Clinical trial NCT02498418
Conditions: Diarrhea
Sponsor: Actavis Inc.
Start date: 2016-01-06; Completion date: 2017-02-28
Enrollment: 739 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to demonstrate rifaximin 200 milligrams (mg) tablets (test) and Xifaxan® 200 mg tablets (reference) are clinically bioequivalent with respect to the clinical cure rates when administered 3 times a day (TID) for 3 days in participants with travelers' diarrhea.

Detailed description:
This is a randomized, placebo-controlled bioequivalent study with a clinical endpoint in the treatment of travelers' diarrhea. After 3 unformed stools are recorded within the 24 hours immediately preceding randomization, participants are to be randomized to receive the generic rifaximin 200 mg oral tablet, Xifaxan (the reference listed drug)200 mg oral tablet, or placebo 3 times daily for 3 days (that is; on Days 1, 2, and 3).

Arms: arm 1: Participants will receive a generic rifaximin 200 mg tablet 3 times daily orally for 3 days. arm 2: Participants will receive a xifaxan 200 mg tablet 3 times daily orally for 3 days. arm 3: Participants will receive a rifaximin placebo tablet 3 times daily orally for 3 days.
Interventions: intervention 1: Rifaximin intervention 2: Xifaxan® intervention 3: Placebo Tablet
Intervention descriptions: intervention 1: Tablets, generic formulation of the brand product. intervention 2: Tablets, brand product. intervention 3: Placebo tablets in the same image of the generic rifaximin. Has no active ingredient.

Protocol documents:
Prot_001.pdf: 
Clinical Study Protocol with Amendment 01 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multicenter, 
Bioequivalence Study with Clinical Endpoint Comparing Rifaximin 200-mg Tablets with 
Xifaxan® 200-mg Tablets in the Treatment of Travelers’ Diarrhea 
Study Number ACTA/RIFX/2015 
NCT02498418 
Protocol with Amendment 01 Approval Date: 27 October 2015 


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Study Protocol 
Version 2  – 27 October 2015 
Amendment 1 
A Randomized, Double-Blind, Placebo-Controlled, Parallel 
Design, Multicenter, Bioequivalence Study with Clinical 
Endpoint Comparing Rifaximin 200-mg Tablets with Xifaxan® 
200-mg Tablets in the Treatment of Travelers’ Diarrhea 
 
 
Study Number: 
ACTA/RIFX/2015 
Study Phase: 
Phase III  
Investigational Product:  
Rifaximin 200-mg Tablets 
Indication:   
 
Travelers’ Diarrhea 
Sponsor:  
 
 
Actavis 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
 
 
 
Version Number 
Version Date 
Original Protocol 
1.0 
21 September 2015 
Amendment 1 
2.0 
27 October 2015 
 
 
Compliance Statement: This study will be conducted in accordance with the clinical 
research guidelines established by the US Code of Federal Regulations (CFR) (Title 21, 
Parts 50 [including Subpart D], 54, 56 and 312), and the International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP). Study documents 
will be maintained in accordance with applicable regulations. 
 
Confidential: The information contained in this protocol is confidential and is intended 
for the use of clinical investigators. It is the property of Actavis or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical 
investigation, unless such persons are bound by a confidentiality agreement with Actavis 
or its subsidiaries. 


Actavis 
 
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Investigator Signature Page 
I have carefully read and understand the foregoing protocol ACTA/RIFX/2015 and agree 
that it contains all the necessary information for conducting this study safely. I will 
conduct this study in strict accordance with this protocol, International Conference on 
Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), the Code of Federal 
Regulations (CFR), the Health Insurance Portability and Accountability Act (HIPAA- in 
countries where applicable) and/or with country-specific local regulatory guidelines. I 
will attempt to complete the study within the time designated.  
 
I will ensure that the rights, safety, and welfare of patients under my care are protected. I 
will ensure control of the drugs under investigation in this study.  
 
