Clinical trial NCT03198507
Conditions: Helicobacter Pylori Infection Dyspepsia
Sponsor: RedHill Biopharma Limited
Start date: 2017-06-18; Completion date: 2018-12-13
Enrollment: 455 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The "test and treat" strategy for treating dyspeptic patients who are H. pylori positive is rapidly becoming the standard of care. This study will test the effectiveness of RHB-105, a new triple therapy to treat H. pylori infection in dyspeptic patients against an active comparator.

Detailed description:
This is a, randomized, double blind, active comparator-controlled study of RHB-105 in adult subjects complaining of epigastric discomfort that have been screened and found to be positive for H. pylori infection via 13C UBT and gastric biopsy.

The biopsy samples will also be used to conduct H. pylori antibiotic susceptibility/resistance assessment.

The study will be conducted at up to 65 sites in the USA. Eligible subjects will be randomized in a ratio of 1:1 between the RHB-105 arm (n=222) and the active comparator arm (n=222). Subjects will receive RHB-105 or active comparator for 14 consecutive days. Eradication of H. pylori infection will be determined at Visit 5 based on 13C UBT testing conducted between 43 and 71 days after initiation of study drug therapy.

All subjects who meet inclusion and exclusion criteria and have positive13C UBT will undergo upper endoscopy with sampling for culture and sensitivity testing (to rifabutin, amoxicillin, clarithromycin, and metronidazole) prior to randomization. After test of cure at Visit 5, all H. pylori eradication failures will receive susceptibility directed Standard of Care therapy based on initial culture results for subjects, and undergo repeat upper endoscopy for post treatment antibiotic susceptibility/resistance assessment.

Arms: arm 1: RHB-105 is an 'all-in-one' combination oral capsule consisting of combination therapy of Amoxicillin, Omeprazole and Rifabutin; as well as separate Riboflavin arm 2: Active comparator is an 'all-in-one' combination oral capsule consisting of combination therapy of Amoxicillin and Omeprazole; as well as separate Riboflavin
Interventions: intervention 1: RHB-105 intervention 2: Active Comparator
Intervention descriptions: intervention 1: The intended dose of RHB-105 (12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole capsules) 4 capsules every eight hours, is equivalent to a total daily dose of:

* Rifabutin 150 mg
* Amoxicillin 3000 mg
* Omeprazole 120 mg

One 50mg Riboflavin tablet to be taken once daily to maintain the blind. intervention 2: The intended dose of the Active Comparator (250 mg amoxicillin, and 10 mg omeprazole capsules) 4 capsules every eight hours, equivalent to a total daily dose of:

* Amoxicillin 3000 mg
* Omeprazole 120 mg

One 50mg Riboflavin tablet to be taken once daily to maintain the blind.

Protocol documents:
Prot_002.pdf: 
 
 
 
 
  
CONFIDENTIAL  
  
  
A Randomized Double Blind Active Comparator Controlled Phase III Study 
to Assess the Safety and Efficacy of RHB-105 in the Treatment of 
Confirmed Helicobacter pylori (H. pylori) Infection 
  
 
ERADICATE Hp2 Study 
  
   
Protocol Number:  
 
 
RHB-105-02  
Sponsor’s Medical Director:   
Ira Kalfus, MD  
Principal Investigator: 
 
David Y. Graham, MD 
 
Version and Date:  
 
 
Final Version, dated 26 February 2017 
  
 
 
 
 
Amendment No. 1, dated 15 August 2017 
  
 
 
 
 
Amendment No. 2, dated 02 October 2017 
  
 
 
 
 
Amendment No. 3, dated 22 March 2018 
   
    
  
   
  
  
  
  
  
  
   
 Statement of Confidentiality 
The information contained in this document is confidential and is not to be disclosed without the express 
consent of RedHill Biopharma Ltd.  


CONFIDENTIAL  
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Amendment 3 – 22 March 2018  
ERADICATE Hp2 Study 
Page 1 of 65 
 
  
  
  
STATEMENT OF COMPLIANCE  
  
  
This study will be carried out in accordance with Good Clinical Practices (GCP) as identified and/or 
required by the following regulations and guidance:  
• 
Declaration of Helsinki (Fortaleza, 2013)   
• 
US Code of Federal Regulations: 45 CFR Part 46, 21 CFR Parts 50, 56, and 312  
• 
ICH E6; Consolidated Guidelines on Good Clinical Practices (1997)    
 
  
  
  
  
  
  
  
  
  
  
  
  
  


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TABLE OF CONTENTS  
  
Page  
STATEMENT OF COMPLIANCE ........................................................................................................... 1 
1.0 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................................. 13 
1.1. Background Information ........................................................................................................ 13 
1.1.1  Helicobacter pylori .................................................................................................. 13 
1.1.2  Current Treatment Options for the Eradication of H. pylori ..................................... 14 
1.1.3 RHB-105 ................................................................................................................. 16 
1.1.4 Study Rationale ....................................................................................................... 17 
2.  OUTCOME MEASURES AND OBJECTIVES .................................................................................. 19 
2.1.  Study Outcome Measures .................................................................................................... 19 
2.2.  Study Objectives .................................................................................................................. 19 
3.  STUDY DESIGN.............................................................................................................................. 20 
4.  STUDY ENROLLMENT AND WITHDRAWAL ................................................................................. 21 
4.1  Inclusion Criteria ................................................................................................................... 21 
4.2  Exclusion Criteria .................................................................................................................. 22 
4.3 Treatment Assignment Procedures ........................................................................................ 23 
4.3.1 Randomization Procedures ..................................................................................... 24 
4.3.2 Post-treatment Standard of Care ............................................................................. 24 
4.3.3 Reasons for Discontinuation of Study Treatment ..................................................... 24 
4.3.4  Handling of Withdrawals ......................................................................................... 25 
4.3.5  Premature Termination or Suspension of Study ..................................................... 25 
5.  INVESTIGATIONAL PRODUCT ...................................................................................................... 26 
5.1 Study Drug Description .......................................................................................................... 26 
5.1.1 Formulation, Packaging, and Labeling ..................................................................... 26 
5.1.2 Study Drug Storage and Stability ............................................................................. 26 
5.1.3  Supply, Handling, and Accountability ...................................................................... 26 
5.2  Dosage and Administration of Study Drug ............................................................................. 27 
5.3  Assessment of Subject Compliance with Study Drug ............................................................ 28 
5.4  Past Medical History, Concomitant Illnesses and Medications .............................................. 28 
5.4.1  Past Medical History  and Concomitant Illnesses ................................................... 28 
5.4.2  Concomitant Medications ....................................................................................... 28 
5.4.3 Prohibited Medications ............................................................................................ 29 
5.4.4  Warning for CYP Interacting Medications ............................................................... 30 
6.  STUDY SCHEDULE ........................................................................................................................ 31 
6.1  Visit 0 - Screening ................................................................................................................. 31 
6.2  Visit 1 - Baseline - Day 1 ....................................................................................................... 31 
6.3  Visit 2 - Telephone follow-up - Day 8 (+ 1 day) ...................................................................... 32 
6.4  Visit 3 - Safety Visit - Day 13 (+ 2 days) ................................................................................ 32 
6.5  Visit 4 - Telephone follow-up - Day 28-60 (+ 2 days) ............................................................. 32 
6.6  Visit 5 – Test of Cure - Day 43 - 71 (+ 7 days) ....................................................................... 33 
6.6.1 Visit 5A – 13C UBT Telephone Follow-up - Day 44 – 72 (+7 days) ........................... 33 
6.7  Visit 6 – Standard of Care Baseline Visit - Endoscopy After Day 44-72 (+14 days) ............... 33 


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6.7.1 Visit 7 - Standard of Care Telephone follow-up - Day 50-79 (+ 2 days) ................... 34 
6.8 Visit 8 - Standard of Care Test of Cure - Day 85 - 140 (+ 14 days) ......................................... 34 
6.9 Early Termination Visit ........................................................................................................... 34 
6.9.1 Unscheduled Visit .................................................................................................... 34 
7.   STUDY PROCEDURES/EVALUATIONS ....................................................................................... 36 
7.1  Clinical Evaluations ............................................................................................................... 36 
7.2  Efficacy Evaluations .............................................................................................................. 37 
7.2.1 13C Urea Breath Test ............................................................................................... 37 
7.2.2  Laboratory Studies ................................................................................................. 38 
7.3  Assessment of Safety ........................................................................................................... 38 
7.3.1  Adverse Events ...................................................................................................... 38 
7.3.2  Clinical Laboratory Tests ........................................................................................ 42 
7.4  Pharmacokinetic Evaluations ................................................................................................ 44 
8.   STATISTICAL CONSIDERATIONS ................................................................................................ 44 
8.1 Analysis Populations .............................................................................................................. 44 
8.2 Statistical Analyses ................................................................................................................ 45 
8.2.1  Primary Endpoint .................................................................................................... 45 
8.2.2  Secondary Endpoints ............................................................................................. 45 
8.2.3 Safety ...................................................................................................................... 46 
8.2.4 Exploratory Endpoints ............................................................................................. 46 
8.3  Interim Analysis ..................................................................................................................... 46 
8.4  Sample Size .......................................................................................................................... 46 
9. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 46 
10. ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................................... 47 
10.1 Ethical Standard ................................................................................................................... 47 
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ Research Ethics 
Board (REB)/Helsinki Committee ................................................................................................. 48 
10.3 Informed Consent ................................................................................................................. 48 
10.4 Subject Confidentiality .......................................................................................................... 49 
10.5 Future Use of Stored Specimens ......................................................................................... 50 
11. DATA HANDLING AND RECORD KEEPING ................................................................................. 50 
11.1 Documentation of Data ......................................................................................................... 50 
11.2 Coding ................................................................................................................................. 51 
11.3 Data-Handling ...................................................................................................................... 51 
11.4 Reporting ............................................................................................................................. 52 
11.5 Study Records Retention ..................................................................................................... 52 
12. FINANCIAL, INSURANCE AND OWNERSHIP ............................................................................... 52 
12.1 Financial Disclosure ............................................................................................................. 52 
12.2 Ownership ............................................................................................................................ 53 
13. PUBLICATION POLICY .................................................................................................................. 53 
14. LITERATURE REFERENCES ........................................................................................................ 54 
15. APPENDICES ................................................................................................................................ 57 


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LIST OF ABBREVIATIONS  
 
ACG 
American College of Gastroenterology 
AE 
Adverse Event 
AGA 
American Gastroenterological Association 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
APO4 
Alkaline Phosphatase 
BL 
Baseline 
BUN 
Blood Urea Nitrogen 
CDC 
Centers for Disease Control and Prevention 
CE 
Covered Entity 
CIOMS 
Council for International Organizations of Medical Sciences 
CLO 
Campylobacter-like organism 
CRA 
Clinical Research Associate 
CRE 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
DHHS 
Department of Health and Human Service 
DO 
Doctor of Osteopathy 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCGF 
estimated Cockcroft-Gault (eCGF) formula 
EDC 
Electronic Data Capture 
EOT 
End-of-treatment 
FAP 
Full Analysis Population 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl-transferase 
GMP 
Good Manufacturing Practices 
HBs Ag 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C Viral antibody   


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HDPE 
High-density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonization of Technical  
Requirements for Registration of Pharmaceuticals for Human Use  
IEC  
Independent Ethics Committee  
IRB  
Institutional Review Board  
ITT  
Intent-to-treat  
IUD  
Intrauterine Device  
IWRS 
Interactive Web Response System 
LDH  
Lactate Dehydrogenase  
MedDRA  
Medical Dictionary for Regulatory Activities  
mITT  
Modified Intent-to-Treat  
NCI  
National Cancer Institute  
NCR  
No Carbon Required  
NSAID  
Nonsteroidal Anti-inflammatory Drug  
PA  
Physician’s Assistant  
PIPEDA  
Personal Information Protection and Electronic Documents Act  
PHI  
Personal Health Information  
PI  
Principal Investigator  
PKP 
PK Population  
PP  
Per Protocol  
PPI  
Proton Pump Inhibitor  
QTc  
Corrected Q-T Interval  
REB  
Research Ethics Board  
RHB  
RedHill Biopharma  
RBC  
Red Blood Cell  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SD  
Standard Deviation  


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SGOT  
Serum Glutamic-Oxaloacetic Transaminase  
SGPT  
Serum Glutamic-Pyruvic Transaminase  
SOC  
Standard of Care  
SOP  
Standard Operating Procedure 
TB 
Total Bilirubin 
TEAE  
Treatment Emergent Adverse Event  
13C UBT  
13Carbon Urea Breath Test  
ULN 
Upper Limit of Normal 
USA 
United States of America 
WBC  
White Blood Cell  
WHO 
World Health Organization 
 


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PROTOCOL SYNOPSIS 
Title:  
A randomized, double blind, active comparator controlled phase III study to assess the 
safety and efficacy of RHB-105 in the treatment of confirmed Helicobacter pylori (H. pylori) 
infection  
Phase:  
Phase III  
Study Population:  
Main Inclusion Criteria  
To be eligible for this protocol, subjects must:  
1. Be ages 18 – 70, inclusive; non-Asian males and females (This population has 
been demonstrated to have significantly elevated omeprazole levels as per the 
prescriber information for other omeprazole products).  A person having origins in 
any of the original peoples of the Far East, Southeast Asia, or the Indian 
subcontinent, including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam should be 
considered Asian, and for this study Asian is defined as having at least one Asian 
grandparent (Shektar et al, 2014, FDA Guidance for Industry 2016);   
2. Positive for H. pylori by 13C Urea Breath Test (UBT) and confirmed positive via 
gastric biopsy for CLO (Rapid Urease Test), or H. pylori culture or histology;  
3. Symptoms consistent with dyspepsia of at least two weeks duration (defined as 
recurrent pain or discomfort centered in the upper abdomen, often with a relation 
to meals);  
4. Females must not be pregnant or lactating and:   
a. at no risk of pregnancy for one of the following reasons: postmenopausal 
for at least one year from the date of informed consent, status post 
hysterectomy or tubal ligation, OR  
b. are prepared to and agree to use of an intrauterine device (IUD) or 
practice double method birth control (barrier plus spermicide) from 
screening through to 30 days post-end of-treatment (EOT); Acceptable 
double contraceptive methods include barrier (condoms or diaphragms) 
plus spermicide 
c. Hormonal contraceptives (birth control pills and hormone implants) are 
not acceptable contraception methods under this protocol.   
5. Males must be surgically sterilized or are prepared to and agree to practice 
double method (barrier plus spermicide) birth control from screening through to 30 
days post-EOT;  
6. Agree to refrain from consuming alcohol from 1 week prior to screening to Test of 
Cure/Visit 5; 
7. Agree to refrain from taking antacids from screening through day 15 and for at 
least 24 hours prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior 
to Visit 8/Test of Cure;  
8. Agree to refrain from taking H2 blockers at least 24 hours prior to screening 13C 
UBT and at least 24 hours prior to Test of Cure/Visit 5 and if applicable at least 24 
hours prior to Visit 8/Test of Cure;  
9. Agree to refrain from taking sucralfate from one week prior to screening through 
Test of Cure/Visit5; 


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PROTOCOL SYNOPSIS 
10. Agree to refrain from taking bismuth containing medications such as Pepto-
BismolTM or other proton pump inhibitors (PPIs) from two weeks prior to screening 
through Test of Cure/Visit 5; 
11. Agree to refrain from consuming grapefruit, or any other food or supplement 
known to significantly affect CYP3A4 or CYP2C19 activity from screening to day 
15; 
12. Provide written informed consent to participate as shown by a signature of subject 
on the consent form.  
 
Main Exclusion Criteria  
To be eligible for this protocol, subjects must not:  
1. Have alarm symptoms/signs (including unexplained anemia [iron deficiency], 
melena / hematemesis, anorexia, dysphagia, jaundice, weight loss);  
2. Have received prior H. pylori eradication therapy  
3. Use of antibiotics in the 4 weeks immediately prior to screening 13C UBT;  
4. Use of any proton pump inhibitors (PPIs) or bismuth-containing medications (such 
as Pepto-BismolTM) within the 2 weeks immediately prior to screening 13C UBT;  
5. Use of any of the following medications within seven days prior screening: 
alfentanil, allopurinol, amlodipine, anti-herpes agents, anti-retroviral agents, 
apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, boceprevir, buspirone, 
carbamazepine, cisapride, citalopram dosed greater than 20 mg /d, clomipramine, 
clopidogrel 
and 
other 
oral 
anticoagulants, 
colchicine, 
dapsone, 
dihydroergotamine, digoxin, diltiazem, ergotamine, felodipine, fluconazole, 
imatinib, hormonal contraceptives that are not exclusively norethindrone or 
norgestrel, imipramine, itraconazole, ketoconazole, lurasidone, lovastatin, 
mycophenolate mofetil, nifedipine, nisoldipine, nitrendipine, phenytoin, pimozide, 
probenecid,  proguanil, quinine, roflumilast, terfenadine and voriconazole;  
6. Use of amiodarone;  
7. Presence of more than two active gastric and/or duodenal ulcers;  
8. History of gastric outlet obstruction; or hypersecretory state (e.g., Zollinger Ellison 
Syndrome);  
9. History of esophageal or gastric surgery, except for simple closure of perforated 
ulcer;  
10. History of gastric cancer;   
11. History of malignancy within the past five years except for basal cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been treated with no evidence 
of recurrence;  
12. Positive screening laboratory results for human immunodeficiency virus (HIV) 
antibody (HIV1 or HIV2), or hepatitis B surface antigen (HBs Ag), or hepatitis C 
antibody (HCV Ab), unless patient has documented sustained viral response 
evidenced by prior and/or current absence of viral RNA at least 24 weeks after 
completing antiviral therapy;  
13. Current drug or alcohol abuse or history of drug or alcohol abuse in the past 5 
years from screening;  
14. Known hypersensitivity or suspected history of hypersensitivity reactions to any of 
the study drugs or related drugs, including cephalosporins and penicillin;  


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PROTOCOL SYNOPSIS 
15. Clinical evidence of any disease that in the opinion of the investigator might 
interfere with the subject’s ability to participate in the trial;  
16. History of QT prolongation (QTc greater than 450ms in males and 460ms in 
females), or ventricular arrhythmia, including torsades de pointes;   
17. AST or ALT >3x ULN, or APO4 >2x ULN, or TB >2x ULN.  Subjects with 
confirmed diagnosis of Gilbert’s Syndrome are excluded if TB > 2.5x ULN; 
18. Unable to communicate well with the Investigators and to comply with the study 
requirements;  
19. Involved in any other experimental drug or device protocol (outside of this RHB-
105-02 study) within the 4 weeks immediately prior to screening visit through end 
of study. 
20. Subjects with creatinine clearance less than 30 ml/min at screening via estimated 
Cockcroft-Gault formula (eCGF):  
eCGF or estimated creatinine clearance = [140 - age in years] * weight (kg) / 
72 * Serum Creatinine (mg/dl) [multiply estimated rate by 0.85 for women], 
using actual body weight at screening.  
Number of 
Subjects:  
Estimated total: 444 subjects will be randomized into the study.   
Number of Sites:  
The study will be conducted at up to 65 sites in the United States of America (USA).   
Study Design: 
This is a, randomized, double blind, active comparator-controlled study of RHB-105 in adult 
subjects complaining of epigastric discomfort that have been screened and found to be positive 
for H. pylori infection via 13C UBT and gastric biopsy. The biopsy samples will also be used to 
conduct H. pylori antibiotic susceptibility/resistance assessment.    
The study will be conducted at up to 65 sites in the USA. Once consent has been obtained and 
upon positive screening and enrollment into the study, eligible subjects will be randomized in a 
ratio of 1:1 between Test (RHB-105) arm (n=222) and the active comparator arm (n=222).  
Subjects will receive RHB-105 or active comparator for 14 consecutive days.   Eradication of H. 
pylori infection will be determined at Visit 5 based on 13C UBT testing conducted between 43 
and 71 days after initiation of study drug therapy.  
All subjects who meet inclusion and exclusion criteria and have positive13C UBT will undergo 
upper endoscopy with sampling for culture and sensitivity testing (to rifabutin, amoxicillin, 
clarithromycin, and metronidazole) prior to randomization.  After test of cure at Visit 5, all H. 
pylori eradication failures will receive susceptibility directed standard of care therapy based on 
initial culture results for subjects, and undergo repeat upper endoscopy for post treatment 
antibiotic susceptibility/resistance assessment.  
Study Visit Schedule:                                                                                  
Screening 
Baseline 
Phone 
Safety 
Phone 
Test of 
Cure 
13C UBT 
Follow-up 
SOC Endo 
Phone 
Test of 
Cure 
Day -42 to 
0 
Day 1 
Day 8 
+1 
Day 13  
+/-2 
Day 
28-60 
+/-2 
Day 43-
71 +7 
Day 44-72 
+7 
After Day 
44-72 
+14 
Day 50-
79+/-2 
Day 85 
- 140 
+14 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 5a 
Visit 6 
Visit 7 
Visit 8 
Subject 
Participation 
Duration:  
Subjects may participate for up to 154 days.   


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RHB-105-02  
  
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PROTOCOL SYNOPSIS 
Treatment:   
RHB-105 is an ‘all-in-one' combination oral capsule consisting of 2 different antibiotics and a 
proton pump inhibitor combined in a single capsule.    
Dose per RHB-105 capsule: 12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole.  
Active comparator is RHB-105 without rifabutin, an ‘all-in-one' combination oral capsule 
consisting of amoxicillin and a proton pump inhibitor combined in a single capsule.    
Dose per active comparator capsule: 250 mg amoxicillin, and 10 mg omeprazole. All subjects 
will also be administered a single 50 mg dose of riboflavin dispensed as a separate tablet in 
order to maintain study blind.   
Route of  
Administration:  
Oral capsule.  
Dosage 
Regimen for 
Investigational 
Product:  
The intended dose is RHB-105 (12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole) 4 
capsules every eight hours with food, equivalent to 50 mg rifabutin, 1000 mg amoxicillin and 40 
mg omeprazole for a total daily dose of:  
• 
Rifabutin 150 mg    
• 
Amoxicillin 3000 mg  
• 
Omeprazole 120 mg  
Subjects will take RHB-105 every 8 hours with food for 14 consecutive days.  
Dosage 
Regimen  
for Active  
Comparator:  
The intended dose active comparator is 250 mg amoxicillin, and 10 mg omeprazole 4 capsules 
every eight hours with food, equivalent to 1000 mg amoxicillin and 40 mg omeprazole for a total 
daily dose of:  
• 
Amoxicillin 3000 mg  
• 
Omeprazole 120 mg  
Subjects will take active comparator every 8 hours with food for 14 consecutive days.  
Outcome 
Measures  
Primary Endpoint:   
The occurrence of H. pylori eradication is confirmed via 13C Urea Breath Test (UBT) testing 
43-71 days after initiation of treatment. 
 
Secondary Endpoints: 
1) Antibiotic Resistance and Susceptibility Subgroup Analyses -  
The primary endpoint will be summarized within subgroups formed by the presence of 
H. pylori susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and 
rifabutin determined based upon samples obtained prior to initiating study treatment. 
The proportion of subjects with failure to eradicate H. pylori and the treatment effect 
(difference in the proportions) will be estimated within each subgroup along with 95% 2-
sided confidence intervals where there are an adequate number of subjects in the 
subgroup (e.g., at least 20 subjects per subgroup). 
2) Pharmacokinetics – The plasma concentrations of amoxicillin, omeprazole, rifabutin, 
and the rifabutin metabolite 25-O-desacetyl-rifabutin on Day 13 will be summarized by 
time following most recent dose 
3) Assess the difference in antibiotic resistance and susceptibility of H. pylori after 
treatment with study drug in treatment failure subjects 
 
Safety: 


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PROTOCOL SYNOPSIS 
The occurrence and severity of treatment emergent adverse events during the study and 
changes 
from 
baseline 
in 
hematology 
and 
chemistry 
laboratory 
values. 
 
