treatment as a factor and age as 
a continuous covariate.   Pvalues and odds ratios of treatment and age from the logistic 
regression will be presented.    
 
9.3. Primary endpoint analysis by logistic regression adjusted by baseline nausea severity  
Primary endpoint will be analyzed using logistic regression with treatment as a factor and 
baseline nausea severity as a continuous covariates (as defined in covariate section).  Pvalues and 
odds ratios of treatment and baseline nausea severity from the logistic regression will be 
presented.    
 
9.4. Primary endpoint analysis by logistic regression adjusted by age and baseline nausea 
severity  
Primary endpoint will be analyzed using logistic regression with treatment as a factor and age as 
a continuous covariate and baseline nausea severity as a continuous covariate (as defined in 
covariate section).  Pvalues and odds ratios of treatment, age and baseline nausea severity from 
the logistic regression will be presented.    
 
10.  SUCCESS AND FAILURE BY INVESTIGATIVE SITE 
A table summarizing success/failure/early dropout or inevaluable by treatment and by site will be 
provided.  Sites accrued at least 20 patients will have its own entry and the remaining low 
recruitment sites will be pulled together.   This will be based on ITT population and Subgroup 
Population 1.  
11. HIERARCHICAL ANALYSIS OF REASON FOR TREATMENT FAILURE 
Based on ITT population and Subgroup Population 1, a hierarchical analysis of reason for 
treatment failure will be provided.   The failure hierarchical order with code for analysis will be: 
1. (code=2) Treatment failure by vomiting, regardless of receipt of IV fluid or rescue 
medication 
2. (code=3) Treatment failure by receipt of IV fluid or rescue med in patients who did not 
vomit 
3. (code=4) Early dropout 
4. (code=5) Patients who don't have sufficient information to be evaluated for the primary 
endpoint 
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
Treatment success will be assigned a code = 1.   Distribution of treatment success and failure 
reasons will be tabulated.  Wilcoxon rank sum test will be used to test between RHB-102 arm 
and Placebo arm.  
12. ANALYSIS OF VOMITTING 
Based on ITT population and Subgroup population 1, subjects who didn’t vomit from 30 minutes 
after first administration of study medication until 24 hours post first dose will be analyzed by 
CMH stratified by age.   Subjects who have missing vomiting status will be treated as “yes.” 
 
13. ANALYSIS OF NAUSEA 
Based on ITT population and Subgroup Population 1, time to No Nausea will be displayed using 
Kaplan-Meier method with pvalues.   
Hourly observation data in ED will be used to derive time to the first “No Nausea” as an event or 
censor.  Time to first rescue medication and time to first IV fluid (volume >100 mL) will also be 
derived for censor.   Time to No Nausea will be evaluated based on the following three time 
duration.    
• Time to first No Nausea (for event or censor) 
• Time to first rescue (for censor) 
• Time to first IV fluid (volume > 100 mL) (for censor) 
The earliest event or censor will be used for Time to No Nausea.   e.g if the earliest is Time to 
first No Nausea event, then it will be used as an event.   If the earliest is rescue or IV fluid, then 
the time to first rescue or first IV fluid will be used for censor.   
 
14. CORRELATION BETWEEN AGE AND BASELINE SEVERITY NAUSEA 
Based on the ITT population, Spearman correlation statistics will be presented between age as 
continuous variable and baseline nausea severity (as defined in covariate section).   
 
15. LISTING OF REDOSED SUBJECTS DUE TO VOMITTING 
Based on ITT population, a listing of patients who were redosed because they vomited within 15 
minutes after the first dose will be provided.  Following variables will be included: 
• Subject ID 
• Treatment received,  
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Supplemental Statistical Analysis Plan 
Protocol RHB-102-01  
 
 
           
 
      
 
     Version 1.0  
• Success/failure/LTF/unknown,  
• Reason for failure (further vomiting regardless of subsequent IV fluid/rescue med, 
received IV fluid only, received rescue meds only, received both IV fluid and rescue 
med),  
• Time of failure relative to FIRST dose of study med, hr:min 
16. LISTING OF SUBJECTS EXCLUDED FROM SUBGROUP POPULATION 1 
There were 22 subjects excluded from Subgroup Population 1.   A listing of reasons being 
excluded from subgroup population 1 will be generated.   The listing should contain Subject ID, 
Treatment Received, and Reason being excluded from Subgroup Population 1. 
 
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