I will provide access to the protocol and all other study-related information supplied by 
the Sponsor to all personnel responsible to me who participate in the study. I will discuss 
this information with them to assure that they are adequately informed regarding the drug 
and conduct of the study.  
 
I agree to keep records on all patient information (source documents, shipment and drug 
return forms and all other information collected during the study) and drug disposition in 
accordance with FDA regulations.  
 
I will not enroll any patients into this protocol until FDA approval (where applicable) or 
country competent authority approval, Local Ethics Committee (LEC)/Institutional 
Review Board (IRB) approval and Sponsor approval are obtained. 
 
 
 
 
 
 
Investigator 
 
 
 
 
__________________________________ 
________________ 
Name, Function: 
Signature and Date 
Institution: 
 


Actavis 
 
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Sponsor’s Representatives 
 
 
 
__________________________________ 
________________ 
  
Date 
 
Actavis Inc 
 
CRO Representatives 
 
 
__________________________________ 
________________ 
  
Date 
 
 
 
 
__________________________________ 
________________ 
  
Date 
 
 
 
 
__________________________________ 
_________________ 
  
Date 
 
 
 
 
Lead Biostatistician 
 
 
 
__________________________________ 
_________________ 
  
Date 
 
 
 
 


Actavis 
 
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Protocol Synopsis 
Sponsor: 
Name of Medical Product: 
Active Ingredient: 
Actavis 
Rifaximin 
Rifaximin 
Study Sites:  
This will be a multicenter, multinational study.  
Study Duration: 
Study Phase: 
Treatment duration for a subject is 3 days.  The duration for 
participation in the study for a subject could be up to 7 days  
Phase III 
Study Title:  
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multicenter, Bioequivalence Study with 
Clinical Endpoint Comparing Rifaximin 200-mg Tablets with Xifaxan® 200-mg Tablets in the Treatment of 
Travelers’ Diarrhea 
Study objectives: 
The primary objectives are: 
(i)  Bioequivalence of rifaximin 200-mg tablets (the test product) and Xifaxan® 200-mg tablets (the 
reference product) with respect to the clinical cure rates on Study Day 5 when administered 3 times a 
day (TID) for 3 days in subjects with Travelers’ Diarrhea (TD).   
Clinical cure is defined as either of the following: 
 No stools or only formed stools within a 48 hour period and no fever, with or without other enteric 
symptoms, OR 
 No watery stools or no more than two soft stools passed within a 24 hour period with no fever and 
no other enteric symptoms except for mild excess gas/flatulence. 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in ≤ 3 days is a 
clinical failure. 
 
(ii) Superiority of test and reference products over placebo with respect to the clinical cure rates on Study 
Day 5, in the treatment of TD, using the mITT population with LOCF. 
 
The secondary objectives of this study are the following: 
• 
To compare “Time to last unformed stool” (TLUS) observed for rifaximin 200-mg tablets and Xifaxan® 
200-mg tablets on test of cure (TOC) visit (Study Day 5, 6 or 7). TLUS is defined as the interval 
beginning with the first dose of study drug and ending with the last unformed stool passed.  
• 
To compare the microbiological cure rate of rifaximin 200-mg tablets and Xifaxan® 200-mg tablets on 
test of cure (TOC) visit (Study Day 5, 6 or 7).  Subjects are considered to have achieved 
microbiological cure if the pathogen identified at Visit 1 is no longer found in the stool at the TOC 
visit. Microbiological cure rate will be a supportive evidence of similarity between the test product and 
the reference product treatment arms and not considered as evidence of clinical bioequivalence. 
 