Exploratory Endpoints:  
1) Upon study completion and unblinding of all subjects, CYP2C19 status will also be 
summarized and subgroup analyses of efficacy based on CYP2C19 status and 
pharmacokinetics will be performed using descriptive methods 
2) Eradication rates in failure to eradicate subjects who receive susceptibility directed 
standard of   care will be analyzed descriptively.  
Objectives:  
  
Primary Objective: To assess the effectiveness of RHB-105 to eradicate H. pylori as indicated 
by 13C UBT for H. pylori.  
 
Secondary Objective: The primary endpoint, the occurrence of H. pylori eradication, will be 
examined within subgroups of subjects formed by the occurrence of antibiotic resistance and 
susceptibility prior to therapy. 
 
Safety Objective: To assess the safety profile of RHB-105.  
Study 
Completion:  
Upon completion of clinical activities and safety follow-up.  
Statistical  
Considerations 
Sample size for this study has been calculated based on a superiority comparison assuming 
83% effectiveness for the new treatment, and 70% effectiveness for the control, with 90% power 
and a 2-sided alpha of 5%. Using these specifications, 222 subjects per arm will be required. 
The primary analysis will use the Full Analysis Population defined as all randomized subjects 
who received at least one dose of study drug. The primary efficacy endpoint is eradication of H. 
pylori via 13C UBT test at Test of Cure Visit 5.  
 
The treatment groups will be compared for the primary endpoint using a chi-squared test. Other 
endpoints, including safety endpoints, will be summarized using descriptive methods. 
The primary endpoint, the occurrence of H. pylori eradication, will be examined within 
subgroups of subjects formed by the occurrence of antibiotic resistance and susceptibility prior 
to therapy. 
 
  
  
  


CONFIDENTIAL  
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Amendment 3 – 22 March 2018 
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RESPONSIBLE PERSONNEL  
Sponsors and Contacts  
RedHill Biopharma Ltd.  
21 Ha’arba’a St.,   
Tel-Aviv 64739, Israel 
Tel.: +972 3 541 3131   
Fax: +972 3 541 3144  
Email: info@redhillbio.com  
Medical Director  
Ira N. Kalfus MD  
251 Central Park West  
New York, NY 10024, USA  
Tel: +1 917 817 7517  
Fax: +1 888 685 5218  
Email: ira@redhillbio.com   
Product Manager  
Gilead Raday M.Sc., M.Phil.  
21 Ha’arba’a St.,   
Tel-Aviv 64739, Israel 
Tel.: +972 3 541 3131   
Fax: +972 3 541 3144  
Email: gilead@redhillbio.com  
VP Research & Development  
Reza Fathi, PhD  
260 Forest Ave 
Oradell, NJ 07649-1307USA  
Tel: +1 609 462 1143  
Fax: + 972 7 376 98990  
Email: reza@redhillbio.com  
Serious Adverse Event Reporting 
 
Email SAEs to ICON Clinical Research icon-mads@iconplc.com 
SAE Hotline US ONLY: +1 888 723 9952 
 
Sponsor’s Local Representative 
  
ICON Clinical Research 
2100 Pennbrook Parkway  
North Wales, PA  
United States, 19454 
 
Central Laboratories  
Safety Laboratory   
ICON Laboratory Services Inc. 
123 Smith Street 
Farmingdale 
NY 11735 
USA 
 
Microbiology Laboratory  
Infectious Diseases Research Laboratory 
Texas Children’s Hospital -Feigin Center -Baylor 
College of Medicine 
1102 Bates Avenue, Ste. 1150 
Houston TX 77030 
USA 
Pk Laboratory  
Algorithme Pharma Inc. 
575 Armand-Frappier Boulevard 
Laval, Quebec,  
H7V 4B3 
Canada 
Histology Laboratory  
Miraca Life Sciences, Inc. 
6655 North MacArthur Boulevard 
Irving, Texas 75039 
USA 
 
 


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RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
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1.0 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
1.1. Background Information  
1.1.1  Helicobacter pylori  
Helicobacter pylori is a common and important transmissible (human-to-human) bacterial human 
pathogen. The prevalence of this infection varies worldwide from as low as 10% in some 
developed western nations to higher than 80% among the indigent populations of many 
developing countries. The World Health Organization (WHO) estimates that H. pylori is present 
in about half of the world’s population while the Centers for Disease Control and Prevention 
(CDC) estimates a total of 30-40% of Americans harbor the infection, with the highest 
prevalence rates in minority subgroups (Wannmacher 2011, Barzilay 2011, Graham 1991, 
Cardenas 2006a).  
  
The major concerns of H. pylori as an infectious agent are as follows:   
• 
It is continuously infectious throughout an initial, clinically latent and often asymptomatic 
stage.  
• 
It induces a pattern of acute-on-chronic gastric inflammation, resulting in disordered gastric 
physiology and progressive gastric mucosal damage.    
• 
It can produce serious pathological effects and clinical sequelae in infected patients.  
  
Patients with H. pylori infection may present with mild dyspepsia. One of the major current 
reasons for H. pylori testing is the presence of dyspepsia (Malfertheiner 2012, Graham 2010a), 
as many H. pylori-related diseases are associated with this symptom. In addition, more than 
50% of dyspeptic patients with no evidence of ulcer disease (non-ulcer dyspepsia or functional 
dyspepsia) are infected with H. pylori (Maconi 2009, Moayyedi 2006) and are at risk for 
progression of gastric mucosal damage (Graham 1997a).  
  
Approximately 20% of patients infected with H. pylori will develop clinically significant sequelae 
(Axon, 1997), including atrophic gastritis, gastric atrophy, duodenal ulcer disease, gastric ulcer 
disease, primary gastric B-cell lymphoma, gastric adenocarcinoma, iron deficiency anemia, and 
vitamin B12 deficiency (Rimbara 2011; Cardenas 2006a; Cardenas 2006b; DuBois 2005; 
Graham 1997b; Dholakia, 2005).   
  
In 1994, H. pylori was classified as a Group 1 agent (carcinogenic to humans) by the WHO’s 
International Agency for Research on Cancer and it is now accepted as a major cause of gastric 
cancer worldwide. Gastric cancer is amongst the most frequent cancers worldwide and is 
associated with a poor prognosis (5-year survival rate of only 10-15% in patients with advanced 
disease) (Selgrad 2010, Ekstrom 2001).  In the first half of the 20th century, gastric cancer was 
the most common cancer in many Western countries including the United States of America 
(USA).  Despite the decreased incidence of gastric cancer since the mid-20th century, the 


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National Cancer Institute [NCI] (Surveillance Epidemiology and End Results [SEERS]) estimates 
that >21,000 Americans will be diagnosed with and almost 11,000 will die of gastric cancer in 
2012 (NCI 2012).  As such, identification and eradication of H. pylori before pre-neoplastic 
lesions are present is vital if gastric cancer is to be prevented (Malfertheiner 2005).  For 
example, population-based eradication of H. pylori in an area where the infection is endemic 
(Taiwan) showed a 67% reduction in new ulcers, 77% reduction in the incidence of gastric 
atrophy, and 25% reduction in gastric cancer, comparing the period before (1995-2003) to the H. 
pylori eradication period (2004-2008) (Lee 2013).  
1.1.2  Current Treatment Options for the Eradication of H. pylori  
H. pylori eradication is a well-established therapy for patients with ulcer disease (Chey 2007). 
Other commonly cited recommendations for treatment include recurrent ulcer hemorrhage, 
uninvestigated dyspepsia (depending upon H. pylori prevalence), plan to start therapy with 
proton pump inhibitors (PPIs) or nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk 
patients, after endoscopic resection of early gastric cancer, and whenever the infection is 
diagnosed.  This “test and treat” strategy is the recommendation of the American 
Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) (Talley 
2005, Chey 2007). Given the potential morbidity of H. pylori infection, which may range from 
non-serious to life-threatening disease states, and given the steady rise in clarithromycin and 
metronidazole resistant H. pylori strains (De Francesco 2010), a therapy that will reliably 
eradicate H. pylori upon detection is sorely needed.   
  
H. pylori infection can be cured using suitable antimicrobial therapies, and a success rate ≥ 85% 
should be achieved (Graham et al, 2007, Graham 2010b).  Unfortunately, this degree of success 
is often clinically impossible to achieve using standard-of-care therapies, due to the increased 
prevalence of antimicrobial resistance. Physicians are often unaware of the resistance rates 
within their region (Graham, 2009) making the empiric selection of effective therapies difficult. 
Due to this, a step-wise approach is commonly used to achieve treatment success by providing, 
as needed, first-line, second-line, third-line, and fourth-line therapies to patients.  However, 
according to the ACG, the first (or primary) course of treatment offers the greatest chance at 
eradication of H. pylori. Therefore, the first treatment regimen is the most important and should 
include only those therapies with proven effectiveness (Graham and Calvet 2012).   
  
Currently approved triple and quadruple therapies often achieve sub-optimal eradication. Two 
separate meta-analyses have demonstrated that effectiveness of both clarithromycin- and 
metronidazole-based triple therapies has decreased to unacceptably low levels of <85% (Per 
Protocol) effectiveness (Graham 2010b).  A meta–analysis of 2751 patients revealed that the 
failure rate for H. pylori eradication with triple therapy in non-ulcer dyspeptic patients and 
duodenal ulcer patients was 33.7% and 21.9%, respectively (a difference which was found to be 
statistically significant). This demonstrates that the high rate of eradication failure is an issue in 
H. pylori infection regardless of the status of ulcer disease secondary to H. pylori. If anything, it 
would seem that triple therapy is less effective in eradication of H. pylori in non-ulcer dyspeptic 
patients as compared to duodenal ulcer patients (Broutet 2003).  


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The Food and Drug Administration (FDA) approved bismuth quadruple therapy Pylera® in 2006 
for the treatment of patients with H. pylori infection and duodenal ulcer disease).  This therapy 
offers bismuth, tetracycline, metronidazole (within a single capsule), and the PPI omeprazole.  
There are broadly varying reports (75-90%) regarding the effectiveness of bismuth-containing 
quadruple therapy in eradication of H. pylori (Chey 2007).  In 2010, a meta-analysis of 
randomized studies comparing triple therapy to quadruple therapy reported an average 
eradication rate of 78.3% using bismuth-based quadruple therapy, which included a PPI, and 
77.0% eradication using clarithromycin triple therapy (Luther 2010). Quadruple therapy regimen 
also requires four times daily (qid) dosing, potentially reducing compliance and treatment 
success. (Malfertheiner 2011, Salazar 2012).  
  
Prevpac®, (amoxicillin, clarithromycin and lansoprazole) wrapped individual daily administration 
pack was approved by the US Food and Drug Administration in February 1999 for the treatment 
of h pylori infection and duodenal ulcer disease. In April 2002, duration of therapy was reduced 
to 10 days. The Prevpac® PI reports eradication rates of 81-86% and these have been steadily 
decreasing. The American College of Gastroenterology Clinical Guideline: Treatment of 
Helicobacter pylori Infection states that for first line therapy, clarithromycin triple therapy should 
be restricted to patients from areas where clarithromycin resistance is low (<15%) and or have 
no previous history of macrolide exposure (Chey 2017).  
 
No US trial of dual antibiotic therapy [Attumi et al 2014, Graham et al 2010, Graham et al 1995, 
Harford et al 1996, Laine et al 1995, Laine et al 1998, Malaty et al 1996] has successfully 
achieved the 85% ITT eradication rate targeted in the literature [Graham et al 2007).  High dose 
amoxicillin/lansoprazole dual therapy is already an FDA approved therapy to eradicate H. pylori 
to reduce recurrence of duodenal ulcer. The dosing of this approved regimen is amoxicillin 1 g 
t.i.d. and lansoprazole 30 mg t.i.d. administered for 14 days. This dosing regimen is equivalent to 
RHB-105 without rifabutin and with omeprazole replacing lansoprazole as per ability to raise 
intragastric pH over 24 hours, and 67% bioavailability of omeprazole in RHB-105 vs reference 
omeprazole (RedHill Biopharma Study RHB-P2-418). Two studies noted in the Prevacid PI 
report H. pylori eradication rates of 77% and 66% in the evaluable data sets and 70 and 61% in 
the intent to treat analyses in those same studies. On the basis of these and published studies, 
first line dual amoxicillin/PPI therapy is not recommended in current treatment guidelines. The 
Prevacid prescribing information states that triple therapy was shown to be more effective than 
all possible dual therapy combinations and that amoxicillin dual therapy is indicated only for 
patients who are either allergic or intolerant to clarithromycin.In summary, there is growing 
consensus among the scientific and medical communities that the currently approved therapies 
for the eradication of H. pylori no longer provide adequate therapy for over 20% of treated 
patients.  Indeed, ineffective treatment may lead to generally increased bacterial resistance as 
well as complicate future treatment attempts to eradicate the H. pylori infection and thus cause 
greater medical and financial burdens.  Given the morbidity associated with H. pylori infection 
and the decline in effectiveness of standard-of-care therapies, there is a clear need for a new 


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highly effective first-line therapy that will reduce treatment burden on the patient and consistently 
achieve a high rate of eradication.    
1.1.3 RHB-105  
RHB-105 is an antibiotics (rifabutin and amoxicillin) and proton pump inhibitor (omeprazole) 
proprietary drug combination under investigation for the treatment of H. pylori infection.  
H. pylori has been shown to be highly sensitive to rifabutin (a derivative of rifamycin). Rifabutin-
based therapy offers an alternative to clarithromycin- or metronidazole-based therapies and 
could establish improved effectiveness of H. pylori eradication, including metronidazole- and/or 
clarithromycin-resistant strains.  
  
Resistance of H. pylori to amoxicillin or rifabutin is very rare (Van Der Poorten 2007). The mean 
rate of H. pylori resistance to rifabutin (calculated from 11 studies including 2982 patients) was 
1.3% in general and 0.6% for patients’ naïve to H. pylori eradication treatment (Gisbert 2011).   
Combining rifabutin, amoxicillin, and a PPI (pantoprazole) has achieved eradication rates of 
96.6% (in the highest dose group), regardless of clarithromycin or metronidazole resistance 
status (Borody 2006). In his study of H. pylori-infected patients who previously failed standard 
clarithromycin-based triple therapy, Borody demonstrated that a 12-day course of rifabutin (150 
mg qd), amoxicillin (1 – 1.5 g tid), and a PPI (pantoprazole; 80 mg tid) was well tolerated and 
highly effective, providing a high eradication rate of 90.7 - 96.6% (Borody 2006).  Therefore, 
RHB-105 can potentially overcome the current resistance issues that are problematic with the 
approved clarithromycin and metronidazole based therapies and may provide efficient and 
widespread H. pylori eradication to treat and prevent the numerous and life-threatening diseases 
associated with H. pylori infection. 
  
RHB-105 has recently completed investigation in RedHill Biopharma Study RHB-105-01.  This 
study, entitled A Randomized Placebo-controlled Phase III Study to Assess the Safety and 
Efficacy of RHB-105 in the Treatment of Confirmed Helicobacter pylori (H. pylori) Infection 
in Dyspepsia Patients, compared RHB-105 to placebo in a double blind fashion to assess 
safety only.  The effectiveness of any combination of 2 out of 3 API components of RHB-105 
was projected to be no more than 70% given the information in the Prevacid and Prilosec 
Prescriber Information. The new regimen was expected to be superior to the 70% historical 
comparator.  Subjects noted to be endoscopically and 13C UBT positive were treated with 
blinded RHB-105 (or placebo) for 14 days and had test of cure via 13C UBT performed at day 28-
35 post completion of therapy.  Subjects who experienced failure to eradicate H. pylori received 
standard of care triple or quadruple therapy as per the local investigator.    
 
Following treatment with the 3-in-1 combination RHB-105, the success rate of eradication 
(based on 13C UBT) of H. pylori 28 days post-EOT was 89.4% based on the primary endpoint of 
mITT (Modified Intent to Treat). The mITT population included all subjects who received at least 
1 dose of randomized study treatment and underwent a 13C UBT test at 28-35 days post 
completion of therapy.  The PP (Per Protocol) Population included all subjects who consumed at 
least 75% of planned study treatment, underwent a 13C UBT test at 28-35 days post completion 


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RHB-105-02  
  
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ERADICATE Hp2 Study 
  
  
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of therapy, and did not have any major protocol violations.  Efficacy in this group was 88.9% due 
to the exclusion of three treatment successes who were assessed for H. pylori eradication 
outside the protocol defined treatment windows. This rate was statistically significantly superior 
to 70%, which was the projected effectiveness of any combination of 2 out of 3 the components 
of RHB-105 given the data in the Prevacid and Prilosec prescribing Information.  In placebo 
subjects who had failure to eradicate H. pylori, and were treated with standard of care therapy, 
there was a 63% (17/27) eradication rate with standard of care therapy.  Fifty percent (2/4) of 
RHB-105 subjects who received standard of care demonstrated eradication of H. pylori with 
standard of care.  
 
RHB-105 was shown to be safe and well-tolerated. The majority of treatment-related AEs were 
mild to moderate; only one RHB-105-treated patient had a treatment-emergent SAE, and this 
was assessed as not related to study treatment. The AE profile, laboratory values, and other 
safety assessments did not indicate any safety concerns with respect to the use of RHB-105 in 
this patient population.  
  
FDA prescribing information for omeprazole and omeprazole containing products note up to a 
fourfold increase in AUC in Asian subjects compared with Caucasians and suggest dose 
reduction in this patient population.  Given the fixed dose combination present in RHB-105 this 
population is excluded from the ERADICATE Hp2 study.  
 
1.1.4 Study Rationale   
Standard treatments fail to eradicate H. pylori in over 20% of infected patients.  These patients 
constitute a significant medical problem as they harbor strains resistant to clarithromycin and/or 
metronidazole, which are major components of the therapies currently available.    
  
In the USA, standard second-line therapy is bismuth, tetracycline and metronidazole in 
conjunction with a PPI or H2 receptor antagonist.  While this therapy is effective, compliance is 
an issue due to the fact that this therapy must be administered four times daily for 10 to 14 days 
(due to metronidazole resistance).    
  
Combining rifabutin with amoxicillin and a PPI, such as omeprazole, overcomes the problem of 
clarithromycin and metronidazole resistance, as this therapy does not contain either; H. pylori 
strains resistant to rifabutin are rare and, rifabutin is effective against clarithromycin and 
metronidazole resistant strains.    
  
RedHill has developed an “all-in-one” capsule formulation, containing 12.5 mg rifabutin, 250 mg 
amoxicillin, and 10 mg omeprazole (RHB-105).  Details about the formulation and its 
components are available in the Investigator’s Brochure.  RHB-105 is intended to maintain or 
improve upon the current demonstrated H. pylori eradication effectiveness, maintain or improve 
the tolerability of anti-H. pylori treatment, and simplify the anti-H. pylori dosing schedule.  It is 


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RHB-105-02  
  
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ERADICATE Hp2 Study 
  
  
Page 18 of 65 
 
being investigated against an active comparator ‘all-in-one' combination oral capsule consisting 
of 250 mg amoxicillin and 10 mg omeprazole.  Both the investigational drug (RHB-105) and the 
active comparator will be administered as 4 capsules three times daily with food. 
 
Rifabutin has been demonstrated to discolor body fluids and in an effort to maintain the study 
blind, all subjects will be administered 50 mg of riboflavin (Vitamin B2) to be taken once daily in 
addition to blinded study drug. 


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2.  OUTCOME MEASURES AND OBJECTIVES  
2.1.  Study Outcome Measures  
Primary Endpoint:   
The occurrence of H. pylori eradication is confirmed via 13C Urea Breath Test (UBT) testing 43-
71 days after initiation of treatment. 
  
Secondary Endpoints: 
The secondary endpoints are as follows and will be assessed using descriptive measures: 
1) Antibiotic Resistance and Susceptibility Subgroup Analyses -  
The primary endpoint will be summarized within subgroups formed by the presence of H. 
pylori susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and rifabutin 
determined based upon samples obtained prior to initiating study treatment.  The proportion 
of subjects with failure to eradicate H. pylori and the treatment effect (difference in the 
proportions) will be estimated within each subgroup along with 95% 2-sided confidence 
intervals where there are an adequate number of subjects in the subgroup (e.g., at least 20 
subjects per subgroup). 
2)   Pharmacokinetics – The plasma concentrations of amoxicillin, omeprazole, rifabutin, and the 
rifabutin metabolite 25-O-desacetyl-rifabutin on Day 13 will be summarized by time following 
most recent dose 
3) Assess the difference in antibiotic resistance and susceptibility of H. pylori after treatment 
with study drug in treatment failure subjects 
 
Safety:   
The occurrence and severity of treatment emergent adverse events during the study and 
changes from baseline in hematology and chemistry laboratory values. 
 
Exploratory Endpoints: 
1) Upon study completion and unblinding of all subjects, CYP2C19 status will also be 
summarized and subgroup analyses of efficacy based on CYP2C19 status and 
pharmacokinetics will be performed using descriptive methods.   
2) Eradication rates in failure to eradicate subjects who receive susceptibility directed standard 
of care will be analyzed descriptively.  
2.2.  Study Objectives  
Primary Objective:    
The primary objective is to assess the effectiveness of RHB-105 to eradicate H. pylori as 
indicated by 13C UBT for H. pylori.  
 
Secondary Objective: 


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The primary endpoint, the occurrence of H. pylori eradication, will be examined within subgroups 
of subjects formed by the occurrence of antibiotic resistance and susceptibility prior to therapy. 
  
Safety Objective   
The safety objective is to assess the safety profile of RHB-105.  
  
  
3.  STUDY DESIGN   
This is a randomized, double blind, active comparator controlled study of RHB-105 in adult 
subjects complaining of epigastric discomfort that have been screened and found to be positive 
for H. pylori infection via 13C UBT and follow up upper endoscopy (culture, histology or urease 
test).  All subjects who meet inclusion and exclusion criteria and have positive13C UBT will 
undergo upper endoscopy with three biopsies taken from each of the antrum and corpus of the 
stomach.  One biopsy from both the corpus and antrum will be combined and tested for H. pylori 
via a rapid urease test at the point of care.  One biopsy from both the corpus and antrum will be 
combined and sent for H. pylori testing at the central histology laboratory.  One biopsy from both 
the corpus and antrum will be combined and sent to the central laboratory for H. pylori culture 
with susceptibility testing assessing amoxicillin, clarithromycin, metronidazole and rifabutin.  
Subject specific pretreatment culture susceptibility and resistance results will be provided to the 
investigator in those subjects who fail to eradicate H. pylori upon post treatment 13C UBT 
analysis.  All other susceptibility results will remain blinded until study completion.  The active 
comparator arm is expected to demonstrate an approximate 70% efficacy rate and RHB-105 is 
being investigated for superiority with an expected approximate 83% efficacy rate.  
 
The study will be conducted at up to 65 sites in the USA. Once informed consent has been 
obtained and upon positive screening and enrollment into the study, eligible subjects will be 
randomized in a ratio of 1:1 between active comparator arm (n=222 and the active 
investigational arm (RHB-105) (n=222). Subjects will receive RHB-105 or active comparator 
(RHB-105-LT) for 14 days.   Eradication of H. pylori infection will be determined based on 13C 
UBT testing conducted between 43 and 71 days after initiation of therapy.  
 
Subjects who fail to eradicate H. pylori upon post treatment 13C UBT analysis will receive 
investigator prescribed susceptibility directed therapy based on culture and sensitivity results 
from biopsy samples prior to therapy.  The investigator may prescribe local standard of care 
therapy if susceptibility results are not contributory or are unavailable. These subjects will also 
undergo repeat endoscopy to assess changes in susceptibility and resistance.  All information 
related to therapy including drugs, doses and duration administered will be collected, and 
subjects will be reassessed for eradication of H. pylori 28 - 60 days following completion of 
therapy, ideally between 43 and 71 days after initiation of therapy.  Susceptibility data will only 
be provided for those subjects who fail to eradicate H. pylori.  


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4.  STUDY ENROLLMENT AND WITHDRAWAL   
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject.   
 