Methodology: 
This is a randomized, double-blind, placebo controlled, parallel design, multicenter, multinational 
bioequivalence study.  Subjects will be adult, non-indigenous travelers with naturally acquired acute 
diarrhea.  Eligible subjects must have at least 3 episodes of unformed stools recorded within the 24 hours 
immediately preceding randomization and at least one of the following signs and symptoms of enteric 
infection:  abdominal pain or cramps, nausea, vomiting, fecal urgency, excessive gas/flatulence, or 
tenesmus.  There will be 2 on-site study visits and 1 telephone visit (on Day 3, after taking about 5 doses of 
study medication).  At the first visit, subjects will be screened and eligible subjects will be randomized 
 
 to receive rifaximin 200-mg tablets, Xifaxan® 200-mg tablets, or placebo tablets, TID for 3 
days, beginning not more than 72 hours after the onset of diarrhea.  The first dose of study drug should be 
preferably administered under the supervision of an unblinded dispenser/unblinded study staff member at 
the first study visit.  For the second study visit, the study staff will contact the subject by telephone.  The 
third visit is the TOC visit, which will occur 24 to 72 hours after the last dose of study drug.  For 5 days 


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Sponsor: 
Name of Medical Product: 
Active Ingredient: 
Actavis 
Rifaximin 
Rifaximin 
after randomization/first dose, subjects will record dosing, stool information (date, time, consistency) and 
enteric symptoms in a daily Diary. Stool samples will be collected pre-treatment (screening) and post-
treatment (TOC) to be cultured for pathogenic organisms and microbiological cure rates. If the stool sample 
collection is not possible at visit 3, a rectal swab will be collected. Adverse events (AEs), concomitant 
medication details and safety laboratory samples will be collected at Visit 1 and Visit 3. AEs and 
concomitant medication details will also be obtained during Visit 2.  
Number of Subjects (Planned): Approximately 618 
 will be 
randomized 
 for test vs. reference vs. placebo 
 
 
assuming that the overall dropout rate from the randomized population 
to mITT population is about 15%. 
Diagnosis and Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria: 
1. Adult male or nonpregnant female aged ≥ 18 years non-indigenous travelers (e.g., visiting 
students/faculty or international tourists) affected by naturally acquired acute diarrhea. Diarrhea is 
defined as the passage of at least three episodes of unformed stools in a 24-hour period. Stools are 
classified as formed (retains shape), soft (assumes shape of container), or watery (can be poured). 
When using this classification, both soft and watery stools are unformed and abnormal. 
2. At least 3 episodes of unformed stools recorded within the 24 hours immediately preceding 
randomization (screening and randomization should occur as closely as possible on the same day, 
i.e. Day 1). 
3. At least one of the following signs and symptoms of enteric infection: 
a. 
abdominal pain or cramps 
b. nausea 
c. 
vomiting 
d. fecal urgency 
e. 
excessive gas/flatulence 
f. 
tenesmus 
4. Females of child bearing potential (WOCBP*) must not be pregnant or lactating at baseline visit 
(as documented by a negative urine pregnancy test with a minimum sensitivity of 25 IU/L or 
equivalent units of beta-human chorionic gonadotropin (Beta-HCG) at screening and urine 
pregnancy at baseline. *All female subjects will be considered to be of childbearing potential 
unless they are postmenopausal. WOCBP are defined as sexually mature women without prior 
hysterectomy, or who have had any evidence of menses in the past 12 months. However, women 
who have been amenorrheic for the past 12 or more months are still considered to be of 
childbearing potential, if the amenorrhea is possibly due to other causes, including prior 
chemotherapy, antiestrogens, or ovarian suppression. Postmenopausal women (defined as women 
who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, 
without other known or suspected primary cause) or women who have been sterilized surgically or 
who are otherwise proven sterile (i.e., total hysterectomy, or bilateral oophorectomy with surgery 
at least 4 weeks prior to randomization) are not considered WOCBP. Subjects who have 
undergone tubal ligation are NOT considered as surgically sterile.   
5. Female subjects of childbearing potential who are sexually active with males, must be willing to 
use an acceptable form of birth control from the day of the first dose administration to 30 days after 
the last administration of study drug. For the purpose of this study the following are considered 
acceptable methods of birth control: oral or injectable contraceptives, contraceptive patches, Depo-
Provera® (Medroxyprogesterone acetate- stabilized for at least 3 months); vaginal contraceptive; 
contraceptive implant; double barrier methods (e.g. condom and spermicide); Nuvaring vaginal 
hormonal birth control, intrauterine device (IUD), or abstinence with a second method of birth 
control should the subject become sexually active. A sterile sexual partner is NOT considered an 
adequate form of birth control. Otherwise, they are not required to use a birth control method if 
they are in a same sex relationship. 
6. All male subjects who are sexually active with females, must agree to use accepted methods of 


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Sponsor: 
Name of Medical Product: 
Active Ingredient: 
Actavis 
Rifaximin 
Rifaximin 
birth control with their partners, from the day of the first dose administration (to 7 days after the 
last administration of study drug). Please see acceptable forms for “Female” birth control above. 
Abstinence is an acceptable method of birth control for males. Otherwise, they are not required to 
use a birth control method if they are in a same sex relationship. 
7. Subject must be willing and able to comply with study procedures for the duration of the study. 
8.  Study subjects must have provided Local Ethics Committee (LEC)/ Institutional Review Board 
(IRB) approved written informed consent using the latest version of the LEC/IRB informed 
consent form.  In addition, study subjects must sign a Health Insurance Portability and 
Accountability Act (HIPAA) authorization, if applicable. 
9. Subject has to be literate and able to sign the informed consent form (ICF) and complete the Diary. 
Exclusion Criteria: 
Potential subjects will be excluded if any of the following exclusion criteria are present: 
1. Is pregnant, breast feeding, or planning a pregnancy. 
2. Immediately prior to randomization, acute diarrhea for > 72 hours. 
3. Has: 
a. 
fever (≥ 100 °F or ≥ 37.8 °C), or 
b. hematochezia (blood in stool), or 
c. 
clinical findings suggesting moderate or severe dehydration. 
4. Has active, uncontrolled, or clinically significant diseases or disorders of the heart, lung, kidney, 
gastrointestinal (GI) tract (other than infectious diarrhea in travelers), or central nervous system. 
5. Administration of any of the following: 
a. 
any antimicrobial agents with an expected activity against enteric bacterial pathogens 
within 7 days preceding randomization 
b. more than two doses of a symptomatic antidiarrheal compound such as antimotility 
agents, absorbent agents, and antisecretory agents within 8 hours preceding randomization 
c. 
any nonsteroidal anti-inflammatory drug or fever-reducing agent, such as aspirin or 
ibuprofen, which can cause GI bleeding within 8 hours preceding randomization. 
Acetaminophen or paracetamol is acceptable. 
d. Use of opioids (in any form) within 48 hours preceding randomization 
6. History or presence of allergic response to rifaximin or related drugs. 
7. People who have lived in or stayed in the country where they acquired travelers’ diarrhea for more 
than 6 months. 
8. Has a history of lactose or gluten intolerance. 
9. Consumed more than 2 alcoholic drinks within 12 hours before screening.  Alcohol consumption is 
not allowed during the study 
10. Has a current or recent history (within 12 months of screening) of drug or alcohol abuse. 
11. A positive urine drug screen test in the absence of therapeutic use will exclude the subject from 
participating in the study at the investigator’s discretion. 
12. Family members of the investigator and the independent dispenser/unblinded staff member, nor site 
staff of this study  
13. Subject currently enrolled in any other clinical investigation or who has participated in any clinical 
investigation within 30 days prior to starting this study. 
Test Product, Dose, and Mode of Administration: 
Rifaximin 200-mg film-coated oral tablets.  Each subject will receive 1 tablet TID (morning, noon and 
evening) for 3 days, which is the recommended dosing regimen for Xifaxan® 
Reference Therapy, Dose, and Mode of Administration: 
Xifaxan® 200-mg film-coated oral tablets; 1 tablet TID for 3 days (morning, noon and evening). 
Placebo, Dose, and Mode of Administration: 
Placebo film-coated oral tablets; 1 tablet TID for 3 days (morning, noon and evening). 