4.1  Inclusion Criteria 
The subject must meet all of the following criteria to be eligible for inclusion in the double-blind 
phase of the trial: 
1. Be ages 18 – 70, inclusive; non-Asian males and females (This population has been 
demonstrated to have significantly elevated omeprazole levels as per the prescriber 
information for other omeprazole products). A person having origins in any of the original 
peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example, 
Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam should be considered Asian, and forr this study Asian is defined as having at 
least one Asian grandparent (Shektar et al, 2014, FDA Guidance for Industry 2016) 
2. Positive for H. pylori by 13C Urea Breath Test (UBT) and confirmed positive via gastric biopsy 
for CLO (Rapid Urease Test), or H. pylori culture or histology; 
3. Symptoms consistent with dyspepsia of at least two weeks duration (defined as recurrent pain 
or discomfort centered in the upper abdomen, often with a relation to meals); 
4. Females must not be pregnant or lactating and:  
a. at no risk of pregnancy for one of the following reasons: postmenopausal for at least 
one year from the date of informed consent, status post hysterectomy or tubal ligation, 
OR  
b. are prepared to and agree to use of an intrauterine device (IUD) or practice double 
method birth control (barrier plus spermicide) from screening through to 30 days post-
end of-treatment (EOT); Acceptable double contraceptive methods include Barrier 
(condoms or diaphragms) plus spermicide  
c. Hormonal contraceptives (birth control pills and hormone implants) are not acceptable 
contraception methods under this protocol.   
5. Males must be surgically sterilized or are prepared to and agree to practice double method 
(barrier plus spermicide) birth control from screening through to 30 days post-EOT;  
6. Agrees to refrain from consuming alcohol from 1 week prior to screening to Test of Cure/Visit 
5; 
7. Agree to refrain from taking antacids from screening through day 15  and for at least 24 hours 
prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior to Visit 8/Test of Cure;  


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8. Agree to refrain from taking H2 blockers at least 24 hours prior to screening 13C UBT and at 
least 24 hours prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior to Visit 
8/Test of Cure 
9. Agree to refrain from taking sucralfate from one week prior to screening through Test of 
Cure/Visit5. 
10. Agrees to refrain from taking bismuth containing medications such as Pepto-BismolTM or other 
proton pump inhibitors (PPIs) from two weeks prior to screening through Test of Cure/Visit 5; 
11. Agrees to refrain from consuming grapefruit, or any other food or supplement known to 
significantly affect CYP3A4 or CYP2C19 activity from screening to day 15;  
12. Provide written informed consent to participate as shown by a signature of subject on the 
consent form. 
4.2  Exclusion Criteria  
The subject must be excluded from the double-blind phase of the study for any of the following 
reasons:  
1. Have alarm symptoms/signs (including unexplained anemia [iron deficiency], melena / 
hematemesis, anorexia, dysphagia, jaundice, weight loss);  
2. Have received prior H. pylori eradication therapy;  
3. Use of antibiotics in the 4 weeks immediately prior to screening 13C UBT;  
4. Use of any proton pump inhibitors (PPIs) or bismuth-containing medications (such as Pepto-
BismolTM) within the 2 weeks immediately prior to screening 13C UBT;  
5. Use of any of the following medications within seven days prior screening: alfentanil, 
allopurinol, amlodipine, anti-herpes agents, anti-retroviral agents, apixaban, aprepitant, 
aripiprazole, astemizole, atorvastatin, boceprevir, buspirone, carbamazepine, cisapride, 
citalopram dosed greater than 20 mg /d, clomipramine, clopidogrel and other oral 
anticoagulants, colchicine, dapsone, dihydroergotamine, digoxin, diltiazem, ergotamine, 
felodipine, fluconazole, imatinib, hormonal contraceptives that are not exclusively 
norethindrone or norgestrel, imipramine, itraconazole, ketoconazole, lurasidone, lovastatin, 
mycophenolate mofetil, nifedipine, nisoldipine, nitrendipine, phenytoin, pimozide, probenecid,  
proguanil, quinine, roflumilast, terfenadine and voriconazole;  
6. Use of amiodarone;  
7. Presence of more than two active gastric and/or duodenal ulcers;  
8. History of gastric outlet obstruction; or hypersecretory state (e.g., Zollinger Ellison Syndrome);  
9. History of esophageal or gastric surgery, except for simple closure of perforated ulcer;  
10. History of gastric cancer;   


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11. History of malignancy within the past five years except for basal cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been treated with no evidence of recurrence. 
12. Positive screening laboratory results for human immunodeficiency virus (HIV) antibody (HIV1 
or HIV2), or hepatitis B surface antigen (HBs Ag), or hepatitis C antibody (HCV Ab), unless 
patient has documented sustained viral response evidenced by prior and/or current absence 
of viral RNA at least 24 weeks after completing antiviral therapy;  
13. Current drug or alcohol abuse or history of drug or alcohol abuse in the past 5 years from 
screening;  
14. Known hypersensitivity or suspected history of hypersensitivity reactions to any of the study 
drugs or related drugs, including cephalosporins and penicillin;  
15. Clinical evidence of any disease that in the opinion of the investigator might interfere with the 
subject’s ability to participate in the trial;   
16. History of QT prolongation (QTc greater than 450ms in males and 460ms in females), or 
ventricular arrhythmia, including torsades de pointes;  
17. AST or ALT >3x ULN, or APO4 >2x ULN, or TB >2x ULN.  Subjects with confirmed diagnosis 
of Gilbert’s Syndrome are excluded if TB > 2.5x ULN; 
18. Unable to communicate well with the Investigators and to comply with the study requirements; 
19. Involved in any other experimental drug or device protocol (outside of this RHB-105-02 study) 
within the 4 weeks immediately prior to screening visit through end of study. 
20. Subjects with creatinine clearance less than 30 ml/min at screening via estimated Cockcroft-
Gault formula (eCGF):  
eCGF or estimated creatinine clearance = [140 - age in years] * weight (kg) / 72 * Serum 
Creatinine (mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight 
at screening.  
 
No waivers will be provided during the conduct of this study.  Subjects may be 
rescreened following discussion with medical monitor. Rescreens must be treated like a 
newly screened patient with a new consent and new screening number.  
 
4.3 Treatment Assignment Procedures 
A list of subjects screened but deemed ineligible will be maintained indicating reason(s) for 
exclusion.  
  
Treatment assignments will be based on a centralized computer-generated randomization 
scheme using permuted block randomization without additional stratification.    
  
Each subject will have a randomization code assigned that corresponds to treatment assignment 
and a unique identifier for drug packaging purposes. Once a subject number and treatment have 


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been assigned to a subject, the subject identification number cannot be reused even if the 
subject discontinues the study early or withdraws prior to receiving any study medication. 
Subjects who discontinue from the study or who have previously participated in the study will not 
be permitted to re-enroll. Subjects may be rescreened if endoscopic results for H pylori are 
unavailable during the screening window. Subjects will be randomized to one of the following 
groups:  
 
Treatment Arms:  
 
4.3.1 Randomization Procedures  
Subjects will be assigned to treatment using permuted block randomization without additional 
stratification. 
4.3.2 Post-treatment Standard of Care   
Subjects who fail to eradicate H. pylori will receive susceptibility directed standard of care 
therapy as prescribed by the treating investigator based on initial pretreatment results, and will 
undergo upper endoscopy with culture to assess changes in susceptibility and resistance. The 
investigator may prescribe local standard of care therapy if susceptibility results are not 
contributory or are unavailable.  Susceptibility data will only be provided for those subjects who 
fail to eradicate H. pylori. 
4.3.3 Reasons for Discontinuation of Study Treatment 
Subjects may be withdrawn from treatment at any time for the following reasons:  
• 
Withdrawn consent by the subject to continue receiving study medication 
• 
Any safety issue leading to inability to continue on study drug  
• 
Lost to follow up  
• 
Administrative decision of investigator or sponsor that It is compulsory to remove                 
the subject from the study 
• 
If the subject becomes pregnant  
Subjects discontinuing treatment will continue with routine study visits unless the subject 
requests that follow-up be discontinued. 
 
444 
Subjects 
Randomized 
Arm 1 
222 Subjects 
RHB-105 
Arm 2 
222 Subjects 
Active Comparator 


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4.3.4  Handling of Withdrawals  
Maximal effort will be made to follow up with all subjects starting study treatment. These subjects 
will be strongly encouraged to attend post treatment 13C UBT visits to undergo primary efficacy 
analysis.   
4.3.5  Premature Termination or Suspension of Study   
The sponsor reserves the right to temporarily suspend or prematurely discontinue this study or 
individual study sites.   
  
The reasons that the sponsor may terminate the study or clinical sites include, but are not limited 
to, any of the following reasons:  
• 
Development of unexpected laboratory toxicities which preclude further investigation 
of the investigational product  
• 
Reporting of unexpected serious adverse events (SAEs) which preclude further 
investigation of the investigational product  
• 
The observation of any new third-party findings related to any of the active agents 
which would preclude further investigation of the investigational product  
• 
The sponsor’s inability to provide sufficient resources to continue the investigation  
  
If this study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. Each Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Board (REB)/Helsinki Committee 
will also be informed promptly and provided the reason(s) for the termination or suspension by 
the sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).  
  
If the investigator terminates or suspends the study without prior agreement of the sponsor, the 
investigator must inform the institution, where required by the regulatory requirements and the 
investigator/institution must promptly inform the sponsor and the IRB/IEC/REB/Helsinki 
Committee, and should provide the sponsor and the IRB/IEC/REB/Helsinki Committee a detailed 
written explanation of the termination or suspension. If the IRB/IEC/REB/Helsinki Committee 
terminates or suspends its approval/favorable opinion of the study, the investigator should inform 
the institution, where required by the applicable regulatory requirements, and the 
investigator/institution should promptly notify the sponsor and provide the sponsor with a 
detailed written explanation of the termination or suspension.   


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5.  INVESTIGATIONAL PRODUCT  
5.1 Study Drug Description  
5.1.1 Formulation, Packaging, and Labeling  
The study drug will be manufactured in accordance with Good Manufacturing Practices (GMP) 
guidelines. The required quantity of blinded formulation, either RHB-105 or active comparator, 
will be encapsulated in opaque capsules to prevent identification.   
  
The necessary quantity of capsules will be prepackaged in high-density polyethylene (HDPE) 
bottles with child-resistant closures.    
  
The study drug, packaged by-subject in accordance with the randomization code, will be labeled 
in accordance with US FDA requirements for clinical trial supplies.  
  
The Investigator will have access to perform emergency unbinding through the IWRS system in 
order to determine what treatment arm the patient was assigned.  
5.1.2 Study Drug Storage and Stability  
All study drug is to be stored at temperature up to 25°C (77°F), with excursions permitted to 15-
30°C (59-86°F) (see USP Controlled Room Temperature).  Each study drug kit will include two 
bottles containing either RHB-105 or active comparator.  Each of the bottles will contain 100 
capsules (adequate study medication for 8 days).  
 
Riboflavin will be provided in bottles of 20 tablets according to the manufacturer’s instructions 
and labeled in accordance with US FDA requirements.  
5.1.3  Supply, Handling, and Accountability   
The sponsor will be responsible for supplying the investigators/institutions with the study drug. 
The study drug will be supplied once the sponsor obtains all required documentation from the 
study site. The sponsor will ensure timely delivery of investigational product(s) to the 
investigator(s) and maintain records within IWRS that document shipment, receipt, disposition, 
return, and destruction of the study drug.  
  
The qualified/principal investigator (PI) is responsible for study drug accountability, reconciliation, 
and record maintenance at his/her site. The PI or designated trained study site personnel will 
document all aspects of drug receipt, inventory, dispensing, return, reconciliation, and shipment 
within IWRS.  
  


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All study drug must be kept in a locked area with access restricted to designated study 
personnel. At the baseline visit a full course of study medication will be dispensed. A list of the 
exact supply of study drug dispensed to each subject at each visit will be included in the supplied 
drug accountability log that will need to be completed at each study visit and maintained within 
EDC. All product containers, with and without residual study drug, will be returned by the subject 
to the clinic in the packaging in which it was provided to the subject. The investigator or 
delegated staff will reconcile all capsules returned with those recorded as being dispensed and 
account for any inconsistencies in writing in the drug accountability log or similar document 
maintained in the investigator study file/Pharmacy Manual. The site monitor will routinely check 
the supplies of study drug to ensure accountability of all study medication used and record 
findings within EDC.   
  
At the conclusion of the study, all unused study drug and all bottles will be returned to the 
sponsor. The sponsor will ensure that a final report of drug accountability is prepared and that 
unused medications are appropriately destroyed.  
5.2  Dosage and Administration of Study Drug   
The intended dose of RHB-105 (12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole) is 
4 capsules every eight hours, equivalent to 50 mg rifabutin, 1000 mg amoxicillin and 40 mg 
omeprazole for a total daily dose of:  
 
• 
Rifabutin 150 mg    
• 
Amoxicillin 3000 mg  
• 
Omeprazole 120 mg  
  
The intended dose of active comparator is (250 mg amoxicillin, and 10 mg omeprazole) 4 
capsules every eight hours, equivalent to 1000 mg amoxicillin and 40 mg omeprazole for a total 
daily dose of:  
• 
Amoxicillin 3000 mg  
• 
Omeprazole 120 mg  
 
Study treatment will be taken orally every 8 hours with food for 14 consecutive days beginning 
on Day 1. Subjects may begin their study drug intake in the afternoon or evening of the first 
study day. In these cases, the study treatment may extend to 15 days to complete the full course 
of the treatment (42 doses, 168 capsules). Subjects will be instructed to take 4 capsules every 8 
hours at approximately the same time each day.    
  
The first morning dose is to be taken as soon upon awakening, with food. The next dose should 
be taken 8 hours later with food and the last dose 8 hours later or before going to bed if that is 
closer, again with food.  
  


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Example of  
Administration Times  
RHB-105  
Active Comparator  
6 AM  
4  
4  
2 PM  
4  
4  
10 PM  
4  
4  
 
 
Any missed dose must be taken as soon as possible and no later than within 2 hours of the next 
scheduled dose.  Subjects should maintain their regular dosing schedule in all situations.   
Subjects are to be instructed to and are expected to note the date and time of their last dose 
prior to Visit 3.   
 
All subjects will be provided with riboflavin 50 mg tablets to be taken once daily throughout the 
14-day study period. Subject may take riboflavin for up to 15 days if the study drug dosing 
schedule requires 15 dosing days.  This should be taken with the morning dose of study drug but 
can be taken with afternoon or evening doses if not taken with the AM dose.  
5.3  Assessment of Subject Compliance with Study Drug  
Subjects will be instructed to bring the remainder study drug and all empty packaging to each 
clinic visit. Compliance will be assessed by capsule counts, conducted by the investigator or 
delegate at each visit. Details will be recorded and reconciled against expected study drug use. 
Compliance will be calculated as a percentage (%) of expected usage in the final analysis and 
the capsule count will be entered on the appropriate page of the case report form (CRF) at each 
applicable study visit.  
5.4  Past Medical History, Concomitant Illnesses and Medications  
5.4.1  Past Medical History  and Concomitant Illnesses  
Past medical history and concomitant illnesses present at the time of informed consent, will be 
will be documented on the appropriate pages of the CRF (see Section 7.3.1, Adverse Events).  
5.4.2  Concomitant Medications  
 
All concomitant and rescue medications will be recorded on the CRF as to the identity of the 
agent (trade and generic names), start date, dose, route, reason for use, and stop date. No 
concomitant medication should be started or stopped without the instructions of the investigator.  
 
All medications being taken by the subjects from the time of informed consent signature until the 
last study visit are regarded as concomitant medications and must be documented preferably by 
generic name on the appropriate pages of the CRF.  


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Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the subject’s welfare and are not likely to interfere with the study, they 
may be given at the discretion of the Investigator.  
5.4.3 Prohibited Medications   
Subjects will not consume grapefruit or any other food or supplement known to significantly 
affect CYP3A4 or CYP2C19 from screening through study day 15.   
 
Subjects will not consume alcohol from one week prior to screening through study Visit 5. 
  
Subjects will not take any antibiotics in the 4 weeks immediately prior to screening 13C UBT visit 
and through Visit 5 except for the study medications.  
  
Subjects will not take any bismuth-containing medications (such as Pepto-Bismol) or proton 
pump inhibitors (PPIs) within the 2 weeks immediately prior to screening 13C UBT through Visit 
5.  
  
Subjects will not take any sucralfate containing medications within one 1 week immediately prior 
to screening through Visit 5. 
  
Subjects will not take any H2 blockers for at least 24 hours prior to any 13C UBT collection 
(Screening, Test of Cure/Visit 5 or Visit 8). 
 
Subjects will not take any antacids from screening through study day 15 and for at least 24 hours 
prior to Test of Cure/Visit 5 and if applicable at least 24 hours prior to Visit 8/Test of Cure; 
     
Subjects will not take any of the following medications through visit 3: alfentanil, allopurinol, 
amlodipine, anti-herpes agents, anti-retroviral agents, apixaban, aprepitant, aripiprazole, 
astemizole, atorvastatin, amiodarone, boceprevir, buspirone, carbamazepine, cisapride, 
citalopram dosed greater than 20 mg /d,  clomipramine, clopidogrel and other oral 
anticoagulants, colchicine, dapsone, dihydroergotamine, digoxin, diltiazem, ergotamine, 
felodipine, fluconazole, imatinib, imipramine, itraconazole, ketoconazole, lurasidone, lovastatin, 
mycophenolate mofetil, nifedipine, nisoldipine, nitrendipine, phenytoin, pimozide, probenecid, 
proguanil, quinine, roflumilast, terfenadine and voriconazole. 
  
Hormonal contraceptives that are not exclusively norethindrone or norgestrel are prohibited 
through visit 3 and subjects on norethindrone or norgestrel contraception may continue these 
medications but must practice double method contraception. 
  
If a subject is discovered to have taken a prohibited medication after screening, the Investigator 
should immediately consult the Medical Monitor or his/her designee and the Medical Monitor will 


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discuss with the sponsor as appropriate.   Subjects will not be discontinued from study treatment 
due to use of prohibited medications unless there is a safety concern. 
5.4.4  Warning for CYP Interacting Medications  
RHB-105 is a CYP3A4 inducer and substrate as well as a CYP2C19 substrate.  Active 
comparator is a CYP2C19 substrate.  Subjects receiving CYP3A4 and CYP2C19 interacting 
drugs may have diminished or elevated plasma levels of these medications and should be 
monitored for potential interactions and clinical effects.  See Appendix 4 for a listing of CYP3A4 
and CYP2C19 interacting drugs.  


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6.  STUDY SCHEDULE   
6.1  Visit 0 - Screening    
Subjects will be assessed for study eligibility during the screening visit (Day -42 to 0). The 
following study procedures will be performed at the screening visit:  
• Provide subject with study information and obtain subject informed consent and 13C UBT 
patient information sheet 
• Assessment of individual inclusion/exclusion criteria  
• Basic subject demographic information  
• Medical history  
• Physical examination including vital signs  
• Concomitant medication assessment  
• Hematology, biochemistry and urinalysis testing  
• Electrocardiogram (ECG)  
• Urine pregnancy test on all females of child-bearing potential  
• 13C UBT following a one hour fast (no liquid or solid intake)  
• Hepatitis B surface antigen and hepatitis C antibody  
• HIV1 and HIV2 antibody  
• Schedule of upper endoscopy for  
o Determination of presence of H. pylori via CLO, culture or histology - results must 
be available by Baseline (V1)/Day 1 Visit  
o H. pylori culture with susceptibility testing (to amoxicillin, clarithromycin, 
metronidazole, and rifabutin) – results to be blinded until study completion except 
in those subjects who fail to eradicate H pylori at visit 5 or who fail eradication at 
Visit 8 Standard of Care 
Only upon successful completion of all screening activities including review of safety data and 
13C UBT, will subjects undergo scheduled upper endoscopy. 
6.2  Visit 1 - Baseline - Day 1  
At visit 1, the subject’s eligibility will be confirmed. Eligible subjects will then be enrolled in the 
study and randomized to a treatment arm.   
  
The following study procedures will be performed at Visit 1 (Baseline):  
• Review of inclusion/exclusion criteria   
• Medical history 
• Physical examination with vital signs 
• Concomitant medications assessment 
• Urine pregnancy test on all females of child-bearing potential 


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• Adverse event assessment (captured for descriptive purposes prior to drug 
administration) 
• Randomization 
• Blood sample will be collected to assess CYP2C19 genotyping   
• Blood sample will be collected for PK assessment of pretreatment amoxicillin, 
omeprazole, rifabutin, and 25-O-desacetyl-rifabutin plasma levels prior to initial dose   
• Dispense paper and electronic diaries and instruct subject on how to complete the diaries 
(record daily time of administration of each dose and any other concomitant medications 
taken every day)  
• Study drug dispensing (study drug to begin on Day 1)  
6.3  Visit 2 - Telephone follow-up - Day 8 (+ 1 day)  
Telephone Call to Stress Compliance, Remind Subjects to Report Adverse Events, 
Note the Time of Last 3 Doses Administered Prior to Next Visit, and Reiterate the 
Importance of attending next study visits.  
 
6.4  Visit 3 - Safety Visit - Day 13 (+ 2 days)  
The following study procedures will occur at visit 3:  
• Physical examination with vital signs  
• Concomitant medication assessment  
• Urine pregnancy test on all females of child-bearing potential  
• Blood samples will be collected for PK and timed in relation to most recent dose of study 
drug to assess plasma levels of amoxicillin, omeprazole, rifabutin, and 25-O-desacetyl-
rifabutin   
• Hematology, biochemistry and urinalysis testing  
• Assess diary and record date and time of last three most recent doses of study drug  
• Adverse events assessment  
• Subject reminded that antibiotics, bismuth, and PPI are prohibited through Visit 5 and that 
H2 blockers are prohibited at least 24 hours prior to Visit 5  
• Study drug accountability/compliance and review of last day/s of scheduled drug 
administration if not day 15 
o Subjects seen prior to Day 15 will be instructed to return their study drug upon 
completion of full 14-day course of therapy and compliance will be finalized at that 
time 
6.5  Visit 4 - Telephone follow-up - Day 28-60 (+ 2 days)   
Telephone Call to Stress Importance of Follow-Up 13C UBT Testing (at least a 1 
hour fast – no liquid or solid intake) and Remind of Upcoming Appointment and 


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Adverse Event Assessment.  Subjects will be reminded that antibiotics, bismuth, 
and PPI are prohibited through Visit 5 and that H2 blockers are prohibited at least 
24 hours prior to Visit 5. 
6.6  Visit 5 – Test of Cure - Day 43 - 71 (+ 7 days)  
The following study procedures will occur at visit 5:  
• Physical examination with vital signs 
• Concomitant medication assessment with specific question related to antibiotic use, 
bismuth, PPI or H2 blockers 
• Urine pregnancy test on all females of child-bearing potential 
• Follow-up hematology, biochemistry and urinalysis testing in subjects with clinically 
significant abnormal results at Visit 3 
• 13C UBT following a one hour fast (no liquid or solid intake)   
• Adverse events assessment  
• Study drug accountability/compliance if not performed to date 
 
Exceptional Visit 5 due to pregnancy 
In the event a female subject becomes pregnant during the course of the double-blind phase of 
the study and refuses to undergo the 13C UBT assessment, then a fecal antigen test may be 
performed at the local lab. Results of the fecal antigen test will substitute for the 13C UBT test of 
cure for this subject in all efficacy analyses.   
 
6.6.1 Visit 5A – 13C UBT Telephone Follow-up - Day 44 – 72 (+7 days)  
This visit will be performed after Visit 5 13C UBT test results have been received.  Delays in visits 
due to delayed results will not be considered protocol deviations.  
• Study site personnel will contact subjects following 13C UBT test results reporting and 
arrange for follow-up care  
o Subjects with positive 13C UBT test results will be scheduled for upper endoscopy 
to be performed at visit 6, with H. pylori culture with susceptibility testing (to 
amoxicillin, clarithromycin, metronidazole, and rifabutin)  
o Subjects with negative 13C UBT test results will be noted to have completed the 
study and will be informed that Visit 5 is considered their End of Study Visit.  
6.7  Visit 6 – Standard of Care Baseline Visit - Endoscopy After Day 44-72 
(+14 days)  
Subjects who are determined to be 13C UBT positive post treatment with investigational drug will 
undergo upper endoscopy, with sampling for H. pylori culture and susceptibility testing to 
amoxicillin, clarithromycin, metronidazole, and rifabutin.    