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Sponsor: 
Name of Medical Product: 
Active Ingredient: 
Actavis 
Rifaximin 
Rifaximin 
Endpoints for Evaluation: 
Primary efficacy endpoint 
The primary efficacy endpoint is clinical cure rate on TOC Visit (Study Day 5, 6 or 7). 
        Clinical cure is defined as either of the following: 
 No stools or only formed stools within a 48 hour period and no fever, with or without other enteric 
symptoms, OR 
 No watery stools or no more than two soft stools passed within a 24 hour period with no fever and 
no other enteric symptoms except for mild excess gas/flatulence. 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in ≤ 3 days is a 
clinical failure. 
 
Secondary efficacy endpoints 
Secondary efficacy endpoints are the following: 
• 
Time to last unformed stool (TLUS). TLUS is defined as the interval beginning with the first dose 
of study drug and ending with the last unformed stool passed.  
Mathematically, TLUS will be calculated as follows: 
TLUS (hours) = date/time of last unformed stool – date/time of first dose  
• 
Microbiological cure rate. Subjects are considered to have achieved microbiological cure if the 
pathogen identified at Visit 1 is no longer found in the stool at the TOC visit. Microbiological cure 
rate will be a supportive evidence of similarity between the test product and the reference product 
treatment arms and not considered as evidence of clinical bioequivalence. 
 
Safety  
All adverse events (AEs) and treatment-emergent AEs (TEAEs) reported during the study will be 
summarized/reviewed in order to assess safety. 
Statistical Methods:  
The following 3 analysis populations will be defined for this study:  
 
• 
Safety analysis set: All randomized subjects who receive at least one dose of study drug.  The 
Safety Analysis Set will be used for all analyses of safety, tolerability, and background 
characteristics. 
• 
mITT analysis set: 
 
 
 
• 
Per protocol (PP) analysis set:
 
 
 
  
 
 
 
 
 
 
. 
 
Note: Visit 2 data i.e. data from the telephone follow-up call on Day 3, after taking about 5 doses of study 
medication, may be used for applying LOCF for mITT population for the cases where TOC data is missing. 
Two sets of null hypotheses will be used for the primary efficacy endpoint to evaluate the clinical 


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Sponsor: 
Name of Medical Product: 
Active Ingredient: 
Actavis 
Rifaximin 
Rifaximin 
bioequivalence between test product and reference products with respect to the clinical cure rate using PP 
population.  The 90% confidence interval (CI) for the difference (test – reference) in clinical cure rates will 
be calculated using Z-test with Yates’ correction. If the lower and upper CIs are within the range of [-0.20, 
+0.20], it can be claimed that the test and the reference products are clinically bioequivalent. Otherwise, the 
two products will be considered as clinically not bioequivalent. The other null hypothesis will evaluate the 
differences between each active arm versus placebo using a two-sided Z-test for proportion with Yates 
correction, each at 0.05 significance level, for testing superiority of each active arm compared to the 
placebo.  This evaluation will be performed on the mITT analysis set using LOCF for missing data 
imputation, and would establish the sensitivity of the study. 
No interim analysis is planned for this study.   
The secondary efficacy endpoints, TLUS & Microbiological cure rate, will be tabulated by treatment group 
on the mITT and PP analysis sets with appropriate descriptive statistics.  The comparisons (test vs placebo, 
reference vs placebo, test vs reference) will be conducted at the 0.05 significance level.  All secondary 
efficacy analyses are considered supportive/confirmative.    
 
All safety endpoints will be tabulated by treatment group on the safety analysis set without formal inferential 
statistics.  AEs will be mapped using Medical Dictionary for Regulatory Activities (MedDRA, using the 
latest available version) with respect to the system organ class (SOC) and the preferred term.  Change from 
baseline in clinical laboratory tests, vital signs, and physical examinations will be summarized by treatment 
group. 
  
Additional summaries will include disposition, baseline characteristics and demographics.  
  
Approximately 618 
 will be randomized 
 
 for test vs. reference vs placebo. 
 
 
The sample size for this study was based on Z-test for proportion with Yates correction for 
bioequivalence of test vs. reference and superiority of the efficacy of the test and reference products over a 
placebo.
 
 To establish bioequivalence for the primary endpoint (proportion 
of subjects with “clinical cure” at study Day 5), the 90% CI of the test - reference difference between products 
must contained within [-0.20, +0.20] for dichotomous variables (cure versus failure), using the PP population. 
As a parameter for determining adequate study sensitivity, the test and reference products should be 
statistically superior to placebo (p<0.05, two-sided) for the primary endpoint using the mITT study 
population with LOCF.  
 


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Table of Contents 
Section 
 
Page 
Protocol Synopsis ..................................................................................................................4 
Table of Contents ..................................................................................................................9 
Glossary of Abbreviations .....................................................................................................12 
1. Introduction and Study Rationale ....................................................................................14 
2. Study Objectives ................................................................................................................15 
3. Investigational Plan ..........................................................................................................16 
4. Selection of Study Population ..........................................................................................17 
4.1 Inclusion Criteria .......................................................................................................17 
4.2 Exclusion Criteria ......................................................................................................18 
4.3 Restrictions..................................................................................................................19 
5. Treatments .........................................................................................................................21 
5.1 Description of Treatment(s) ......................................................................................21 
5.2 Selection and Timing of Dose for Each Subject ......................................................21 
5.3 Method of Assigning Subjects to Treatment Groups ..............................................21 
5.4 Unblinding ..................................................................................................................22 
5.5 Packaging and Labeling.............................................................................................22 
5.6 Retention Sample Selection, Storage and Accountability .......................................22 
5.7 Treatment Compliance ..............................................................................................24 
5.8 Concomitant Medications and Therapy ...................................................................24 
6. Study Procedures...............................................................................................................25 
6.1 Schedule of Events ......................................................................................................25 
6.2 Screening, Randomization and Treatment Visit .....................................................25 
6.3 Treatment ....................................................................................................................27 
6.4 Telephone Follow-Up .................................................................................................27 


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6.5  Test of Cure ................................................................................................................28 
6.6  Unscheduled Visits and Early Discontinuation Visit .............................................28 
7. Efficacy and Safety Assessments ......................................................................................30 
7.1 Methods of Assessment ..............................................................................................30 
7.2 Primary Efficacy Parameter......................................................................................30 
7.3 Secondary Efficacy Parameters ................................................................................30 
7.4 Safety Parameters .......................................................................................................31 
7.5 Adverse Events ...........................................................................................................31 
7.6 Laboratory Safety Measurements and Variables ....................................................36 
7.7 Vital signs and Physical Examination ......................................................................36 
7.8 Procedures in Case of Medical Emergency ..............................................................36 
7.9 Procedures in Case of Pregnancy ..............................................................................37 
7.10 Appropriateness of Measurements .........................................................................37 
8. Data Quality Assurance ....................................................................................................38 
9. Statistical Methods ............................................................................................................40 
9.1 Statistical and Analytical Plans .................................................................................40 
9.2 Study Populations .......................................................................................................40 
9.3 Demography and Baseline Characteristics ..............................................................41 
9.4 Analysis of Efficacy Parameters ...............................................................................41 
9.4.1 Null Hypothesis for Primary Efficacy Parameter ..................................................41 
9.4.2 Null Hypothesis for Other Efficacy Parameters ....................................................43 
9.4.3 Primary Efficacy Variable Analysis ......................................................................43 
9.4.4 Secondary Efficacy Variables Analysis .................................................................44 
9.5 Analysis of Safety Parameters ...................................................................................45 
9.6 Sample Size Calculation .............................................................................................45 
9.7 Handling of Drop-outs and Discontinuations ..........................................................46 
9.8 Interim Analyses .........................................................................................................46 