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The following study procedures will occur at Standard of Care visit 6:  
• Assess vital signs 
• Concomitant medication assessment 
• Urine pregnancy test on all females of child bearing potential 
• Susceptibility directed initiation of standard of care therapy based on initial culture results 
for subjects  
• Endoscopy with biopsy for H. pylori culture and susceptibility  
• Schedule Visit 8 for 13C UBT (Standard of Care Test of Cure visit), remind subject that 
he/she must be tested following at least a one hour fast (no liquid or solid intake) and that 
he/she should not take PPI, antibiotics, bismuth through Visit 8 or H2 blockers 24 hours 
prior to Visit 8.  
6.7.1 Visit 7 - Standard of Care Telephone follow-up - Day 50-79 (+ 2 days) 
• Telephone Follow-up to Stress Compliance, Follow-up and Schedule 13C UBT Testing (at 
least a 1 hour fast – no liquid or solid intake) and reminded that antibiotics, bismuth, and 
PPI are prohibited through Visit 8 and that H2 blockers and antacids are prohibited 24 
hours prior to Visit 8 
6.8 Visit 8 - Standard of Care Test of Cure - Day 85 - 140 (+ 14 days) 
•  Post treatment 13C UBT Testing 
6.9 Early Termination Visit  
In the event of an early termination for any reason, the investigator will perform all procedures as 
described for Visit 5. All subjects will be asked to return for post treatment 13C UBT assessment 
28-60 days after last dose of study drug, ideally between 43 and 71 days after initiation of study 
drug.  Every effort will be made to obtain 13C UBT assessment as this is the primary efficacy data 
point.  The investigator will record the reasons for any early termination or deviation from required 
procedures within the CRF.  
 
All subjects who early terminate from the study, during a clinic visit or 
hospitalization for SAE (if possible), while in the 14-day course of study drug 
administration, will have amoxicillin, omeprazole, rifabutin, and 25-O-desacetyl-
rifabutin levels drawn at that date with best efforts made at capturing exact date 
and time of most recent study drug administration. 
6.9.1 Unscheduled Visit   
If, in the investigator’s opinion, the subject for medical reasons is required to be seen outside of 
the proposed visit schedule, then an unscheduled visit may be performed. Additional CRFs will be 


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provided to accommodate such visits. Activities at these visits will be dependent upon the 
investigator’s concerns. The investigator will record the reasons for the unscheduled visit.   


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7.   STUDY PROCEDURES/EVALUATIONS  
7.1  Clinical Evaluations  
  
The following clinical evaluations will be conducted according to the study schedule described in 
Appendix 2:  
  
Screening  
An initial assessment of subject demographics, review of ICF, inclusion/exclusion criteria and        
concomitant medications will be conducted.  
  
Upper Endoscopy and biopsies 
All subjects who meet inclusion and exclusion criteria and have positive 13C UBT will undergo 
upper endoscopy with three biopsies taken from each of the antrum and corpus of the stomach.   
 
One biopsy from both the corpus and antrum will be combined in a single container and tested for 
H. pylori via a rapid urease test at the point of care.  Rapid urease tests (CLO) must be 
completed within 24 hours of sample collection.   
 
One biopsy from both the corpus and antrum will be combined in a single container and sent for 
H. pylori testing at the central histology laboratory.   
 
One biopsy from each the corpus and antrum will be combined in a single container and sent to 
the microbiology central laboratory for H. pylori culture with susceptibility testing assessing 
amoxicillin, clarithromycin, metronidazole and rifabutin prior to therapy and after therapy in those 
subjects with persistent positive 13C UBT  
 
All samples should be handled as detailed within the laboratory manual.  
 
Post treatment endoscopies in subjects with persistent positive 13C UBT will require two biopsies 
– one from each of the antrum and corpus.  These will be combined in a single container and sent 
to the microbiology central laboratory for H. pylori culture with susceptibility testing assessing 
amoxicillin, clarithromycin, metronidazole and rifabutin following treatment with RHB-105. 
 
Laboratory Testing  
Includes hematology, chemistry, pregnancy test, urinalysis, viral serologies, H. pylori status,  
and PK assessment of amoxicillin, omeprazole, rifabutin, and 25-o-desacetyl-rifabutin.  
  


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Medical History  
An initial medical history will be obtained during the interview with the study subject to evaluate 
the subject’s suitability for consent and baseline assessment. At baseline, a focused follow-up 
medical history and related medications will be obtained by interview and review of medical 
records. Medical history should include review of the inclusion/exclusion criteria, and ensure that 
current medications are not prohibited or unstable in dose.  Medical histories obtained during 
standard of care treatment will assess subjects for non-treatment emergent adverse events, drug 
compliance, and concomitant medications via direct questioning.  
  
 
 
Physical Examination   
A physical examination will non-invasively assess the subject’s major body systems: general 
appearance, head/eyes/ears/nose/throat, neck, lungs, heart, abdomen, genitourinary, if clinically 
indicated, extremities, neurological, skin, and lymphatics.  
  
Vital Signs   
Vital signs will be recorded - height, weight, respiratory rate, temperature, supine blood pressure 
and pulse. Height measurement should be measured once during the screening visit. All other 
vital signs measurements should be measured as detailed in the study schedule.  
  
Electrocardiogram (ECG) 
An ECG will be performed at the screening visit.  
 
Diary  
Diaries will be used by subjects to note missed doses, concomitant medications, and          
adverse events or changes in well-being while administered study drug.  
  
Drug Compliance  
Study drug compliance will be based upon capsule counts after return of drug and final drug 
accountability.  
7.2  Efficacy Evaluations  
7.2.1 13C Urea Breath Test   
The 13C UBT (BreathTek®, Otsuka America Pharmaceutical Inc.) will be conducted at screening 
visit, visit 5 and visit 8 if applicable.  This will be used to verify H. pylori status prior to study drug 
administration and to determine if H. pylori has been successfully eradicated. Subjects will be 
asked to fast (no liquid or solid intake) for at least 1 hour prior to their visit. They must not have 
had any other antibiotics for 4 weeks prior to screening through test of cure Visit5 and Visit 8, or 
proton pump inhibitors or bismuth preparations two weeks prior to screening through Test of cure 
Visit 5 or Visit 8 or H2 receptor antagonists or antacids 24 hours prior to any 13C UBT testing 
(screening visit, visit 5 and visit 8 if applicable). Step-by-step procedures are presented in the 
BreathTek® Package Insert (provided in the laboratory manual).   


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7.2.2  Laboratory Studies   
Pharmacogenetics  
Pharmacogenetic testing to assess cytochrome P450 (CYP) 2C19 status and effect on response 
to RHB-105 as well as relationship to pharmacokinetics.                  
7.3  Assessment of Safety  
7.3.1  Adverse Events  
7.3.1.1 Definition of Treatment Emergent Adverse Event  
Timely accurate and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of patients and is mandated by regulatory agencies worldwide. In 
this study a treatment emergent adverse event (TEAE) is defined as any unfavorable and 
unintended sign, symptom, physical finding or disease, whether or not believed to be related to 
the investigational product that arises after the first dose of study drug was administered. This 
includes any occurrence that was new in onset or aggravated in severity or frequency from the 
time the first dose of study drug was administered.   
 
Any event reported between signature of Informed Consent form and first dose of study drug will 
be considered medical history and will be reported as such.  
  
Abnormal results of diagnostic procedures, or laboratory test abnormalities, should also be 
considered as TEAEs, ONLY if they result in any of the following:   
• 
Discontinuation of study drug  
• 
Require treatment or any other therapeutic intervention and/or  
• 
Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality)  
 
All events, TEAEs and SAEs, regardless of severity or causality, that occur between the time of 
first study drug administration and within 28 days following the last dose of blinded study drug are 
to be documented on the adverse event case report form with indications of onset, duration, 
severity (mild, moderate, and severe), seriousness, relationship to study drug (unrelated, unlikely, 
possible, probable, definite), remedial actions taken, and outcome.  
  
All SAEs occurring during the administration of standard of care (SOC) drug are to be 
documented as SAEs on serious adverse event case report form (for SOC) with indications of 
onset, duration, severity (mild, moderate, and severe), relationship to SOC drug (unrelated, 
unlikely, possible, probably, definite), remedial actions taken, and outcome.  If the SAE is deemed 
to be related to any of the standard of care drugs, it is the responsibility of the investigator to 
report the event to the manufacturer of the related drug, through the manufacturer’s post-
marketing surveillance system. Determination of eradication of H. pylori infection will be based on 


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13C UBT testing done between 43 and 71 days after initiation of blinded therapy. Due to this delay 
in time of 28-60 days, any SAEs that occur during the SOC dosing period will NOT be considered 
related to the study treatment regimen of RHB-105 or Active comparator.    
  
A TEAE is considered associated with the use of the study drug if the attribution was possible, 
probable, or definite (see Appendix 3 for Definitions for Clinical and Laboratory Adverse Events). 
Abnormal laboratory values that qualify as TEAEs will be followed until repeat test results return 
to normal, stabilize, or are no longer clinically significant. Any positive pregnancy test result must 
be repeated, study drug withdrawn, and any pregnancy must be followed to term.  
7.3.1.2 Definition of Serious Adverse Event   
A serious adverse event or reaction is any untoward medical occurrence that at any dose:   
• 
results in death  
• 
is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe  
• 
requires inpatient hospitalization or prolongation of existing hospitalization  
• 
results in persistent or significant disability/incapacity  
• 
results in a congenital anomaly/birth defect  
• 
is considered medically significant  
  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of such medical events include those events requiring 
intensive treatment in an emergency room or at home, that do not result in inpatient 
hospitalization, or the development of drug dependency or treatment-related substance abuse.   
7.3.1.3 Definition of Unexpected Adverse Drug Reaction  
An adverse drug reaction is generally defined as all noxious and unintended responses to a 
medicinal product related to any dose. An unexpected adverse drug reaction is one that is not 
consistent with the current Investigator’s Brochure.   
7.3.1.4 Adverse Event/Serious Adverse Event Recording and Reporting  
Treatment-emergent adverse events (TEAEs) will be recorded up to 28 days after completion of 
the blinded study period in the source documents and in the CRFs. The occurrence of an AE may 
come to the attention of study personnel during study visits and interviews of a study recipient 
presenting for medical care, or upon review by a study monitor. Adverse events will be clinically 
assessed only by those with the training and authority to make a diagnosis and medical 


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evaluation, which would include an MD, Physician’s Assistant (PA), Nurse Practitioner, or Doctor 
of Osteopathy (DO).  
  
Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE or SAE when appropriate.   
  
All AEs and/or TEAEs including local and systemic reactions, should be captured on the 
appropriate CRF. The investigator will rate AEs for severity, causality, action taken, and outcome. 
Severity will be rated on a three-point scale as mild, moderate, or severe.  
• 
Mild is noticeable to the subject, does not interfere with the subject’s daily activities and 
usually does not require additional therapy or dose adjustment.  
• 
Moderate may interfere with the subject’s daily activities and may require additional 
therapy.  
• 
Severe may severely limit the subject’s daily activities and typically requires therapy or 
intervention.  
  
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of severity noted. Causality will be based upon medical assessment of 
the suspected relationship to the study medication.  
 
Relationship  Causality  Description  
Not related to 
investigational 
agent  
Unrelated  
The AE is clearly not related to the investigational agent.  
Unlikely  
The AE is doubtfully related to the investigational agent.  
Related to 
investigational 
agent  
Possible  
The AE may be related to the investigational agent.  
Probable  
The AE is likely to be related to the investigational agent.  
Definite  
The AE is clearly related to the investigational agent.  
 
AEs considered unrelated or unlikely will be deemed not related, and AEs considered possible, 
probable, or definite will be deemed related.   Any actions taken to ameliorate the AE will be 
recorded such as dose withdrawn, pharmacological intervention, and no action taken. Outcome 
will provide information as to whether the event was resolved, resolved with sequelae, or remains 
ongoing.   
  
Any SAE, including death from any cause that occurs during this investigation, whether or not 
related to the investigational drug, must be reported on the SAE pages of the CRF. In case of 
unavailability of electronic CRF, the SAE form provided must be filled out and send via fax to 
CRO Pharmacovigilance/Safety (contact details below) within 24 hours. In addition, CRO 
Pharmacovigilance/Safety group, including the medical monitor should be notified immediately for 
any death or life-threatening event believed to be possibly related to study drug.  


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Email SAEs to ICON Clinical Research icon-mads@iconplc.com 
SAE Hotline US ONLY: +1 888 723 9952 
 
Any change in well-being defined as any unfavorable and unintended sign, symptom, physical 
finding or disease that occurs following initiation of standard of care therapy will NOT be 
considered a TEAE.  This data will be captured via medical history for descriptive purposes only.   
  
Laboratory abnormalities in hematology or chemistry will be reviewed by the investigator for 
clinical significance and will be reported only if considered significant.  
      
  
Other supporting documentation of the event may be requested by the medical monitor and 
should be provided as soon as possible.  
  
Expedited regulatory reporting by the sponsor/medical monitor is required for serious unexpected 
adverse drug reactions. The time frame for reporting is as follows: for fatal or life-threatening 
unexpected drug reactions regulatory agencies will be informed no later than 7 days after the 
CRO or sponsor’s first knowledge of the reaction, followed by as complete a report as possible 
within 8 additional days. In the case of non-fatal, non-life-threatening unexpected drug reactions, 
these events must be reported no later than 15 days after the CRO or sponsor’s first knowledge 
of the reaction. All other SAEs that do not meet expedited regulatory reporting will be reported to 
the regulatory agencies at least annually in a summary format. This includes SAEs thought to be 
not related as well as expected, related SAEs and unexpected, not related SAEs.  
If expedited reporting is required (due to a safety event/ Serious Adverse Event reporting), the 
Pharmacovigilance/Safety representative will request emergency unblinding in order to comply 
with the FDA regulatory requirements, as described in the section 4.3.1, in order to include the 
subject’s treatment assignment within the report.  Only the CRO Pharmacovigilance/Safety 
representative will have access to the unblinded code; all other study personnel (including site 
personnel) will remain blinded.   
  
7.3.1.5 Adverse Event Follow-up  
AEs and TEAEs will be followed until resolution or the last study visit, whichever comes first. All 
SAEs will be followed until event resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the patient is lost to follow-up. The investigator is responsible for 
ensuring that follow-up includes any supplemental investigations as may be reasonably indicated 
to elucidate the nature and/or causality of the SAE. Any follow-up information regarding SAEs 
must be reported to within 24 hours.  
7.3.1.6 Reporting of Pregnancy  
Pregnancy occurring in a female subject, or in the partner of a male subject, must be reported to 
the sponsor. Pregnancies are considered immediately reportable (within 24 hours, and must be 


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captured up to 30 days after completion of the blinded study period) and are to be documented 
on the Pregnancy Form. In the event of pregnancy in a female subject, the investigational 
treatment will be immediately discontinued and treated in the way least likely to harm both subject 
and fetus. The investigator and/or primary care physician will follow the pregnancy to term, and 
document the maternal and fetal outcomes. This information will be provided to the sponsor as 
soon as possible thereafter.  
7.3.2  Clinical Laboratory Tests   
7.3.2.1 Identification of the Clinical Laboratory Tests  
Samples will be obtained for the laboratory tests listed in the following table according to the 
schedule in Appendix 2. Clinical laboratory tests (hematology, biochemistry, urinalysis, 
pharmacokinetic, genotyping, and gastric biopsy histology and microbiology) will be performed at 
a central laboratory. Central lab collections, processing and shipping will be detailed within the lab 
manual.  Urine pregnancy test and CLO testing will be performed at each local site. Tests 
performed at unscheduled visits will be at the discretion of the investigator.   
  
  


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Laboratory Assessments  
Hematology  
Clinical Chemistry  
Special Testing  
Urinalysis  
Hematocrit  
Hemoglobin  
Red blood cell (RBC) count  
White blood cell (WBC) count 
Neutrophils  
Bands Lymphocytes  
Monocytes Basophils  
Eosinophils  
Platelet count (estimate not 
acceptable)  
Blood urea nitrogen (BUN)  
Creatinine  
Total bilirubin (Direct and indirect fractionated) 
Lactate Dehydrogenase (LDH)  
Serum glutamic-pyruvic   transaminase 
(SGPT)/alanine  aminotransferase (ALT) 
Serum glutamic-oxaloacetic transaminase 
(SGOT)/aspartate  
 
aminotransferase (AST)  
Creatine phosphokinase  
eCGF or estimated creatinine clearance 
Alkaline phosphatase  
Sodium  
Potassium  
Chloride  
Gamma-glutamyltransferase (GGT)  
Bicarbonate  
Calcium  
Magnesium  
Inorganic phosphorus  
Amylase  
Uric acid  
Total cholesterol  
Total protein  
Glucose  
Albumin  
CYP 2C19 genotyping  
HBs Ag  
HCV Ab  
HIV1 antibody  
HIV2 antibody  
 
Pharmacokinetic  
testing for: 
amoxicillin, omeprazole, rifabutin, and 
25-O-desacetylrifabutin  
 
Urine pregnancy 
 
13C Urea Breath Test 
 
Culture and Resistance/ Susceptibility 
for H. pylori  
 
CLO – Chlamydia Like Organism 
(Rapid Urease Test) 
 
Histology for H. pylori 
  
 
Leucocytes  
Nitrite  
Protein  
pH  
Blood 
Specific gravity  
Ketones  
Glucose  
Sediment microscopy, If 
indicated by the dipstick  


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7.3.2.2 Recording of Clinical Laboratory Tests  
All laboratory values will be filed in the source documents. The lab report must be interpreted by 
the investigator (i.e., signed and dated with the clinical significance of any abnormal values 
indicated).  
  
Abnormal laboratory findings or other abnormal assessments (e.g., vital signs) that are judged by 
the investigator as clinically significant must be recorded as AEs or SAEs, if they meet the 
definition of an AE/SAE. The investigator should exercise his/her medical and scientific judgment 
in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Laboratory findings that are considered adverse or serious adverse events will be 
reported and followed-up in the same manner as previously described.  
7.4  Pharmacokinetic Evaluations  
Blood samples for the determination of pretreatment and Visit 3 plasma concentrations of 
amoxicillin, omeprazole, rifabutin, and 25-O-desacetyl-rifabutin will be collected as described in 
Sections 6.2 and 6.4.    The following will be recorded in the CRF: 
• 
Date and time of the three most recent doses of study drug before collection of PK sample  
• 
Date and time of collection of PK sample  
 
Time of blood sample collection will be noted and determined relative to most recent dose of 
study drug.  All PK samples will be collected and processed according to the procedure outlined 
in the laboratory manual. Plasma samples will be analyzed using validated methodology.   
  
Plasma concentration data for each analyte will be summarized through data tabulations and 
descriptive statistics. 
    
  
8.   STATISTICAL CONSIDERATIONS   
8.1 Analysis Populations  
8.1.1 Full Analysis Population (FAP) 
The full analysis population (based upon the intention-to-treat principle as described in ICH-E9) will 
include all subjects who received at least one dose of randomized study treatment and will be 
identical with the safety population.  
8.1.2 Modified Intent-to-Treat (mITT) Population  
The mITT population will include all subjects who received at least one dose of randomized study 
treatment and undergo a 13C UBT test at Visit 5.  


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8.1.3 Per Protocol (PP) Population  
The PP population will include all subjects who consume at least 75% of planned study treatment 
received and undergo a 13C UBT test at Visit 5.  
8.1.4 PK Population (PKP) 
The PKP will include those subjects in the full analysis population (FAP) that have demonstrable 
presence of any component of investigational drug at Visit 3. 
8.2 Statistical Analyses  
8.2.1  Primary Endpoint  
The primary efficacy endpoint in this study is eradication of H. pylori among subjects, 
documented by 13C UBT test results at the test of cure visit (Visit 5).  Subjects with negative test 
results will be considered treatment successes.  Subjects who test positive for H. pylori infection 
will be considered treatment failures.  Those subjects with indeterminate, not assessable, or 
missing results from actual test of cure visits will undergo repeat 13C UBT testing.  Persistent 
indeterminate results will be considered treatment failures. 
  
The primary endpoint will be assessed statistically in the full analysis population data set. The 
treatment groups will be compared with respect to the difference between the two treatment arms 
for the proportion of subjects with negative test results using a chi-squared test at the 5% level of 
significance (2-sided).  The primary analysis will be repeated using the mITT and PP populations 
as sensitivity analyses. 
 
Those subjects lost to follow-up or who fail to complete the test of cure visit will be excluded from 
the MITT and PP analyses.  All efforts will be made to obtain data from the test of cure visit for 
each subject receiving randomized treatment.  
8.2.2  Secondary Endpoints 
The secondary endpoints are as follows and will be assessed using descriptive measures: 
1) Antibiotic Resistance and Susceptibility Subgroup Analyses -  
The primary endpoint will be summarized within subgroups formed by the presence of H. 
pylori susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and rifabutin 
determined based upon samples obtained prior to initiating study treatment.  The proportion 
of subjects with failure to eradicate H. pylori and the treatment effect (difference in the 
proportions) will be estimated within each subgroup along with 95% 2-sided confidence 
intervals where there are an adequate number of subjects in the subgroup (e.g., at least 20 
subjects per subgroup). 
2)   Pharmacokinetics – The plasma concentrations of amoxicillin, omeprazole, rifabutin, and the 
rifabutin metabolite 25-O-desacetyl-rifabutin on Day 13 will be summarized by time following 
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3) Assess the difference in antibiotic resistance and susceptibility of H. pylori after treatment 
with study drug in treatment failure subjects 
 
 
8.2.3 Safety 
The occurrence and severity of treatment emergent adverse events during the study and 
changes from baseline in hematology and chemistry laboratory values 
8.2.4 Exploratory Endpoints  
1) Upon study completion and unblinding of all subjects, CYP2C19 status will also be 
summarized and subgroup analyses of efficacy based on CYP2c19 status and 
pharmacokinetics will be performed using descriptive methods.   
2)  Eradication rates in failure to eradicate subjects who receive susceptibility directed standard 
of care will be analyzed descriptively.  
8.3  Interim Analysis  
No interim analysis is planned for this study.  
 
8.4  Sample Size   
 
Sample size for this study has been calculated based on a superiority comparison assuming 83% 
effectiveness for the new treatment, and 70% effectiveness for the control, with 90% power and a 
2-sided alpha of 5%. Using these specifications, 222 subjects per arm will be required. 
 
9. QUALITY CONTROL AND QUALITY ASSURANCE  
RedHill Biopharma (RHB) and its CRO delegate shall implement and maintain quality control 
procedures in accordance with written standard operating procedures (SOPs) to ensure that the 
study, and specifically that the study data, are being generated, documented, and reported in 
compliance with the protocol, GCP and applicable laws and regulations. Central to the assurance 
of a high standard of quality of the data at the acquisition stage is study monitoring.  
  
During study conduct, RHB or its agent will conduct periodic monitoring visits to ensure that the 
protocol and GCPs are being followed. The monitors will review source documents to confirm that 
the data recorded on CRFs is accurate. The investigator and institution will allow RHB monitors or 
its agents and appropriate regulatory authorities direct access to source documents to perform 
this verification.  
  


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The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)/Research Ethics Committee/Helsinki Committee, and/or to quality 
assurance audits performed by RHB, or companies working with or on behalf of RHB, and/or to 
inspection by appropriate regulatory authorities.  
  
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.    
  
RHB reserves the right to temporarily suspend or prematurely discontinue this study or individual 
study sites based on the findings of quality assurance audits. If such action is to be taken, RHB 
will discuss the specific reasons with the investigator(s). The investigator(s) must inform their 
IRB/IEC/REB/Helsinki Committee in a timely fashion, and provide them with the reason for the 
suspension or termination.  
  
If the study is prematurely discontinued, all study materials and data must be returned to RHB 
once a final disposition assessment of all unused study drug and materials is performed, in 
accordance with the required study procedures.  
  
The investigator and RHB share the responsibility to ensure data quality and integrity. The 
investigator will personally ensure the quality of the data by overseeing all study activities, 
including the timely review of both source data and CRF data as transferred from source. The 
investigator, or medically responsible delegate, will sign and date a declaration for each CRF 
attesting to his/her responsibility for the quality of all data recorded, stating that the data 
represents a complete and accurate record of each subject’s participation in the study, and that 
the data has been medically reviewed in a timely fashion throughout the data acquisition period.  
  
All processes and procedures undertaken by RHB once the data have been sequestered from 
the investigational sites will be subject to a rigorous quality control program. This includes data 
management (Section 12), statistics (Section 8), and Medical Writing (ICH E3).  
 
10. ETHICS/PROTECTION OF HUMAN SUBJECTS  
10.1 Ethical Standard  
The sponsor, investigator, and institution will ensure that this study is conducted in full conformity 
with the principles set forth in the following documents and guidance:  
• 
the Declaration of Helsinki (Tokyo, 2004)   
• 
the Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research; The USA National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979)  
• 
the USA Code of Federal Regulations: 45 CFR Part 46, 21 CFR Parts 50, 56, and 312  


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• 
the Canadian Food and Drug Regulations F-27 – C.R.C., c. 870: Division 5 (C.05.)  
• 
ICH E6; Consolidated Guidelines on Good Clinical Practices (1997)    
• 
International Ethical Guidelines for Biomedical Research Involving Human Subjects 
(CIOMS, 2002)  
10.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Research Ethics Board (REB)/Helsinki Committee  
It is the investigator’s responsibility to ensure that this protocol is reviewed and approved by a 
properly constituted IRB/IEC/REB/Helsinki Committee that is functioning and operating in 
accordance with CFR Part 56 requirements and in accordance with the ICH GCP Guidelines in 
Section 3.2. The IRB/IEC/REB/Helsinki Committee must also review and approve the site’s 
informed consent form (ICF) and any other written information provided to the subject, as well as 
any advertisement that will be used for subject recruitment. The investigator or his/her designee 
must forward to RHB or its delegate, copies of the IRB/IEC/REB/Helsinki Committee study 
approval(s) and the approved informed consent materials, specific versions being duly identified 
and dated by the IRB/IEC/REB/Helsinki Committee as being approved (e.g., signed, stamped, 
electronic signature).  
  
If, during the study, it is necessary to amend the protocol and/or the ICF, or any other salient 
review documents, the investigator will be responsible for ensuring that the IRB/IEC/REB/Helsinki 
Committee reviews and approves these amended documents. IRB/IEC/REB/Helsinki Committee 
approval of the amended ICF must be obtained before new subjects can provide their consent to 
take part in the study using the revised versions of the form. Copies of all approvals must be 
forwarded to RHB or its’ delegates as soon as available.  
10.3 Informed Consent  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of this therapy will be provided to the study subject. Consent forms 
describing in detail the study interventions/products, study procedures, and risks are given to the 
subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. Consent forms will be IRB/IEC/REB/Helsinki Committee 
approved and the subject will be asked to read and review the document. Upon reviewing the 
document, the investigator will explain the research study to the subject as well as answer any 
questions that may arise. The subject will sign the informed consent document prior to any 
procedures being done specifically for the study.   
  
The subject should have reasonable opportunity to discuss the study with their family, physician, 
and/or surrogates prior to giving their consent to participate. The subjects may withdraw consent 
at any time throughout the course of the trial. A copy of the informed consent document will be 
given to the subject for their records.  


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In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic updates on the conduct of the study at his/her site to the IRB/IEC/REB/Helsinki 
Committee. Such timely periodic updates and notifications are the responsibility of the 
investigator.  
10.4 Subject Confidentiality  
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover the testing of biological 
samples and genetic tests, in addition to the clinical information relating to participating subjects. 
Any records sent to RHB will not identify the subjects. All subjects’ identities will be restricted to 
their initials and a unique subject number.  
  
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
  
The study monitor (or other authorized representatives of the sponsor), regulatory agencies or 
representatives of the IRB/IEC/REB/Helsinki Committee may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the subjects in this study. The clinical study site will 
permit access to such records.  
  
The confidentiality of personal health information has been the subject of recent laws and 
regulations in the US and Canada.  
  
In the US, investigators and their affiliated institutions that are considered covered entities (CE) 
under the Health Insurance Portability and Accountability Act (HIPAA) will request that the subject 
sign a fully informed authorization that will accompany the consent form. The authorization will 
include the Authorization Core Elements (see Privacy Rule, 45 CFR §164.508I(1)) and the 
Authorization Required Statements (see Privacy Rule, 45 CFR § 164.508(c)(2)). These activities 
are intended to ensure that subjects understand how their Protected Health Information (PHI) 
arising from this research study is to be handled. The Privacy Rule is an additional but similar 
obligation to those that have been required under the Department of Health and Human Services 
(DHHS) or the Food and Drug Administration (FDA) Protection of Human Subjects Regulations 
(e.g., 45 CFR part 46 or 21 CFR parts 50 and 56, respectively) to take measures to protect such 
PHI from inappropriate use or disclosure.  
  
The investigator’s and other study site personnel’s obligations do not apply to:  
• 
Information that becomes publicly available through no fault of the investigator or study 
site personnel;  


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• 
Information that it is necessary to disclose in confidence to an IRB/IEC/REB/Helsinki 
Committee solely for the evaluation of the study;  
• 
Information that it is necessary to disclose in order to provide appropriate medical care to 
a study subject; or   
• 
Study results that may be published as described under the Publication Section.  
10.5 Future Use of Stored Specimens  
The de facto assumption of the donor of any biomaterial is that nothing will be done in regards to 
any specimen(s) to his or her detriment, or to that of his/her family. To ensure that this is so, the 
consent form is central to the donor’s need to be apprised of certain details as to the fate of the 
sample. The investigator and REB/institution (specimen custodians) have an obligation to ensure 
that the subject is fully informed in this regard. To do so, the consent form will include the 
following information:  
• 
purpose of research on the biomaterial  
• 
type and amount of blood and tissue biopsies  
• 
manner in which blood/tissue will be taken, safety/invasiveness of procedure, and 
conditions/duration of preservation  
• 
potential uses for the blood/tissue  
• 
safeguards to privacy and confidentiality  
• 
identifying information and traceability (linkage)  
• 
how blood/tissue use could affect privacy  
  
In summary, all biological samples provided by the subject for the purposes of this study are to be 
used only for assessments and testing that have been explicitly agreed to in the consent form. 
The degree to which any retained samples will be protected for identification to a given individual 
will be specified.   
 
11. DATA HANDLING AND RECORD KEEPING  
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. CRO will be responsible for the design of the electronic case report form 
(eCRF), monitoring the trial according to GCP guidelines, preparation of data queries and reports 
to assist the clinical monitoring, and training each study site staff member entering data in the 
eCRF.  CRO will also be responsible for preparation of analysis files from the database prior to 
analyses, assisting with the statistical analyses and statistical report, and preparation of the 
integrated clinical study report.  
11.1 Documentation of Data   
The electronic data capture (EDC) will be used for electronic data acquisition and storage.  EDC 
will provide eCRFs for transfer of all research data by site personnel from data source 


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documentation to the study database.  Each responsible person at a site will have user access to 
EDC through their unique username and password, with permissions providing each person their 
needed access.  Some personnel will have data entry, data review, and query resolution 
permissions, while others may only have data read permissions, based on their individual study 
roles.  EDC is flexible to allow customizable permissions as needed for study personnel.  
11.2 Coding  
The following coding dictionaries will be used:  
  
 
  
Coding Dictionaries  
Diseases:  
Medical Dictionary for Regulatory Activities 
(MedDRA)  
Adverse events:  
MedDRA   
Drugs:  
World Health Organization (WHO) Drug 
Reference List   
11.3 Data-Handling   
Study data will be checked for completeness and correctness as it is entered by the real-time 
online checks applied by EDC.  Off-line checks will also be run to perform any additional data 
review required.  Any issues identified will be transferred to the study site via query for resolution 
by the investigator or his/her designee.  All queries will be managed through EDC and audit trails 
of all queries and their resolution, along with any data changes, will be recorded. 
  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
  
Clinical research associates (CRAs) will monitor the data, verifying all captured data against its 
source.  Monitoring will be enhanced by computer assisted data management identifying missing 
or possibly erroneous data as soon as data is entered into the system.  This approach will allow 
initial remote monitoring, and communication between CRAs and site personnel before and 
between site visits, and will expedite data review and cleaning.  Missing data and identified data 
errors (or possible errors) will be communicated by the CRAs to site investigators using the Query 
feature in EDC for correction or acknowledgement that data is correct as entered.  As each 
subject’s data entry is completed and fully monitored with all queries resolved, that subject’s data 
will be locked by Data Management to only allow read access for the remainder of the study.  
 
EDC and all study data are housed in a secure computing environment.  EDC further provides a 
complete audit trail of all data entry, monitoring, and query activity.  EDC is compliant with HIPAA 
and meets all requirements for 21 CFR Part 11.    


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
Page 52 of 65 
 
11.4 Reporting  
The statistical team will create a dedicated statistical report to support the clinical study report 
(CSR). The CSR will be written in accordance with the ICH E3 guidance.  
11.5 Study Records Retention   
As per US regulations, study documents will be retained at least 2 years after the last approval of 
a marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or at least when 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by local regulations.   
   
At the end of the retention period, the investigator or medical institution can arrange with the 
sponsors for continued retention at the sponsors' facilities. No records will be destroyed without 
the written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained.   
  
12. FINANCIAL, INSURANCE AND OWNERSHIP  
12.1 Financial Disclosure  
As described in CFR Title 21, Part 54, RHB will obtain a completed Form FDA 3454 attesting to 
the absence of financial interests by the investigator, or a completed Form FDA 3455 disclosing 
completely and accurately the following:   
• 
Any financial arrangement entered into between the sponsor of the covered study and the 
clinical investigator involved in the conduct of a covered clinical trial.  
• 
Any significant payments of other sorts from the sponsor of the covered study, such as a 
grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria;  
• 
Any proprietary interest in the tested product held by any clinical investigator involved in a 
study;  
• 
Any significant equity interest in the sponsor of the covered study held by any clinical 
investigator involved in any clinical study; and   
• 
Any steps taken to minimize the potential for bias resulting from any of the disclosed 
arrangements, interests, or payments.   
  
The investigator must update this information if any relevant changes occur in the course of the 
study, or for one year following completion of the study.  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
Page 53 of 65 
 
 12.2 Ownership  
All data and records provided by RHB or generated during the study (other than a subject’s 
medical records/source documents) and all inventions discovered in the course of conducting the 
study are the property of RHB.   
13. PUBLICATION POLICY   
Data derived from the trial are the exclusive property of RHB. Any publication or presentation 
related to the trial must be reviewed and approved by RHB before submission of the manuscript. 
Prior to submitting for publication, presentation, use for instructional purposes, or other disclosure 
of the results of the study, the investigator(s) shall allow RHB a period of at least 30 days (or, for 
abstracts, at least 10 working days) to review the proposed publication or disclosure prior to its 
submission. Publications or disclosures of study results shall not include confidential information 
belonging to RHB. Publication or disclosure of study results must include the results from all sites 
combined. If the proposed publication/disclosure risks RHB‘s ability to patent any invention 
related to the study or seriously impairs its competitive strategy with respect to regulatory 
submission, licensing, or marketing of the final product, the publication or disclosure will be 
modified or delayed a sufficient time to allow RHB to seek patent protection of the invention or to 
realize its expected benefits, in so far as such requirement is reasonable. This statement does 
not give RHB any editorial rights over the content of a publication or disclosure, other than to 
restrict the disclosure of RHB’s confidential information.  
  
A clinical study report will be prepared by RHB in accordance with the ICH E3 guidance. RHB will 
retain final editorial control over the final clinical report.  
  
  
 
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
Page 54 of 65 
 
14. LITERATURE REFERENCES  
Axon A, Forman D. Helicobacter gastroduodenitis: a serious infectious disease. British Medical 
Journal. 1997;314:1430-1431.  
Barzilay EJ, Fagan RP. Chapter 3: Infectious Diseases Related to Travel. IN 2012 Yellow Book - 
Travelers' Health - CDC. 2011.  New York: Oxford University Press Inc.  
Borody TJ. Efficacy and safety of rifabutin-containing ‘rescue therapy’ for resistant Helicobacter 
pylori infection. Aliment Pharmacol Therap. 2006;23:481-488.  
Broutet N, Tchamgoue S, Pereira E, Lamouliatte H, Salamon R, Megraud F. Risk factors for 
failure of Helicobacter pylori therapy– results of an individual data analysis of 2751 patients. 
Aliment Pharmacol Therap.  2003;17:99–109.  
Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in 
the United States. Am J Epidemiol. 2006a;163:127-134.  
Cardenas VM, Ortiz M, Graham DY. Helicobacter pylori Eradication and Its Effect on Iron Stores: 
A Reappraisal. J Infect Dis. 2006b;194:714.  
Chey WD, Wong BCY. American College of Gastroenterology Guideline on the management of 
Helicobacter pylori Infection. Am J Gastroenterol. 2007;102:1808-1825.  
Chey WD, Leontiadis GI, Howden CW, Moss SF.  American College of Gastroenterology 
Guideline on the management of Helicobacter pylori Infection. Am J Gastroenterol. 2017;advance 
on line publication. 
De Francesco V, Giorgio F, Hassan C, Manes G, Vannella L, PanellaC, Ierardi E, Zullo A. 
Worldwide H. pylori antibiotic resistance: a systematic review. J Gastro Liver Dis. 
2010;19(4):409414.  
Dholakia KR, Dharmarajan TS, Yadav D, Oiseth S, Norkus EP, Pitchumoni CS.  Vitamin B12 
deficiency and gastric histopathology in older patients.  World J Gastroenterol. 
2005;11(45):70787083.  
DuBois S, Kearney DJ. Iron-deficiency anemia and Helicobacter pylori infection: a review of the 
evidence. Am J Gastroenterol. 2005;100:453-459.  
Ekstrom AM, Held M, Hansson LE et al. Helicobacter pylori in gastric cancer established by CagA 
immunoblot as a marker of past infection. Gastroenterology. 2001;121(4):784-791.  
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126396.pdf 
Collection 
of 
Race and Ethnicity Data in Clinical Trials, Guidance for Industry and Food and Drug 
Administration Staff October 2016 


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
Page 55 of 65 
 
Gisbert JP. “Rescue” regimens after Helicobacter pylori treatment failure. World J Gastroenterol. 
2008;14(35):5385-5402.  
Gisbert JP Calvet X. Review article: rifabutin in the treatment of refractory Helicobacter pylori 
infection. Aliment Pharmacol Therap. 2012;35: 209-221.  
Graham DY, Adam E, Reddy GT, Agarwal JP, Agarwal R, Evans DJ, Jr., Malaty HM, Evans DG. 
Seroepidemiology of Helicobacter pylori infection in India. Comparison of developing and 
developed countries. Dig Dis Sciences. 1991;36:1084-1088.  
Graham DY. Editorial: Can therapy ever be denied for Helicobacter pylori infection? 
Gastroenterology. 1997a;113:S113-S117.  
Graham DY. Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric 
cancer: a model. Gastroenterology. 1997b;113:1983-1991.  
Graham DY, Lu H, Yamaoka Y.  A report Card to Grade Helicobacter pylori Therapy.  
Helicobacter 2007;12:275-278 
 Graham DY. Efficient identification and evaluation of effective Helicobacter pylori therapies. Clin 
Gastroenterol Hepatol. 2009;7:145-148.  
Graham DY, Rugge M. Clinical practice: diagnosis and evaluation of dyspepsia. J Clin 
Gastroenterol. 2010a;44:167-172.  
Graham, DY. Helicobacter pylori eradication therapy research: ethical issues and description of 
results. Clin Gastroenterol Hepatol. 2010b;8:1032-1036.  
Graham, DY, Dore, M. Helicobacter pylori therapy demystified. Helicobacter. 2011;16:343-345.  
Graham DY, Calvet X. Guide regarding choice of second-line therapy to obtain a high cumulative 
cure rate. Helicobacter 2012;17:243-245.  
Lee YC, Chen TH, Chiu HM, Shun CT, Chiang H, Liu TY, Wu MS, Lin JT. The benefit of mass 
eradication of Helicobacter pylori infection: a community-based study of gastric cancer 
prevention. Gut. 2013; 62:676-682.  
Luther J, Higgins P, Schoenfeld PS, Moayyedi P, Vakil N, Chey WD. Empiric quadruple vs. triple 
therapy for primary treatment of Helicobacter pylori infection: systematic review and metaanalysis 
of efficacy and tolerability. Am J Gastroenterol. 2010;105:65–73.  
Maconi G, Sainaghi M, Molteni M et al. Predictors of long-term outcome of functional dyspepsia 
and duodenal ulcer after successful Helicobacter pylori eradication--a 7-year follow-up study. 
European J Gastroenterol Hepatol. 2009;21(4):387-393.  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
  
  
Page 56 of 65 
 
Malfertheiner P. Management of H. pylori infection: Maastricht III – 2005.  
Malfertheiner P, Bazzoli F, Delchier JC, Celinski K, Giguere M, Riviere M, Megraud F. 
Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, 
metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: 
a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011;377:905-913.  
Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, Gensini GF, Gisbert 
JP, Graham DY, Rokkas T, El-Omar EM, Kuipers EJ; The European Helicobacter Study Group  
(EHSG). Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus 
Report. Gut. 2012;61(5):646-664  
Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M et al. Eradication of Helicobacter 
pylori for non-ulcer dyspepsia (Review). 2006, Issue 2. Art. No.: CD002096. DOI:  
10.1002/14651858.CD002096.pub4.  
NCI.  Surveillance Epidemiology and End Results. SEER Stat Fact Sheet: Stomach. 
http://seer.cancer.gov/statfacts/html/stomach.html. Accessed March 2013.  
Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nature 
Reviews Gastroenterology & Hepatology. 2011;8:79-88.   
Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY. Greater than 
95% success with 14-day bismuth quadruple anti-Helicobacter pylori therapy: A pilot study in US 
Hispanics. Helicobacter 2012;17:382-389.  
Selgrad M, Bornschein J, Rokkas T, Malfertheiner P. Clinical aspects of gastric cancer and 
helicobacter pylori – screening, prevention, and treatment. Helicobacter. 2010;15(suppl. 1):40-45.  
Shektar SS, Ramakrishnan S, Seth S. CYP 450 2C19 polymorphisms in Indian patients with 
coronary artery disease. Indian Heart J. 2014 Jan-Feb; 66(1): 16–24. 
Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol. 
2005;100:2324-2337.  
Van Der Poorten D, Katelaris PH. The effectiveness of rifabutin triple therapy for patients with 
difficult-to-eradicate Helicobacter pylori in clinical practice. Aliment Pharmacol Therap.  
2007;26:1537-1542.  
Wannmacher, L. Review of the evidence for H. pylori treatment regimens: Section 17.1 (Review) -
- Adults and Children. 18th Expert Committee on the Selection and Use of Essential Medicines. 
2011. World Health Organization.  
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 57 of 65 
 
 
15. APPENDICES  
  
APPENDIX 1 SPONSOR APPROVAL AND SIGNATURES  
APPENDIX 2 SCHEDULE OF EVENTS  
APPENDIX 3 DEFINITIONS FOR CLINICAL AND LABORATORY ADVERSE EVENTS  
APPENDIX 4 CYP-INTERACTING DRUGS  
 
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 58 of 65 
 
 
APPENDIX 1 
 SPONSOR APPROVAL AND SIGNATURES  
 
The signatures below indicate the approval of this protocol and its attachments, and provide the 
necessary assurances that this trial will be conducted according to all requirements of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable Canadian and US regulations and to ICH guidelines.  
 
MEDICAL DIRECTOR SIGNATURE:  
   
  
_______________________________________ Date: _____________  
Signature  
  
Ira Kalfus, M.D.  
  
  
  
  
CHIEF EXECUTIVE OFFICER SIGNATURE:  
  
_______________________________________ Date: ______________ 
Signature  
  
Dror Ben-Asher  
 
 


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 59 of 65 
 
 
INVESTIGATOR’S APPROVAL  
  
The signature below indicates the approval of this protocol and its attachments, and provides the 
necessary assurances that this trial will be conducted according to all requirements of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable Canadian and US regulations and to ICH guidelines.  
  
  
  
  
INVESTIGATOR SIGNATURE:  
  
  
  
_______________________________________ Date: _____________  
Signature  
  
  
_______________________________________  
  
Print Name  
  
 


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 60 of 65 
 
APPENDIX 2 
SCHEDULE OF EVENTS – DOUBLE-BLIND PHASE OF STUDY 
Assessments and Recordings 
Visit 0 
Screening 
Day -42 to 0 
Visit 1 
Baseline 
Day 1 
Visit 2 
Phone 
follow-up 
Day 8 
(+1 day) 
Visit 3 
Safety Visit 
Day 13 
(+2 days) 
Visit 4 
Phone  
follow-up 
Day 28-60 
(+2 days) 
Visit 5  
Test of Cure 
Day 43-71 
(+7 days) 
 
Subject Information and Demographics 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Urine Pregnancy Test on Females of Child Bearing 
Potential 
X 
X 
 
X 
 
X 
Medical History 
X 
X 
 
 
 
 
Physical Examination with Vital Signs 
X 
X 
 
X 
 
X 
Concomitant Medications 
X 
X 
 
X 
 
X 
Laboratory Studies 
 
 
 
 
 
 
• Hematology, Chemistry, Urinalysis 
X 
 
 
X 
 
Xb 
• 13C UBTa 
Xa 
 
 
 
 
Xa 
• HBs Ag, HCV Ab, HIV1 /HIV2 Abs 
X 
 
 
 
 
 
Upper Endoscopy to determine H pylori status) 
• Biopsy for CLO  
• Biopsy for histology  
• Biopsy for culture and susceptibility  
 
X 
X 
           X 
 
 
 
 
 
• CYP2C19 Genotyping 
 
X 
 
 
 
 
Blood Sample for PK Assessment of amoxicillin, 
omeprazole, rifabutin, and 25-O-desacetyl-rifabutin – 
TO BE PERFORMED ON SUBJECTS WHO EARLY 
TERMINATE DURING 14 DAY COURSE OF 
TREATMENT IF POSSIBLE) 
 
 
Xc 
 
 
 
Xc 
 
 
Electrocardiogram 
X 
 
 
 
 
 
Diary Dispensed 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Study Drug Dispensed 
 
X 
 
 
 
 
Critical Review of Diary for: 
 
 
 
 
 
 
• Missed Doses 
 
 
 
X 
 
 
• Concomitant Medications 
 
 
 
X 
 
 
Drug Accountability/Compliance 
 
 
 
X 
 
X 


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 61 of 65 
 
Assessments and Recordings 
Visit 0 
Screening 
Day -42 to 0 
Visit 1 
Baseline 
Day 1 
Visit 2 
Phone 
follow-up 
Day 8 
(+1 day) 
Visit 3 
Safety Visit 
Day 13 
(+2 days) 
Visit 4 
Phone  
follow-up 
Day 28-60 
(+2 days) 
Visit 5  
Test of Cure 
Day 43-71 
(+7 days) 
 
Adverse Event Assessment (SAEs through Visit 5/43-
71 days post initiation of study drug). 
(Reminder at Visits 2 and 4) 
 
 
X 
 
X 
 
X 
 
X 
X 
Stress Compliance and Follow-up 
 
 
X 
 
 
 
Stress 13C UBT Testing and Reminder of Upcoming 
Appointment 
 
 
 
 
X 
 
a Subject is to fast (no liquid or solid intake) for at least one hour for 13C UBT prior to blood draw. 
b For subjects with abnormal results at Visit 3. 
c Blood samples taken prior to first dose at visit 1, and at visit 3 to assess plasma levels of amoxicillin, omeprazole, rifabutin, and 25-O-desacetyl-rifabutin.  
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 62 of 65 
 
SCHEDULE OF EVENTS – STANDARD OF CARE PHASE OF STUDY 
Assessments and Recordings 
Visit 5A 
Phone 
13C UBT 
Follow-up  
Day 44-72  
(+7 days) 
Visit 6 
SOC Baseline and 
Endoscopy After 
Day 44-72  
(+ 14 days) 
Visit 7 
Phone follow-up 
Day 50 - 79 
(+2 days) 
Visit 8 
SOC 
Test of Cure 
Day 85 – 140 
(+14 days) 
Urine Pregnancy Test on Females of Child Bearing 
Potential 
 
X 
 
 
Vital Signs 
 
X 
 
 
Concomitant Medications 
 
X 
 
 
Unblinded 13C UBT Results: 
• Subjects with positive result – schedule upper 
endoscopy 
• Subjects with negative result – Visit 5 is their end-of-
study visit 
X 
 
 
 
Susceptibility Directed (initial endoscopy samples) or 
Standard of Care Therapy to Eradication Failure Subjects 
with Positive 13C UBT 
 
X 
 
 
Endoscopy with Biopsy (x2) for Culture and Susceptibility 
in Subjects with Positive 13C UBT  
 
X 
 
 
Stress Compliance Follow-up and Schedule 13C UBT 
 
 
X 
 
13C UBTa 
 
 
 
X 
 
 


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 63 of 65 
 
APPENDIX 3  
DEFINITIONS FOR CLINICAL AND LABORATORY ADVERSE EVENTS  
  
All adverse events (clinical and laboratory) will be rated as follows:  
  
Severity (Clinical Events Only)   
 
Severity of clinical events are to be graded as follows:  
1 = Mild:  
Event Is noticeable to the subject, does not interfere with the 
subject’s daily activities and usually does not require additional 
therapy or dose adjustment.  
2 =  Moderate:  
Event may interfere with the subject’s daily activities and may 
require additional therapy  
3 = Severe:  
Event may severely limit the subject’s daily activities and typically 
requires therapy or intervention.  
  
 
Causal Relationship  
The investigators are to assess the causal relationship of all AEs using the following five 
categories:  
Relationship  
Causality  
Description  
Not related to 
investigational 
agent  
Unrelated  
The AE is clearly not related to the investigational 
agent.  
Unlikely  
The AE is doubtfully related to the investigational 
agent.  
Related to 
investigational 
agent  
Possible  
The AE may be related to the investigational agent.  
Probable  
The AE is likely to be related to the investigational 
agent.  
Definite  
The AE is clearly related to the investigational 
agent.  
  
  
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 64 of 65 
 
APPENDIX 4  
CYP-INTERACTING DRUGS   
  
CYP2C19 
INDUCERS  
INHIBITORS  
SUBSTRATES  
artemisinin  
 
carbamazepine  
norethindrone  
prednisone rifampicin 
allicin (garlic 
derivative) 
armodafinil  
carbamazepine,  
chloramphenicol 
cimetidine  
esomeprazole 
etravirine   
 fluconazole  
fluvoxamine  
human growth 
hormone  
indomethacin 
ketoconazole 
lansoprazole   
moclobemide   
modafinil  
omeprazole  oral  
contraceptives 
oxcarbazepine  
pantoprazole  
probenecid  
rabeprazole  
ticlopidine 
topiramate  
amitriptyline  
carisoprodol  
citalopram  
chloramphenicol  
clomipramine  
clopidogrel  
cyclophosphamide 
diazepam   
hexobarbital   
indomethacin 
lansoprazole   
S-mephenytoin  
Rmephobarbital  
moclobemide 
nelfinavir  
nilutamide 
omeprazole   
phenobarbitone 
phenytoin  
primidone  
progesterone 
proguanil  
propranolol  
rabeprazole  
teniposide  
R-warfarin  
felbamate  
fluoxetine  
voriconazole  
imipramine NDeME  pantoprazole   
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed [12Mar2013].  
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers – Tables 5, 6,+7.  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm093664.htm#cypEnzymes. 
Accessed [12Mar2013]  
  


CONFIDENTIAL  
RHB-105-02  
  
Amendment 3 – 22 March 2018 
ERADICATE Hp2 Study 
Page 65 of 65 
 
 
CYP3A  
INDUCERS  
INHIBITORS  
SUBSTRATES  
amprenavir 
aprepitant  
armodafinil 
avasimibe  
barbiturates 
bosentan  
carbamazepine 
echinacea efavirenz  
etravirine  
glucocorticoids 
modafinil nafcillin  
nevirapine  
oxcarbazepine  
phenobarbital 
phenytoin  
pioglitazone  
prednisone rifabutin 
rifampin  
rufinamide  
St. John's wort 
troglitazone  
alprazolam  
amiodarone 
amlodipine  
amprenavir 
aprepitant  
atazanavir 
atorvastin  
bicalutamide  
boceprevir  
chloramphenicol  
clarithromycin 
cilostazol  
cimetidine  
ciprofloxacin 
conivaptan  
cyclosporine  
darunavir/ ritonavir  
delaviridine diethyl- 
dithiocarbamate 
diltiazem  
erythromycin 
fluconazole  
fluoxetine  
fluvoxamine  
fosamprenavir  
gestodene ginkgo  
goldenseal  
grapefruit juice 
imatinib indinavir 
indinavir  
isoniazid  
itraconazole  
ketoconazole  
lopinavir/ritonavir 
mibefradil  
mifepristone 
nefazodone 
nelfinavir nilotinib  
norfloxacin  
norfluoxetine  
oral contraceptives 
posaconazole 
ranitidine  
ranolazine 
ritonavir  
saquinavir starfruit 
telithromycin 
telaprevir  
tipranavir/ritonavir 
verapamil  
voriconazole 
zileuton  
alfentanil 
alprazolam 
amlodipine 
aprepitant 
aripiprazole 
astemizole 
atorvastatin 
boceprevir 
budesonide 
buspirone 
cafergot 
cerivastatin 
chlorpheniramine 
clarithromycin 
cilostazol cisapride 
cocaine 
codeine-N- 
demethylation 
conivaptan 
cyclosporine 
dapsone 
darifenacin 
darunavir 
 
dasatinib  
dexamethasone  
dextromethorphan 
diazepam  
dihydroergotamin e  
diltiazem  
docetaxel  
domperidone  
dronedarone eletriptan  
erythromycin 
ergotamine eplerenone 
estradiol  
everolimus felodipine 
fentanyl  
finasteride  
fluticasone imatinib  
haloperidol  
hydrocortisone indinavir 
irinotecan  
  
  
LAAM   
lercanidipine 
lidocaine 
lopinavir  
lovastatin  
lurasidone  
methadone 
maraviroc  
midazolam 
nateglinide 
nelfinavir  
nifedipine  
nisoldipine  
nitrendipine  
ondansetron 
pimozide  
progesterone 
propranolol 
quetiapine 
quinidine 
quinine  
risperidone 
ritonavir  
salmeterol  
  
saquinavir 
sildenafil  
simvastatin 
sirolimus  
sorafenib 
sunitinib  
tacrolimus  
tamoxifen 
taxol  
telaprevir  
telithromycin 
terfenadine  
testosterone 
tipranavir 
tolvaptan 
torisel  
trazodone 
triazolam  
vardenafil 
verapamil  
vincristine 
zaleplon  
ziprasidone 
zolpidem  
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed [12Mar2013].  
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers – Tables 5, 6,+ 7. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ DrugInteractionsLabeling/ucm093664.htm#cypEnzymes. 
Accessed [12Mar2013]  
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Protocol Title: A Randomized Double Blind Active Comparator 
Controlled Phase III Study to Assess the Safety and Efficacy of RHB-
105 in the Treatment of Confirmed Helicobacter pylori (H. pylori) 
Infection 
 
 
NCT Number: NCT03198507 
 
 
Protocol Number: RHB-105-02 
 
 
Protocol Version, Date Protocol Amendment 3, 22 Mar 2018 
 
 
SAP Document Version, Date:  
Final 2.0, 20 Nov 2018 
Addendum 1.0, 06 Feb 2019 
 


 
Statistical Analysis Plan (SAP) 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                       Version: Final 2.0, Date: 20 Nov 2018 
                                                                                   Page 1 of 36 
 
Protocol Title: 
A Randomized Double Blind Active Comparator Controlled Phase 
III Study to Assess the Safety and Efficacy of RHB-105 in the 
Treatment of Confirmed Helicobacter pylori (H. pylori) Infection 
Protocol Number: 
RHB-105-02 
Protocol Version, Date 
Protocol Amendment 3, 22 Mar 2018 
ICON ID:  
3101/0005 
Document Version, Date: 
Final 2.0, 20 Nov 2018  
 
 
 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
RedHill Biopharma Ltd. 
 
 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information contained 
within this document or any related information to other persons without the 
permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


 
Statistical Analysis Plan (SAP) 
RedHill Biopharma Ltd. 
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018 
Page 3 of 36 
 
REVISION HISTORY 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Version Draft 1.0/ 
24 Apr 2017 
Initial version 
N/A 
N/A 
Version Draft 2.0/ 
12 Apr 2018 
2nd Draft 
N/A 
Update after RedHill Review and release of Protocol Amendment 
3 
Version Draft 3.0/ 
25 Jun 2018 
3rd Draft 
N/A 
Update of compliance calculation 
Clarification of summary of concomitant medications 
Addition of pre-final analysis 
Version Final 1.0/ 
06 Sep 2018 
Final 1.0 
N/A 
Minor updates regarding the handling of repeated test of cure visits 
Addition of subgroup analyses by pharmacokinetics  
Addition of subgroup analyses by SOC therapy categories for H. 
pylori eradication in the SOC phase 
Addition of summary of susceptibility by USA regions 
Update of secondary efficacy endpoint: eradication of H.pylori 
instead of failure of eradication 
Version Final 2.0/ 
20 Nov 2018 
Final 2.0 
N/A 
Update of the analysis of patient disposition 
Addition of primary efficacy by site 
Addition of a listing for physical examination after screening 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 4 of 36 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE ............................................................................................................. 2 
REVISION HISTORY........................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................... 4 
LIST OF ABBREVIATIONS ................................................................................................ 6 
1 INTRODUCTION ........................................................................................................... 7 
2 STUDY OBJECTIVES .................................................................................................... 8 
2.1 Primary objective(s) ................................................................................................ 8 
2.2 Secondary objective(s) ............................................................................................ 8 
2.3 Safety objective(s) .................................................................................................. 8 
3 STUDY DESIGN ............................................................................................................. 9 
3.1 General study design ............................................................................................... 9 
3.2 Randomization and blinding ................................................................................... 9 
3.3 Study treatments and assessments ........................................................................ 10 
3.4 Post-treatment Standard of Care ........................................................................... 10 
4 STUDY ENDPOINTS ................................................................................................... 13 
4.1 Primary efficacy endpoint(s) ................................................................................. 13 
4.2 Secondary efficacy endpoint(s) ............................................................................. 13 
4.3 Safety endpoint(s) ................................................................................................. 13 
4.4 Exploratory endpoint(s) ........................................................................................ 13 
4.5 Pharmacokinetic endpoint(s) ................................................................................ 13 
5 SAMPLE SIZE AND POWER ...................................................................................... 14 
6 ANALYSIS POPULATIONS ....................................................................................... 15 
6.1 Full Analysis Set (FAS) / Safety population......................................................... 15 
6.2 Modified Intent-to-treat (mITT) population ......................................................... 15 
6.3 Per-Protocol population (PP) ................................................................................ 15 
6.4 PK Population (PKP) ............................................................................................ 15 
6.5 Protocol deviations/violations and exclusions from analysis sets ........................ 15 
7 STATISTICAL CONSIDERATIONS AND ANALYSIS ............................................ 17 
7.1 Derived variables .................................................................................................. 17 
7.2 Handling of missing or incomplete data ............................................................... 17 
8 STATISTICAL METHODS .......................................................................................... 19 
8.1 General statistical conventions ............................................................................. 19 
8.1.1 Model structure or SAS codes .................................................................. 20 
8.2 Subject disposition ................................................................................................ 20 
8.3 Protocol deviations................................................................................................ 21 
8.4 Demographics and baseline characteristics .......................................................... 21 
8.4.1 Demographics ........................................................................................... 21 
8.4.2 Baseline and disease characteristics .......................................................... 22 
8.4.3 Medical history ......................................................................................... 22 
8.4.4 Prior and concomitant medications ........................................................... 23 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 5 of 36 
 
8.5 Extent of exposure ................................................................................................ 23 
8.5.1 Treatment duration .................................................................................... 23 
8.5.2 Treatment compliance ............................................................................... 24 
8.6 Efficacy analyses .................................................................................................. 24 
8.6.1 Analysis of primary efficacy endpoint(s) ................................................. 24 
8.6.2 Analysis of secondary efficacy endpoint(s) .............................................. 26 
8.6.3 Analysis of exploratory endpoint(s).......................................................... 26 
8.7 Safety analyses ...................................................................................................... 26 
8.7.1 Adverse events .......................................................................................... 27 
8.7.2 Serious adverse events .............................................................................. 28 
8.7.3 Clinical laboratory evaluations ................................................................. 28 
8.7.4 Vital signs ................................................................................................. 31 
8.7.5 Physical examinations ............................................................................... 31 
8.7.6 Electrocardiograms ................................................................................... 31 
8.8 Pharmacokinetic (PK) analyses ............................................................................ 31 
8.9 Subgroup analyses ................................................................................................ 32 
8.10 Interim analysis ..................................................................................................... 32 
8.11 Analysis after the double-blind phase of the study ............................................... 32 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ..................... 33 
10 REFERENCES .............................................................................................................. 34 
11 APPENDICES ............................................................................................................... 35 
 
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 6 of 36 
 
LIST OF ABBREVIATIONS 
Abbreviation 
or 
special term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine  aminotransferase  
AST 
Aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body mass index  
BUN 
Blood urea nitrogen  
CI 
Confidence Interval  
CLO 
Campylobacter-like organism 
CSR 
Clinical Study Report  
FAS 
Full Analysis set 
GCP 
Good clinical practice 
H. pylori 
Helicobacter pylori  
ICH 
International Conference on Harmonisation  
IRB/EC 
Institutional Review Board/Independent Ethics Committee 
LDH 
Lactate Dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Affairs®  
MIC 
Minimum inhibitory concentration 
mITT 
Modified Intent-to-treat  
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred term 
RBC 
Red blood cell  
SAE 
Serious Adverse Events  
SAF 
Safety Analysis population 
SAP 
Statistical Analysis Plan  
SD 
Standard deviation  
SGOT 
Serum glutamic-oxaloacetic transaminase  
SGPT 
Serum glutamic-pyruvic transaminase  
SOC 
System organ class (in context of adverse events or medical history) 
SOC 
Standard of care (in context of study phase) 
TEAE 
Treatment emergent adverse event  
TFL 
Table, Figure and Listings  
UBT 
Urea Breath Test  
USA 
United States of America 
WBC 
White blood cell  
WHO 
World Health Organization  


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 7 of 36 
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the statistical 
methods, data derivations and data displays for study protocol RHB-105-02 “A Randomized Double 
Blind Active Comparator Controlled Phase III Study to Assess the Safety and Efficacy of RHB-105 
in the Treatment of Confirmed Helicobacter pylori (H. pylori) Infection”, Amendment 3 dated 22 Mar 
2018 for final analysis. The table of contents and templates for the Table, Figure, Listings (TFL)s will 
be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). The 
preparation of this SAP has been based on International Conference on Harmonisation (ICH) E9 
guidelines. 
The SAP is finalized and signed prior to any of the following: study unblinding and database hard 
lock. For operational efficiency, an earlier time is usually targeted. If needed, revisions to the approved 
SAP may be made prior to database hard lock. Revisions will be version controlled. 
All data analyses and generation of TFLs will be performed using SAS 9.3® or higher. 
 
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 8 of 36 
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objective of this study is to assess the effectiveness of RHB-105 to eradicate H. pylori as 
indicated by 13C Urea Breath Test (UBT) for H. pylori. 
 
2.2 
Secondary objective(s) 
The secondary objective of this study is the examination of the primary endpoint, the occurrence of H. 
pylori eradication, within subgroups of subjects formed by the occurrence of antibiotic resistance and 
susceptibility prior to therapy. 
  
2.3 
Safety objective(s) 
The safety objective is to assess the safety profile of RHB-105.  
 
 
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 9 of 36 
 
3 
STUDY DESIGN 
3.1 
General study design 
This is a randomized, double-blind, active comparator controlled study of RHB-105 in adult subjects 
complaining of epigastric discomfort that have been screened and found to be positive for H. pylori 
infection via 13C UBT and follow up upper endoscopy (culture, histology or urease test). All subjects 
who meet inclusion and exclusion criteria and have positive 13C UBT will undergo upper endoscopy 
with three biopsies taken from each of the antrum and corpus of the stomach. One biopsy from both 
the corpus and antrum will be combined and tested for H. pylori via a rapid urease test at the point of 
care. One biopsy from both the corpus and antrum will be combined and sent for H. pylori testing at 
the central histology laboratory. One biopsy from both the corpus and antrum will be combined and 
sent to the central laboratory for H. pylori culture with susceptibility testing assessing amoxicillin, 
clarithromycin, metronidazole and rifabutin. Subject specific pretreatment culture susceptibility and 
resistance results will be provided to the investigator in those subjects who fail to eradicate H. pylori 
upon post treatment 13C UBT analysis. All other susceptibility data will remain blinded until study 
completion. The active comparator arm is expected to demonstrate an approximate 70% efficacy rate 
and RHB-105 is being investigated for superiority with an expected approximate 83% efficacy rate. 
The study will be conducted at up to 65 sites in the United States of America (USA). Once informed 
consent has been obtained and upon positive screening and enrollment into the study, eligible subjects 
will be randomized in a ratio of 1:1 between active comparator arm (n=222) and the active 
investigational arm (RHB-105) (n=222). Subjects will receive RHB-105 or active comparator (RHB-
105-LT) for 14 days. Eradication of H. pylori infection will be determined based on 13C UBT testing 
conducted between 43 and 71 days after initiation of therapy. In the event a female subject becomes 
pregnant during the course of the double-blind phase of the study and refuses to undergo the 13C UBT 
assessment, then a fecal antigen test may be performed at the local lab. Results of the fecal antigen test 
will substitute for the 13C UBT test of cure for this subject in all efficacy analyses. 
Subjects who fail to eradicate H. pylori upon post treatment 13C UBT analysis will receive investigator 
prescribed susceptibility directed therapy based on culture and sensitivity results from biopsy samples 
prior to therapy. The investigator may prescribe local standard of care therapy if susceptibility results 
are not contributory or are unavailable. These subjects will also undergo repeat endoscopy to assess 
changes in susceptibility and resistance. All information related to therapy including drugs, doses and 
duration administered will be collected, and subjects will be reassessed for eradication of H. pylori 28 
- 60 days following completion of therapy, ideally between 43 and 71 days after initiation of therapy. 
Susceptibility data will only be provided for those subjects who fail to eradicate H. pylori. 
3.2 
Randomization and blinding 
Subjects will be assigned to treatment using permuted block randomization without additional 
stratification. 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 10 of 36 
 
3.3 
Study treatments and assessments 
A list of subjects screened but deemed ineligible will be maintained indicating reason(s) for exclusion.  
Treatment assignments will be based on a centralized computer-generated randomization scheme 
using permuted block randomization without additional stratification. 
Each subject will have a randomization code assigned that corresponds to treatment assignment and a 
unique identifier for drug packaging purposes. Once a subject number and treatment have been 
assigned to a subject, the subject identification number cannot be reused even if the subject 
discontinues the study early or withdraws prior to receiving any study medication. Subjects who 
discontinue from the study or who have previously participated in the study will not be permitted to 
re-enroll. Subjects may be rescreened if endoscopic results for H. pylori are unavailable during the 
screening window. Subjects will be randomized to one of the following groups: 
 
Treatment Arms:  
 
 
444 
Subjects 
Randomized 
 
Arm 1 
 
222 Subjects 
 
RHB-105 
 
Arm 2 
 
222 Subjects 
 
Active Comparator 
 
3.4 
Post-treatment Standard of Care   
Subjects who fail to eradicate H. pylori will receive susceptibility directed standard of care therapy as 
prescribed by the treating investigator based on initial pretreatment results, and  will undergo upper 
endoscopy with culture to assess changes in susceptibility and resistance. The investigator may 
prescribe local standard of care therapy if susceptibility results are not contributory or are unavailable.  
Susceptibility data will only be provided for those subjects who fail to eradicate H. pylori. 
A detailed description of procedures and assessments to be conducted during this study is summarized 
in the Scheduled of Study Assessments in Table 1 below. 


 
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RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 11 of 36 
 
Table 1: Schedule of Study Assessments - Double-Blind Phase of Study 
Assessments and Recordings 
Visit 0 
Screening 
Day -42 
to -2 
Visit 1 
Baseline 
Day 1 
Visit 2 
Phone 
follow-up 
Day 8 
(+1 day) 
Visit 3 
Safety 
Visit 
Day 13 
(+2 days) 
Visit 4 
Phone  
follow-up 
Day 28-60 
(+2 days) 
Visit 5  
Test of 
Cure Day 
43-71 
(+7 days) 
Subject Information and Demographics 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Urine Pregnancy Test on Females of 
Child Bearing Potential 
X 
X 
 
X 
 
X 
Medical History 
X 
X 
 
 
 
 
Physical Examination with Vital Signs 
X 
X 
 
X 
 
X 
Concomitant Medications 
X 
X 
 
X 
 
X 
Laboratory Studies 
 
 
 
 
 
 
 Hematology, Chemistry, Urinalysis 
X 
 
 
X 
 
Xb 
 13C UBTa 
Xa 
 
 
 
 
Xa 
 HBs Ag, HCV Ab, HIV1 /HIV2 Abs 
X 
 
 
 
 
 
Upper Endoscopy to determine H 
pylori status) 
 Biopsy for CLO  
 Biopsy for histology  
 Biopsy for culture and 
susceptibility  
 
 
X 
X 
X 
 
 
 
 
 
 
 CYP2C19 Genotyping 
 
X 
 
 
 
 
Blood Sample for PK Assessment of 
amoxicillin, omeprazole, rifabutin, and 
25-O-desacetyl-rifabutin – TO BE 
PERFORMED ON SUBJECTS WHO 
EARLY TERMINATE DURING 14 
DAY COURSE OF TREATMENT IF 
POSSIBLE 
 
 
Xc 
 
 
 
Xc 
 
 
Electrocardiogram 
X 
 
 
 
 
 
Diary Dispensed 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Study Drug Dispensed 
 
X 
 
 
 
 
Critical Review of Diary for: 
 
 
 
 
 
 
 Missed Doses 
 
 
 
X 
 
 
 Concomitant Medications 
 
 
 
X 
 
 
Drug Accountability/Compliance 
 
 
 
X 
 
X 
Adverse Event Assessment (SAEs 
through Visit 5/43-71 days post 
initiation of study drug). 
(Reminder at Visits 2 and 4) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Stress Compliance and Follow-up 
 
 
X 
 
 
 
Stress 13C UBT Testing and Reminder 
of Upcoming Appointment 
 
 
 
 
X 
 
a Subject is to fast from solid food for at least one hour for 13C UBT prior to blood draw. 
b For subjects with abnormal results at Visit 3. 


 
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Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 12 of 36 
 
c Blood samples taken prior to first dose at visit 1, and prior to AM dose at visit 3 to assess plasma levels of amoxicillin, 
omeprazole, rifabutin, and 25-O-desacetyl-rifabutin. 
Table 1: Schedule of Study Assessments - Standard of Care (SOC) Phase of Study 
a Subject is to fast from solid food for at least one hour for 13C UBT prior to blood draw. 
 
Assessments and Recordings 
Visit 5A 
13C UBT 
Follow-up  
Day 44-72  
(+7 days) 
Visit 6 
SOC Baseline 
and Endoscopy 
After Day 44-
72  
(+ 14 days) 
 
Visit 7 
Phone follow-up 
Day 50 - 79 
(+2 days) 
Visit 8 
SOC 
Test of Cure 
Day 85 – 140 
(+14 days) 
Urine Pregnancy Test on Females of Child 
Bearing Potential 
 
X 
 
 
Vital Signs 
 
X 
 
 
Concomitant Medications 
 
X 
 
 
Unblinded 13C UBT Results: 
 Subjects with positive result – 
schedule upper endoscopy 
 Subjects with negative result – Visit 
5 is their end-of-study visit 
X 
 
 
 
Susceptibility Directed (initial endoscopy 
samples) or Standard of Care Therapy to 
Eradication Failure Subjects with Positive 
13C UBT 
 
X 
 
 
Endoscopy with Biopsy (x2) for Culture 
and Susceptibility in Subjects with Positive 
13C UBT  
 
X 
 
 
Stress Compliance Follow-up and Schedule 
13C UBT 
 
 
X 
 
13C UBTa 
 
 
 
X 


 
Statistical Analysis Plan (SAP) 
 
 
 
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Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 13 of 36 
 
4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint(s) 
The primary efficacy endpoint of this study is: 
 
The occurrence of H. pylori eradication as confirmed via 13C UBT testing 43-71 days after 
initiation of treatment. In the event a female subject becomes pregnant during the course of 
the double-blind phase of the study and refuses to undergo the 13C UBT assessment, results of 
a fecal antigen test may be performed at the local lab as a substitute. 
4.2 
Secondary efficacy endpoint(s) 
The secondary efficacy endpoints of this study are: 
 
Antibiotic Resistance and Susceptibility Subgroup Analyses - 
The primary endpoint will be summarized within subgroups formed by the presence of H. 
pylori susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and rifabutin 
determined based upon samples obtained prior to initiating study treatment.  The proportion 
of subjects with eradication of H. pylori and the treatment effect (difference in the proportions) 
will be estimated within each subgroup along with 95% 2-sided confidence intervals where 
there are an adequate number of subjects in the subgroup (e.g., at least 20 subjects per 
subgroup). 
 
Assess the difference in antibiotic resistance and susceptibility of H. pylori after treatment 
with study drug in treatment failure subjects. 
4.3 
Safety endpoint(s) 
The safety endpoints of this study are: 
 
The occurrence and severity of treatment emergent adverse events during the study. 
 
Changes from baseline in hematology and chemistry laboratory values. 
4.4 
Exploratory endpoint(s) 
The exploratory endpoints of this study are: 
 
Upon study completion and unblinding of all subjects, CYP2C19 status will also be 
summarized and subgroup analyses of efficacy based on CYP2C19 status and 
pharmacokinetics will be performed using descriptive methods.   
 
Eradication rates in failure to eradicate subjects who receive susceptibility directed standard 
of care will be analyzed descriptively. 
4.5 
Pharmacokinetic endpoint(s) 
The pharmacokinetic endpoint of this study is: 
 
The plasma concentrations of amoxicillin, omeprazole, rifabutin, and the rifabutin metabolite 
25-O-desacetyl-rifabutin on Day 13 will be summarized by time following most recent dose. 


 
Statistical Analysis Plan (SAP) 
 
 
 
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Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 14 of 36 
 
5 
SAMPLE SIZE AND POWER 
Sample size for this study has been calculated based on a superiority comparison assuming 83% 
effectiveness for the new treatment, and 70% effectiveness for the control, with 90% power and a 2-
sided alpha of 5%. Using these specifications, 222 subjects per arm will be required. 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 15 of 36 
 
6 
ANALYSIS POPULATIONS 
6.1 
Full Analysis Set (FAS) / Safety population 
The FAS (based upon the intention-to-treat principle as described in ICH-E9) will consist of all 
subjects who received at least one dose of randomized study treatment and will be identical with the 
safety population (SAF). In the FAS subjects will be analyzed as randomized, in the SAF subjects will 
be analyzed as treated. If after unblinding it is detected that at least one subject did not receive the 
randomized study treatment summaries specified for the FAS may also be repeated for the SAF.  
6.2 
Modified Intent-to-treat (mITT) population 
The mITT population is a subset of the FAS and will consist of all subjects who received at least one 
dose of randomized study treatment and undergo a 13C UBT test at Visit 5 (with the allowed exception 
for female women becoming pregnant outlined in Section 4.1). In the mITT population subjects will 
be analyzed as randomized. 
6.3 
Per-Protocol population (PP) 
The PP population is a subset of the mITT and will consist of all subjects who consume at least 75% 
of planned study treatment received, have no major protocol violations leading to exclusion from the 
PP population as determined during the Population Classification meeting (see Section 6.5) and 
undergo a 13C UBT test at Visit 5 (with the allowed exception for females becoming pregnant as 
outlined in Section 4.1). In the PP population subjects will be analyzed as randomized. 
6.4 
PK Population (PKP) 
The PKP will include those subjects in the FAS that have demonstrable presence of any component of 
investigational drug at Visit 3. 
6.5 
Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of subjects from analysis sets will be identified at the Classification 
Meeting just prior to study unblinding, through clinical review input provided by RedHill. 
Protocol deviations will be classified as major (key) or minor (non-key) as outlined in Protocol 
Deviation Criteria Form Version 2.0, 08 December 2017. According to the definition in this document 
a major (key) protocol deviation is any change, divergence or departure from the study design or 
procedures defined in the protocol that might significantly affect a subject's rights, safety or welfare 
or the completeness, accuracy and/or reliability of the study data. A major protocol deviation in this 
sense does not necessarily lead to exclusion from the PP population. Examples of major protocol 
deviations that might be exclusive are: 
 
Subject or caregiver did not provide informed consent prior to participation in any study 
procedures as required and in compliance with ICH/Good Clinical Practice (GCP) 


 
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Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 16 of 36 
 
 
Subject randomized in the study and does not meet inclusion/exclusion criteria 
 
Subject did not complete the final study visit of the double-blind phase (Visit 5) 
 
Subject is not fasting from food and drink 1 hour before 13C UBT test at Visit 5 
 
Subject is assigned or provided wrong study medication kit/ Errors in treatment assignment 
 
Compliance less than 75% with double-blind study drug per pill count 
 
Subject taking a prohibited medication 
 
Subject/investigator were unblinded to treatment 
 
Visit 5 performed earlier than 42 days from Visit l 
Major protocol deviations leading to exclusion from the PP population will be defined at the 
Classification Meeting. 
Major protocol deviations leading to exclusion from the PP population will be summarized with 
descriptive statistics by category. A listing of all deviations (minor and major, also including major 
deviations not leading to exclusion from PP) with date of deviation and specifics of events will also 
be included. 
  
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 17 of 36 
 
7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived variables 
The below table provides the list of derived variables for Demographic and baseline characteristics, 
various duration derivations, drug compliance, baseline derivations and other important derivations 
applicable for this study. 
Variables 
Formula 
Demographic and Baseline characteristics 
Body mass index (BMI) (kg/m2)   weight (kg)/[height (m)]^2 
Derivation of Duration 
Study day at any visit 
Date of interest – date of first dose of study drug. One day is 
added if this difference is ≥ 0 
Extent of Exposure (Days) 
Date of last randomized study medication intake – Date of first 
randomized study medication intake + 1 
Baseline Derivations 
Baseline 
Visit 1 Day 1  
Laboratory or vital signs 
baseline 
The baseline value is defined as the last observation prior to the 
first dose of study drug. 
Change from baseline 
Post baseline value – Baseline value 
 
7.2 
Handling of missing or incomplete data 
Imputation rules for missing or partial Adverse Event (AE) start date for the purpose of identifying 
treatment-emergent AEs (TEAE) are defined below. These imputed dates are only created for the 
purpose of identifying TEAE programmatically; they will not be used in any data displays 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date, then: 
 
If the full (or partial) AE end date is NOT before the first dose date or AE end date is missing, 
then impute the AE start day as the day of first dose date; otherwise, impute the AE start day 
as 1. 
 
Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with treatment exposure period to determine whether the AE is 
pre-treatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 


 
Statistical Analysis Plan (SAP) 
 
 
 
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Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 18 of 36 
 
If AE start year = first dose year, then: 
 
If the full (or partial) AE end date is NOT before the first dose date or AE end date is missing, 
then impute the AE start Month and Day as the Month and Day of first dose date; otherwise, 
impute the AE start Month as January and the Day as 1. 
 
Otherwise, impute the AE start Month as January and the Day as 1. 
Compare the imputed AE start date with treatment exposure period to determine whether the AE is 
pre-treatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then compare the full (or 
partial) AE end date to the first dose date. If the AE end date is before the first dose date then the AE 
should be considered as a pre-treatment AE. Otherwise, the AE will be considered as TEAE.  
Imputation rules for missing or partial medication start/stop dates are defined below: 
Missing or partial medication start date: 
 
If only Day is missing, use the first day of the month. 
 
If Day and Month are both missing and Year is not missing, use the first day of the year. 
 
If Day, Month and Year are all missing, use a date before the first dose date. 
Missing or partial medication stop date: 
 
If only Day is missing, use the last day of the month. 
 
If Day and Month are both missing, use the last day of the year. 
 
If Day, Month and year are all missing, assign ‘continuing’ status to stop date 
Date imputation will only be used for computational purposes, e.g., determination of treatment-
emergent status. Actual date values as they appear in the original CRFs will be shown in the data 
listings. 
Non-date Values: 
There will be no imputation for missing data for non-date values. 
  
 


 
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.3® or higher. Specifications for table, 
figure, and data listing formats can be found in the TFLs specifications for this study. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. Two-sided 95% confidence intervals (CI) will be provided when 
relevant. P-values will be presented with 4 decimal places. P-values less than 0.0001 will be presented 
as <0.0001 and p-values greater than 0.9999 will be presented as >0.9999. 
Continuous variables will be summarized using descriptive statistics, including number of subjects (n), 
mean, median, standard deviation (SD), minimum and maximum.  
For categorical variables, summaries will include counts of subjects and percentages. Percentages will 
be rounded to one decimal place. 
For summary purposes, baseline will be defined as the last available pre-dose value; all summaries 
will be presented by treatment group, unless otherwise specified. 
All subject data, including those derived, will be presented in individual subject data listings. Unless 
otherwise stated, unscheduled visit results will be included in date/time chronological order, within 
subject listings only. All listings will be sorted by investigational site, subject number, date/time and 
visit. The treatment group (Investigation Arm, Active comparator) as well as subject’s sex and age 
will be stated on each listing. Unless otherwise stated, data listings will be based on All Subjects 
Randomized. 
All analyses and summary tables will be displayed by treatment group. Primary and few key secondary 
endpoints will be analyzed by sub-groups. For the definition of subgroups of interest please refer to 
Section 8.9. 
 
 


 
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8.1.1 Model structure or SAS codes  
Chi-Square test without continuity correction  
The following SAS statements will be used for the primary and secondary endpoint analyses: 
PROC  FREQ data=<dataset name>; 
TABLES response variable*treatment group /CHISQ OUT=< output dataset name> 
 OUTPUT OUT=stats; 
RUN; 
8.2 
Subject disposition 
Subject disposition information will be presented for all subjects and summarized by treatment group 
and overall. The number and percent of subjects who are randomized, who received at least one dose 
of randomized study treatment, who were randomized and not treated, and who were treated and not 
randomized will be presented. Further, the number and percent of subjects who had a test of cure at 
the end of the double-blind phase, who had a test of cure and a (calculated) compliance ≥ 75%, who 
had a test of cure and a (calculated) compliance < 75%, who had no test-of cure after the double-blind 
phase, who were eligible for the standard of care (SOC) phase, who were eligible for and entered the 
SOC phase, and who were eligible for but did not enter the SOC phase will be presented. For the 
calculation of compliance see Section 8.5.2. In addition the number of subjects who discontinued their 
double-blind treatment but who completed the double-blind phase and vice versa will be shown.  For 
the subjects who had a test of cure at the end of the double blind phase but with (calculated) compliance 
less than 75%, the reason for treatment discontinuation will be summarized by treatment group and 
overall with the following categories:  
 
Adverse event 
 
Death 
 
Lost to follow-up 
 
Physician decision 
 
Withdrawal by subject 
 
Protocol deviation 
 
Randomized in error 
 
Other. 
The number of subjects randomized will be used as the denominator for the percentage calculation. 
For the subjects who entered the SOC phase of the trial the number and percentage of subjects who 
completed the SOC treatment, who discontinued SOC treatment, who completed the SOC phase at 
Visit 8 and who discontinued the SOC phase prematurely will be presented. Primary reason for 
discontinuation of the SOC phase and for discontinuation of SOC treatment will be summarized with 
the following categories:  
 
Adverse event 


 
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 
Death 
 
Lost to follow-up 
 
Non-compliance with standard of care 
 
Physician decision 
 
Withdrawal by subject 
 
Protocol deviation 
 
Other. 
The number of subjects who entered the SOC phase of the trial will be used as the denominator for the 
percentage calculation. 
Subject disposition will be listed. 
The number and percent of subjects in each analysis set will also be tabulated. 
The number and percentage of subjects excluded from the mITT and PP population by reason for 
exclusion will be summarized by treatment group for the FAS. 
8.3 
Protocol deviations 
The number of subjects with major protocol deviations leading to exclusion from the PP population 
will be summarized by treatment group and overall. Subjects deviating from a major criterion more 
than once will be counted once for the corresponding criterion. Any subjects who have more than one 
major protocol deviation will be counted once in the overall summary.  
A data listing will be provided by site and subject for all the major and minor protocol deviations. 
The protocol deviations criteria will be uniquely identified in the summary table and listing. The 
unique identifiers will include but are not limited to the following: 
 
< 75% of planned study treatment received 
 
Developed withdrawal criteria during the trial and was not withdrawn 
 
Received wrong treatment or incorrect dose 
 
Received excluded concomitant medications 
 
Other 
8.4 
Demographics and baseline characteristics 
Demographic and baseline characteristics, including upper endoscopy to determine H. pylori status, 
will be summarized with descriptive statistics by treatment group. 
8.4.1 Demographics 
Age (in years), baseline weight (in kg), BMI (kg/m2) and height (in cm) and other continuous 
demographic variables at baseline will be summarized descriptively for the FAS.  Age category (< 65, 
≥ 65 years), sex, primary race, ethnicity and other categorical variables will be summarized using 
frequency counts for the FAS. 


 
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8.4.2 Baseline and disease characteristics 
The categorical baseline characteristics such as baseline ECG overall assessment, Biopsy for 
Campylobacter-Like Organism (CLO), CYP2C19 status, Biopsy for histology and Biopsy for culture 
and susceptibility (categorized) will be summarized using frequency counts for the FAS. Categorized 
susceptibility will also be summarized by region (sub-regions of the United States), where a 
classification of the study sites to region will be done according to the following table. 
Region 
States 
West 
California, Nevada, Utah, Colorado, Arizona 
South 
Texas, Oklahoma, Arkansas, Louisiana, Tennessee 
Southeast 
Florida, Alabama, Georgia, South Carolina, North Carolina, Virginia 
Northeast 
Maryland, Connecticut, New York  
Central 
South Dakota, Wisconsin, Michigan 
Categorized susceptibility may also be summarized by state or study site as a post-hoc analysis. 
Minimum inhibitory concentration (MIC) values at baseline will be summarized together with the MIC 
values from Visit 6 for subjects entering the SOC phase. Continuous baseline variables such as vital 
signs: temperature (°C), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate 
(beats/min) and respiratory rate (breaths/min) will be summarized by descriptive statistics in the same 
way as continuous demographic variables for the FAS.  
Categorization for Susceptibility of Amoxicillin, Clarithromycin, Metronidazole and Rifabutin will be 
derived according to the following rules: 
MIC Values (ug/mL) 
Antibiotic 
Susceptible 
Intermediate 
Resistant 
Amoxicillin 
≤ 0.125 
- 
> 0.125 
Clarithromycin 
≤ 0.25 
0.5 
> 0.5 
Metronidazole 
≤ 8 
- 
> 8 
Rifabutin 
≤ 1 
- 
> 1 
Source (except for Clarithromycin): "The European Committee on Antimicrobial Susceptibility Testing. 
Breakpoint tables for interpretation of MICs and zone diameters. Version 8.1, 2018. http://www.eucast.org.". 
For Clarithromycin: “CLSI (Clinical and Laboratory Standards Institute), Methods for Antimicrobial Dilution 
and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria, M45, 3rd Edition, 2016.” 
8.4.3 Medical history 
A summary of medical history will be presented by treatment group, system organ class (SOC) and 
preferred term (PT) using Medical Dictionary for Regulatory Affairs® (MedDRA) Version 19.0 or 
higher. 


 
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A comprehensive data listing will also be included. 
8.4.4 Prior and concomitant medications 
A prior medication is defined as medication that stopped before the date of the first dose of 
randomized treatment (i.e. last medication intake is prior to first dose of treatment date (exclusive)).  
A concomitant medication is defined as a medication with either 
 
a recorded medication start date falling within the double-blind or SOC phase of the trial, or 
 
a recorded medication start date prior to the first day of study medication during the 
randomized treatment period without any recorded medication stop date prior to the start of 
the randomized treatment period. 
Medications with incomplete start or stop dates will be considered concomitant medications if it is 
possible that they could have been concomitant medications. 
Concomitant medications will be coded with the World Health Organization (WHO) drug dictionary 
(Enhanced – Format C, 03MAR2015 or later version). Concomitant medications will be summarized 
for each treatment group by Anatomical Therapeutic Chemical (ATC) 3rd level and preferred name for 
the following two categories (not exclusive): 
 
concomitant medications given during the double-blind phase (ie concomitant medications 
with a start date before or during the double blind phase of the study), and 
 
concomitant medications (excluding prescribed standard of care (SOC) medications) given 
during the SOC phase for subjects entering the SOC phase of the trial (ie concomitant 
medications either ongoing on the first day of  SOC medication or with a start date on or 
after the first day of SOC medication). 
A data listing will be included that shows all medications by preferred name and verbatim name. Prior 
medications will be excluded from the summaries but will be included in the listing. 
Prescribed SOC medications will be summarized by ATC 3rd level and preferred name for those 
subjects who entered the SOC phase of the study. The summary will be done by treatment group of 
the double-blind phase and overall. 
8.5 
Extent of exposure 
The following information on drug exposure will be presented for each treatment group for the SAF: 
 
Descriptive statistics for number of days treatment was received and number of capsules 
taken will be presented by treatment group 
8.5.1 Treatment duration 
Duration of double-blinded study drug (in days) will be calculated as: last dose date – first dose 


 
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Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
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date + 1 day, regardless of study drug interruption. 
Treatment duration will be summarized by treatment group on the SAF using descriptive statistics. 
Duration of SOC treatment for subjects entering the SOC phase of the trial will be calculated as last 
dose date of SOC treatment  – first dose date of SOC treatment + 1 day and summarized in the 
pertaining group of subjects. The summary will be done by treatment group of the double-blind phase 
and overall. 
8.5.2 Treatment compliance 
Subjects will be instructed to bring their study medication and all empty packaging to each clinic visit. 
Compliance with double-blinded study drug will be assessed by capsule counts, and details will be 
recorded and reconciled against expected medication use. Compliance will be calculated as a 
percentage of expected usage at each study visit as follows: 
For all subjects (including those who do not complete the treatment with study medication) compliance 
(%) will be calculated as 
100 x [(total number of capsules dispensed) –  (total number of capsules returned)]
168
 
Subjects taking too many capsules will have a resulting compliance of over 100%. 
Study drug compliance will be summarized by treatment group with descriptive statistics. They will 
also be summarized in categories “<=75% compliant”, “>75% – 90% compliant”, “>90% – 100% 
compliant”, and “> 100% compliant” using frequency tables. 
Compliance with SOC treatment will not be considered. 
All exposure and compliance data will be provided in data listings. 
8.6 
Efficacy analyses 
All efficacy analyses will be conducted on the FAS as primary analyses and repeated on the mITT and 
PP populations as sensitivity analyses. 
8.6.1 Analysis of primary efficacy endpoint(s) 
The primary endpoint is this study is eradication of H. pylori as confirmed via 13C UBT test results at 
the test of cure Visit 5 (Day 43-71) or fecal antigen test. Subjects with negative test results will be 
considered treatment successes. Subjects who test positive for H. pylori infection will be considered 
treatment failures, those subjects with indeterminate, not assessable, or missing results from actual test 
of cure visits will undergo a repeat 13C UBT testing. Persistent indeterminate results and subjects 
without any 13C UBT test after baseline will be considered as treatment failures and will be included 
as additional (sub-)category in the pertaining summary tables. 
Subjects who have their test of cure visit prior to 28 days after their last dose of study medication will 


 
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have a re-test within the protocol defined visit window of Visit 5. In this case the result of the re-test 
will be used in the primary analysis. In case this happens in more than 5 cases, a sensitivity analysis 
will be done in the FAS where the results from the first 13C UBT test will be used instead of the results 
from the re-test. 
 
Hypotheses: 
Let pO denote the response rate under RHB-105 and pP denote the response rate under the active 
comparator then the primary two-sided hypothesis to be tested is  
H0: pO - pP = 0  
vs the alternative  
H1: pO - pP ≠ 0 
This hypothesis will be evaluated using the FAS as the primary analysis population. 
 
Proportion of subjects with eradication of H. pylori will be tested between two treatment groups using 
the chi-square test at the 5% level of significance; in addition the estimated treatment difference along 
with the corresponding 95% CI will be presented.    
As sensitivity analyses the analysis of the primary endpoint will be repeated in the mITT and PP 
populations (where those subjects lost to follow-up or not completing Visit 5 will be excluded from 
the analysis). Further, the following sensitivity analyses to investigate the impact of imputation rules 
for subjects who did not provide a result of the 13C UBT test at Visit 5 will be added in the FAS: 
1. Eradication rates by treatment will be calculated in subjects with observed data (mITT 
population), and the same eradication rates will be assumed for subjects with unobserved 
(missing) data. For this purpose, multiple imputations will be used where for a subject 
with missing data the event of eradication/non-eradication will be randomly assigned 
according to a Bernoulli-distribution with rate as estimated from the subjects with 
observed data. The results of this multiple imputation will be combined over the iterations 
according to the method of Rubin (1987) to generate an estimator for the treatment 
difference with corresponding 95% CI and a p-value for the associated chi-square test. 
2. All active-controlled subjects with missing data will be assumed as treatment successes 
while all subjects treated with the investigational regimen will be assumed as treatment 
failures. This method is used only to give a lower bound on the upper limit of the 
confidence interval for the difference in eradication rates because such a scenario would 
be unlikely to actually occur.  
3. All subjects with missing data will be assumed as treatment successes. 
Sensitivity analyses  2. and 3. will be conducted in a similar manner to the primary analysis.  


 
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A further analysis of the primary efficacy parameter will be performed by study site. For this analysis, 
sites which have randomized less than 5 subjects will be pooled by region of the United States (see 
table in Section 8.4.2) to form clusters of sites by region. If after this step there is still a (pooled) site 
with less than 5 subjects, this site will be pooled with the smallest pooled site from the other regions. 
8.6.2 Analysis of secondary efficacy endpoint(s) 
Antibiotic Resistance and Susceptibility Subgroup Analyses -  
The primary endpoint will be summarized within subgroups formed by the presence of H. pylori 
susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and rifabutin determined 
based upon samples obtained prior to initiating study treatment. 
Proportion of subjects with eradication of H. pylori will be tested between two treatment groups using 
the chi-square test at the 5% level of significance; in addition estimated differences within each 
subgroup along with 95% CIs will be presented.  
Assess the difference in antibiotic resistance: 
The difference in antibiotic resistance and susceptibility of H. pylori after treatment with study drug 
in treatment failure subjects will be summarized by treatment group. No formal statistical tests will be 
performed for group comparison. 
8.6.3 Analysis of exploratory endpoint(s) 
Upon study completion and unblinding of all subjects, CYP2C19 status (performed at baseline) will 
be summarized by treatment arm. CYP2C19 status is classified as ultra rapid metabolizers, extensive 
metabolizers, intermediate metabolizers and poor metabolizers. A summary table of CYP2C19 status 
and H. pylori infection eradication success will be presented, and a chi-square test will be performed 
to test if CYP2C19 status is associated with treatment success. 
Further subgroup analyses of efficacy will be done by subgroups based on pharmacokinetic measures. 
Definition of these measures will be provided after finalization of the double-blind study phase.   
Subjects who have a positive 13C UBT test at Visit 5 will receive SOC therapy for a certain time and 
then have a further test-of cure visit (Visit 8). Eradication rates for H. pylori at V8 will be summarized 
overall and by treatment group in the double-blind study phase. 
8.7 
Safety analyses 
Safety analyses will be conducted on the SAF and will be performed for all safety variables specified 
below.  
All safety data will be summarized by treatment group.  
No statistical tests will be performed. 


 
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8.7.1 Adverse events 
A treatment emergent adverse event (TEAE) is defined as any unfavorable and unintended sign, 
symptom, physical finding or disease, whether or not believed to be related to the investigational 
product that arises after the first dose of study drug was administered and not later than 28 days 
following the last dose of study drug. This includes any occurrence that was new in onset or aggravated 
in severity or frequency from the time the first dose of study drug was administered. Abnormal results 
of diagnostic procedures, or laboratory test abnormalities, should also be considered as TEAEs, ONLY 
if they result in any of the following:   
 
Discontinuation of study drug  
 
Require treatment or any other therapeutic intervention and/or  
 
Require further diagnostic evaluation (excluding a repetition of the same procedure to confirm 
the abnormality)  
All events, TEAEs and Serious adverse events (SAE)s, regardless of severity or causality, that occur 
between the time of first study drug administration and within 28 days following the last dose of 
blinded study drug are to be documented on the adverse event case report form with indications of 
onset, duration, severity (mild, moderate, and severe), seriousness, relationship to study drug 
(unrelated, unlikely, possible, probable, definite), remedial actions taken, and outcome.  
All SAEs occurring during the administration of standard of care (SOC) drug are to be documented as 
SAEs on serious adverse event case report form (for SOC) with indications of onset, duration, severity 
(mild, moderate, and severe), relationship to SOC drug (unrelated, unlikely, possible, probably, 
definite), remedial actions taken, and outcome. If the SAE is deemed to be related to any of the standard 
of care drugs, it is the responsibility of the investigator to report the event to the manufacturer of the 
related drug, through the manufacturer’s post-marketing surveillance system. Determination of 
eradication of H. Pylori infection will be based on 13C UBT testing done between 43 and 71 days after 
initiation of blinded therapy. Due to this delay in time of 28-60 days, any SAEs that occur during the 
SOC dosing period will NOT be considered related to the study treatment regimen of RHB-105 or 
active comparator. 
All Adverse events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred Term 
(PT) according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.0 or higher. 
In summaries by SOC and PT, adverse events will be sorted by decreasing frequency in the overall 
total of SOC and of PT within each SOC. Events of the same frequency within classification level are 
sorted alphabetically. 
AE summary tables will be presented for TEAEs only and will include the following: 
 
All TEAEs 
 
Related TEAEs (AE will be defined as related if causality is definite or probable or possible) 


 
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 
TEAE’s by closest related 
 
TEAEs by action taken 
 
TEAEs by maximum severity 
 
TEAEs leading to treatment discontinuation  
All TEAEs will be summarized by SOC, PT and treatment group using frequency counts and 
percentages (i.e., number and percentage of subjects with an event). In addition an overall summary 
for the categories above will be prepared by treatment group and overall. 
Where a subject has multiple adverse events within the same system organ class/with the same 
preferred term in the treatment period, the subject will only be counted once at the system organ class 
level/for this preferred term in adverse event frequency tables. 
Events without recorded intensity/causality taken are summarized as severe /related. 
All AEs will be included in comprehensive data listings. A separate listing will be included for AEs 
leading to discontinuation from study. 
8.7.2 Serious adverse events 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose:   
 
Results in death  
 
Is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe  
 
Requires inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Is considered medically significant. 
Separate data listings and summaries will be presented for all SAEs and deaths. 
 
Serious TEAEs 
 
Serious related TEAEs 
Individual subject data listings will be provided for all deaths and discontinuation of study 
medication due to TEAEs. 
8.7.3 Clinical laboratory evaluations 
Key laboratory data (Chemistry and hematology, see Table 2Table 2) will be subjected to both a 
quantitative analysis and qualitative analysis where frequencies of normal, abnormal low, and 
abnormal high values will be computed. Additionally, abnormal results will be summarized with 
frequencies and percentages by clinical significance, panel, test, treatment group, and time point. 


 
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Urinalysis results and viral serology results at baseline will not be summarized but only presented in 
data listings. Pregnancy test results will also be summarized. 
Shift tables demonstrating the changes (low/normal/abnormal) from baseline to worst post-baseline 
value will be displayed in cross-tabulations by panel, test and treatment group. 
Other laboratory assessments and change from baseline, where applicable, will be summarized with 
descriptive statistics by panel, test, treatment group, and time point. For these quantitative analyses US 
conventional units will be used for all summaries.  
Data listings will display all laboratory test results along with findings. 
 
 


 
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Table 2: Laboratory assessments in the RHB-105-20 study 
Hematology  
Clinical Chemistry  
Special Testing  
Urinalysis  
Hematocrit  
Hemoglobin  
Red blood cell 
(RBC) count  
White blood cell 
(WBC) count 
Neutrophils  
Bands 
Lymphocytes  
Monocytes 
Basophils  
Eosinophils  
Platelet count 
(estimate not 
acceptable)  
Blood urea nitrogen (BUN)  
Creatinine  
Creatinine Clearance 
Total bilirubin (Direct and 
indirect fractionated) 
Lactate Dehydrogenase 
(LDH)  
Serum glutamic-pyruvic   
transaminase 
(SGPT)/alanine  
aminotransferase (ALT) 
Serum glutamic-oxaloacetic 
transaminase 
(SGOT)/aspartate 
aminotransferase (AST)  
Creatine phosphokinase  
Alkaline phosphatase  
Sodium  
Potassium  
Chloride  
Gamma-glutamyltransferase 
(GGT)  
Bicarbonate  
Calcium  
Magnesium  
Inorganic phosphorus  
Amylase  
Uric acid  
Total cholesterol  
Total protein  
Glucose  
Albumin  
CYP 2C19 genotyping  
HBs Ag  
HCV Ab  
HIV1 antibody  
HIV2 antibody  
 
Pharmacokinetic 
testing for: 
amoxicillin, 
omeprazole, 
rifabutin, and 25-
O-desacetylrifabutin  
 
Urine pregnancy 
 
13C Urea Breath Test 
 
Culture and 
Resistance/ 
Susceptibility for H. 
pylori  
 
CLO – Campylobacter 
Like Organism 
(Rapid Urease Test) 
 
Histology for H. 
pylori 
  
 
Leucocytes  
Nitrite  
Protein  
pH  
Blood 
Specific gravity  
Ketones  
Glucose  
Sediment 
microscopy, If 
indicated by 
the dipstick  
 
 


 
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8.7.4 Vital signs 
The results and changes from baseline of vital signs (pulse, respiratory rate, supine systolic and supine 
diastolic blood pressure, oral temperature, and weight) will be summarized with descriptive statistics 
by treatment group and time point. A data listing of all vital signs data (including height at screening) 
will also be included. 
8.7.5 Physical examinations 
The physical examination listing will include date of exam, result (normal, abnormal, not examined), 
and 
description 
of 
abnormality 
for 
each 
major 
body 
system 
(general 
appearance, 
head/eyes/ears/nose/throat, neck, lungs, heart, abdomen, genitourinary, extremities, neurological, skin, 
and lymphatics). Detailed results of the general physical examination are only provided for the 
screening visit, otherwise it will only be denoted whether any clinically significant changes since the 
last study visit have been observed.  
The results of physical examinations at screening will be summarized with frequencies and 
percentages by body system and treatment group.  
All physical examination data will be displayed in data listings, one for the screening results and one 
for the subsequent changes. 
8.7.6 Electrocardiograms 
ECG measurements (heart rate, PR, QRS, QT, QTcF) as well as ECG results (normal, abnormal not 
clinically significant, abnormal clinically significant) are measured at screening only. ECG 
measurements will be summarized by descriptive statistics and ECG results with frequencies and 
percentages by treatment group. All ECG data will be displayed in a data listing.  
8.8 
Pharmacokinetic (PK) analyses  
All PK analyses will be performed in the PK population. 
Blood samples will be collected to assay the plasma concentrations of amoxicillin, omeprazole, 
rifabutin, and the rifabutin metabolite 25-O-desacetyl-rifabutin at baseline Visit 1 (Day 1) before the 
first dose of double-blinded study medication and Visit 3 (Day 13). 
Plasma samples will be analyzed using validated methodology. Plasma concentration data for each 
analyte by time and treatment will be summarized through data tabulations and using descriptive 
statistics (n, mean, standard deviation, coefficient of variation [CV%], geometric mean, geometric 
CV%, median, minimum, and maximum). Comprehensive data listings will also be included. 
Plasma concentration data will also be summarized by the primary efficacy endpoint. 


 
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8.9 
Subgroup analyses 
The primary efficacy endpoint will be analyzed within subgroups formed by the presence of H. pylori 
susceptibility and resistance to amoxicillin, clarithromycin, metronidazole and rifabutin determined 
based upon samples obtained prior to initiating study treatment. Further subgroup analyses or the 
primary efficacy endpoint will be performed by CYP2C19 status and by subgroups based on 
pharmacokinetic measures. 
8.10 Interim analysis 
No interim analysis is planned for this study. 
8.11 Analysis after the double-blind phase of the study 
To allow for early availability of the primary efficacy and most important safety results there will be 
a primary lock of the databases after all patients have finalized the double-blind study phase and only 
the patients evaluable for the SOC phase continue their participation. Unblinding of the study and also 
the Population Classification meeting (see section 6.5) will be done at this stage.  
The following analyses will be part of the primary study results: 
 
Subject disposition and location to analysis populations 
 
Demography 
 
Treatment exposure and compliance 
 
Responder analysis of eradication of H. pylori 
 
Responder analysis by resistance/susceptibility to antibiotics 
 
Eradication of  H. pylori by CYP2C19 Status 
 
Treatment emergent AEs and SAEs. 
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 33 of 36 
 
9 
CHANGES 
TO 
PLANNED 
ANALYSIS 
FROM 
STUDY 
PROTOCOL 
For the secondary endpoints the protocol states that “The proportion of subjects with failure to 
eradicate H. pylori and the treatment effect (difference in the proportions) will be estimated 
within each subgroup along with 95% 2-sided confidence intervals…” For the primary 
endpoint the proportion of subjects with treatment success (eradication of H. pylori) is 
evaluated, this proportion will now also be used for all secondary endpoints to ensure 
comparable results.  


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 34 of 36 
 
10 
REFERENCES 
1. 
ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- adopted 
December 1995). 
2. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
3. 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
& Sons. 
 
 


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 35 of 36 
 
11 
APPENDICES 
Appendix A - Definitions for Clinical and Laboratory Adverse Events  
  
All adverse events (clinical and laboratory) will be rated as follows:  
  
Severity (Clinical Events Only)  
 
 
 
Severity of clinical events are to be graded as follows:  
1 = Mild:  
Event Is noticeable to the subject, does not interfere with the subject’s 
daily activities and usually does not require additional therapy or dose 
adjustment.  
2 = Moderate:  
Event may interfere with the subject’s daily activities and may require 
additional therapy  
3 = Severe:  
Event may severely limit the subject’s daily activities and typically requires 
therapy or intervention.  
  
 
Causal Relationship  
The investigators are to assess the causal relationship of all AEs using the following five categories:  
Relationship  
Causality  
Description  
Not related to 
investigational 
agent  
Unrelated  
The AE is clearly not related to the investigational agent.  
Unlikely  
The AE is doubtfully related to the investigational agent.  
Related to 
investigational 
agent  
Possible  
The AE may be related to the investigational agent.  
Probable  
The AE is likely to be related to the investigational 
agent.  
Definite  
The AE is clearly related to the investigational agent.  


 
Statistical Analysis Plan (SAP) 
 
 
 
RedHill Biopharma Ltd.  
 
Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: Final 2.0, Date: 20 Nov 2018
                                                                                 Page 36 of 36 
 
Appendix B - Visit Window 
Day 1 for the treatment period is the start date of double-blinded study medication.  
Table 3: 
Visit windows for treatment period (up to Visit 8)  
Visit 
Period 
Day range 
Visit 0 
Screening 
Day -42 to -2 
Visit 1 
Baseline 
Day 1 
Visit 2 
Phone 
Day 8 +/- 1 
Visit 3 
Safety 
Day 13 +/- 2 
Visit 4 
Phone 
Day 28 – 60 +/- 2 
Visit 5 
Test of Cure 
Day 43 – 71 + 7 
Visit 5a 
13C UBT Follow-up 
Day 44 – 72 +7 
Visit 6 
SOC Baseline 
After Day 44 – 72 +14 
Visit 7 
Phone 
Day 50 – 79 +/- 2 
Visit 8 
Test of Cure 
Day 85 – 140 + 14 
 


 
Addendum to the Statistical 
Analysis Plan (SAP) 
RedHill Biopharma Ltd.  
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                   Page 1 of 11 
 
Protocol Title: 
A Randomized Double Blind Active Comparator Controlled Phase 
III Study to Assess the Safety and Efficacy of RHB-105 in the 
Treatment of Confirmed Helicobacter pylori (H. pylori) Infection 
Protocol Number: 
RHB-105-02 
Protocol Version, Date 
Protocol Amendment 3, 22 Mar 2018 
ICON ID:  
3101/0005 
Document Version, Date: 
Version 1.0,  06 Feb 2019  
 
 
 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
RedHill Biopharma Ltd. 
 
 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information contained 
within this document or any related information to other persons without the 
permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


 
Addendum to the Statistical Analysis Plan (SAP) 
RedHill Biopharma Ltd. 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
Version: 1.0, Date: 06 Feb 2019
Page 3 of 11
 
REVISION HISTORY 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Version 1.0/ 06 
Feb 2019 
Initial version 
N/A 
N/A 


Addendum to the Statistical Analysis 
Plan (SAP) 
RedHill Biopharma 
Ltd. 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                      Version: Final 1.0, Date: 06 Feb 2019 
                                                                                               Page 4 of 11 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE ............................................................................................................. 2 
REVISION HISTORY........................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................... 4 
1 INTRODUCTION ........................................................................................................... 5 
2 Specification Of additionaL Analyses ............................................................................. 6 
2.1 Additional Analyses of Efficacy ............................................................................. 6 
2.2 Additional Analyses of Safety ................................................................................ 6 
 
 


Addendum to the Statistical Analysis 
Plan (SAP) 
RedHill Biopharma 
Ltd. 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                      Version: Final 1.0, Date: 06 Feb 2019 
                                                                                               Page 5 of 11 
 
1 
INTRODUCTION 
The purpose of this Addendum to the Statistical Analysis Plan (SAP) is to provide a description of 
additional ad-hoc analyses performed after the final statistical analysis for study protocol RHB-105-
02 “A Randomized Double Blind Active Comparator Controlled Phase III Study to Assess the Safety 
and Efficacy of RHB-105 in the Treatment of Confirmed Helicobacter pylori (H. pylori) Infection”, 
Amendment 3 dated 22 Mar 2018.  
 
 


Addendum to the Statistical Analysis 
Plan (SAP) 
RedHill Biopharma 
Ltd. 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                      Version: Final 1.0, Date: 06 Feb 2019 
                                                                                               Page 6 of 11 
 
2 
SPECIFICATION OF ADDITIONAL ANALYSES 
2.1 
Additional Analyses of Efficacy 
To investigate the primary efficacy outcome in relation to pharmacokinetic results three sensitivity 
analyses will be performed: 
1. A sensitivity analyses performed in the Full Analysis Set (FAS) excluding patients from the 
active comparator group that have a measurable rifabutin concentration at Visit 3. 
2. A sensitivity analysis performed in the Pharmacokinetic (PK) population, defined as subjects 
in the FAS that have demonstrable presence of any component of investigational drug at 
Visit 3 or for whom the PK assessment at Visit 3 was performed more than 250 hours after 
the last dose of randomized study drug before this assessment.  
3. A sensitivity analysis performed in the PK population where in addition, as in the first 
sensitivity analysis, patients from the active comparator group that have a measurable 
rifabutin concentration at Visit 3 will be excluded from the analysis. 
 
2.2 
Additional Analyses of Safety 
To investigate the comparability of tolerance and safety of RHB-105 over the different phenotypes 
according to CYP2C19 genotyping results the number of treatment-emergent adverse events 
(TEAE)/number of subjects with any TEAE and the number of serious adverse events (SAE)/number 
of subjects with any SAE will be provided by phenotype.  


 
Addendum to the Statistical Analysis Plan (SAP) 
 
RedHill Biopharma Ltd. 
 
 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                                                                                                                                                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                                                                                                                                                                              Page 7 of 11 
 
3 
TABLE MOCKS 
 
Ad-hoc Table 1 
Responder Analysis of Eradication of H. pylori: Sensitivity Analysis Excluding Subjects in the Active Comparator Group with Nonnegative Concentrations of 
Rifabutin at Visit 3 
Full Analysis Set 
 
 
Eradication of H. pylori  
RHB-105 
(N=xxx) 
Active Comparator 
 (N=xxx) 
Treatment Difference 
       
 
 
 
n 
xx 
xx 
 
Responder 
xx (xx.x) 
xx (xx.x) 
 
95% CI for proportion of responder 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
Non-responder 
xx (xx.x) 
xx (xx.x) 
 
   Positive test result  
xx (xx.x) 
xx (xx.x) 
 
   Missing post-baseline test result   
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Difference of Response rates (RHB-105 – Active Comparator) 
xx.x 
95% CI  
 
 
(xx.x, xx.x) 
p-value[a] 
 
 
0.xxx 
 
 
 
 
 
 
 
 
CI = Confidence Interval. 
RHB-105 – all-in-one' combination oral capsule containing 12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole. 
Active Comparator - all-in-one' combination oral capsule containing 250 mg amoxicillin, and 10 mg omeprazole. 
n is the number of subjects in FAS population excluding subjects in the Active Comparator Group with nonnegative concentrations of Rifabutin at Visit 3. 
Percentages are based on n. 
Eradication of H. pylori as confirmed via 13C UBT test results at the test of cure Visit 5 (Day 43-71) or fecal antigen test. Subjects with negative test 
results are considered as treatment successes (responder). Subjects who test positive for H. pylori infection are considered as treatment failures (non-
responder). Subjects with indeterminate, not assessable, or missing results from actual test of cure visits should undergo a repeat 13C UBT testing.  
Subjects with persistent indeterminate results and subjects without any 13C UBT test after baseline will be considered as treatment failures. 
95% CI for the proportion of responder are based on Wilson’s method. 
[a] P-value based on Chi-square test. 
 
          
Source: Listing 16.2.6.1 
Program Name: xxxxxx.SAS                                            DB Snapshot/Lock Date: DDMMMYYYY                            Runtime: DDMMMYYYY HH:MM 


 
Addendum to the Statistical Analysis Plan (SAP) 
 
RedHill Biopharma Ltd. 
 
 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                                                                                                                                                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                                                                                                                                                                              Page 8 of 11 
 
 
Ad-hoc Table 2 
Responder Analysis of Eradication of H. pylori 
PK Analysis Set 
 
 
 
Eradication of H. pylori  
RHB-105 
(N=xxx) 
Active Comparator 
 (N=xxx) 
Treatment Difference 
       
 
 
 
Responder 
xx (xx.x) 
xx (xx.x) 
 
95% CI for proportion of responder 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
Non-responder 
xx (xx.x) 
xx (xx.x) 
 
   Positive test result  
xx (xx.x) 
xx (xx.x) 
 
   Missing post-baseline test result   
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Difference of Response rates (RHB-105 – Active Comparator) 
xx.x 
95% CI  
 
 
(xx.x, xx.x) 
p-value[a] 
 
 
0.xxx 
 
 
 
 
 
 
 
 
CI = Confidence Interval. 
RHB-105 – all-in-one' combination oral capsule containing 12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole. 
Active Comparator - all-in-one' combination oral capsule containing 250 mg amoxicillin, and 10 mg omeprazole. 
N is the number of subjects in PK analysis set. Percentages are based on N. 
Eradication of H. pylori as confirmed via 13C UBT test results at the test of cure Visit 5 (Day 43-71) or fecal antigen test. Subjects with negative test 
results are considered as treatment successes (responder). Subjects who test positive for H. pylori infection are considered as treatment failures (non-
responder). Subjects with indeterminate, not assessable, or missing results from actual test of cure visits should undergo a repeat 13C UBT testing.  
Subjects with persistent indeterminate results and subjects without any 13C UBT test after baseline will be considered as treatment failures. 
95% CI for the proportion of responder are based on Wilson’s method. 
[a] P-value based on Chi-square test. 
 
          
Source: Listing 16.2.6.1 
Program Name: xxxxxx.SAS                                            DB Snapshot/Lock Date: DDMMMYYYY                            Runtime: DDMMMYYYY HH:MM 
 
 
 
 
 
 


 
Addendum to the Statistical Analysis Plan (SAP) 
 
RedHill Biopharma Ltd. 
 
 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                                                                                                                                                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                                                                                                                                                                              Page 9 of 11 
 
Repeat Ad-hoc table 1 for: 
 
Ad-hoc Table 3 
Responder Analysis of Eradication of H. pylori: Sensitivity Analysis Excluding Subjects in the Active Comparator Group with Nonnegative Concentrations of 
Rifabutin at Visit 3 
PK Analysis Set 
 
 


 
Addendum to the Statistical Analysis Plan (SAP) 
 
RedHill Biopharma Ltd. 
 
 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                                                                                                                                                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                                                                                                                                                                              Page 10 of 11 
 
Ad-hoc Table 4 
Overall Summary of Treatment Emergent Adverse Events (TEAEs) by CYP2C19 Status 
Safety Analysis Set 
 
             
CYP2C19 Status at Baseline 
       Overall Incidence 
RHB-105 
(N=xxx) 
n (%) 
Active 
Comparator 
 (N=xxx) 
n (%) 
Overall 
(N=xxx) 
n (%) 
 
 
 
 
 
 
 
 
Ultrarapid metabolizers 
 
 
 
       n 
xx 
xxx 
xxx 
       Number of TEAEs in the double blind phase 
xxx 
xxx 
xxx 
       Number of Subjects with any TEAE in the double blind phase  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
       Number of Serious Adverse Events (SAEs) in the double blind phase  
xxx 
xxx 
xxx 
       Number of Subjects with any SAE in the double blind phase 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Rapid metabolizers 
 
 
 
       … 
 
 
 
 
 
 
 
Normal metabolizers 
 
 
 
       …  
 
 
 
 
 
 
 
Intermediate metabolizers 
 
 
 
       … 
 
 
 
 
 
 
 
Poor metabolizers 
 
 
 
       … 
 
 
 
 
 
 
 
AE=Adverse Events; SAE=Serious Adverse Events; TEAE=Treatment Emergent Adverse Events 
N=number of subjects in the treatment group analysis set. 
RHB-105 – all-in-one' combination oral capsule containing 12.5 mg rifabutin, 250 mg amoxicillin, and 10 mg omeprazole. 
Active Comparator - all-in-one' combination oral capsule containing 250 mg amoxicillin, and 10 mg omeprazole. 
n is the number of subjects in the Safety Analysis Set in each treatment group by CYP2C19 status at baseline. Percentages are based on n. 
Treatment emergent adverse event is defined as any event that occurs on or after the first dose of study drug administration and not later than 28 days 
following the last dose of study drug or any pre-existing event which worsened in severity after dosing. 
 
Source: Listing 16.2.7.1.1 


 
Addendum to the Statistical Analysis Plan (SAP) 
 
RedHill Biopharma Ltd. 
 
 
 
Addendum to the Statistical Analysis Plan 
Protocol Number: RHB-105-02 
                                                                                                                                                                                                       Version: Final 1.0, Date: 06 Feb 2019 
                                                                                                                                                                                                                                              Page 11 of 11 
 
Program Name: xxxxxx.SAS                                            DB Snapshot/Lock Date: DDMMMYYYY                            Runtime: DDMMMYYYY HH:MM