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9.9 Data Monitoring Board .............................................................................................46 
10. Study Administration ......................................................................................................47 
10.1 Investigators and Study Administrative Structure ...............................................47 
10.2 Local Ethics Committee (LEC)/Institutional Review Board (IRB) Approval ....47 
10.3 Ethical Conduct of the Study ..................................................................................48 
10.4 Subject Information and Consent ...........................................................................48 
10.5 Subject Confidentiality ............................................................................................49 
10.6 Study Monitoring .....................................................................................................49 
10.7 Case Report Forms and Study Records .................................................................50 
10.8 Data Monitoring Committee ...................................................................................50 
10.9 Protocol Violations/Deviations ................................................................................51 
10.10 Access to Source Documentation ..........................................................................51 
10.11 Data Generation and Analysis ..............................................................................51 
10.12 Retention of Data ....................................................................................................51 
10.13 Termination of the Study .......................................................................................52 
10.14 Financial Disclosure ...............................................................................................52 
10.15 Publication and Disclosure Policy .........................................................................52 
10.16 Clinical Study Report .............................................................................................53 
11 References ........................................................................................................................54 
12 Appendix - Detailed Protocol Summary of Changes ......................................................55 
 
 


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Glossary of Abbreviations 
 
Abbreviation 
 
Definition 
AE(s) 
Adverse event(s) 
ATC 
Anatomical Therapeutic Chemical 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
CRO 
Contract research organization 
eCRF 
Electronic Case report form 
ETEC 
Enterotoxigenic Escherichia coli  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
LEC 
Local Ethics Committee 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent to treat 
N 
Number of subjects 
NDA 
New Drug Application 
O&P 
Ova and parasites 
OTC 
Over-the-counter 
PP 
Per protocol 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SE 
Standard error 
SOC 
System organ class 
SOP 
Standard operating procedure 
SQRT 
Square root 
TEAE 
Treatment-emergent adverse event 
TD 
Travelers’ diarrhea 
TID 
Three times per day 
TLF 
Tables, listings and figures 
TLUS 
Time to last unformed stool 
TOC 
Test of cure 
US 
United States 


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Abbreviation 
 
Definition 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of child-bearing potential 
WMA 
World Medical Assembly 
 


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1. Introduction and Study Rationale 
Travelers' diarrhea (TD) is the most common illness affecting travelers. Each year between 
20%-50% of international travelers, an estimated 10 million persons, develop diarrhea 
(Centers for Disease Control [CDC] 2014).  The onset of TD usually occurs within the 
first week of travel. Episodes of TD are typically benign and self-limited, lasting anywhere 
from 2 to 5 days. High-risk destinations for TD are the developing countries of Latin 
America, Africa, the Middle East, and Asia. Persons at particularly high-risk include 
young adults, immunosuppressed persons, persons with inflammatory-bowel disease or 
diabetes, and persons taking H-2 blockers or antacids. Attack rates are similar for men and 
women.  The primary source of infection is ingestion of fecally contaminated food or 
water (CDC 2014).  A variety of bacterial, viral, and parasitic organisms can cause TD, but 
bacterial pathogens (especially enterotoxigenic Escherichia coli [ETEC]) predominate. 
Standard treatment typically consists of 3 components - fluid replacement, antibiotics, and 
antimotility agents.  Fluid replacement is important to avoid dehydration.  Antibiotics help 
shorten the disease duration (typically to one day), while antimotility agents may limit the 
frequency of loose stools. 
Current antibiotic choices include fluoroquinolones, azithromycin, and rifaximin. Bactrim 
was widely used in the past, but due to widespread resistance among routine enteric 
pathogens, this medication is less useful now. Fluoroquinolones are frequently used, as 
they are readily available, easy to tolerate, and have activity against many of the common 
pathogens. However, resistance is growing, particularly among Campylobacter jejuni 
isolates in Southeast Asia, which increases the importance of alternative choices such as 
azithromycin and rifaximin. 
Rifaximin (marketed as Xifaxan®) is primarily effective in treating ETEC-associated TD 
and less effective for treating Campylobacter-associated TD. This results in 
destination-based antibiotic recommendations from clinical practitioners, which is 
reflected in the choice of region for the current trial.  This trial is designed to demonstrate 
that a generic formulation of rifaximin 200-mg tablets is clinically bioequivalent to 
Xifaxan® 200-mg tablets (Salix Pharmaceuticals, Inc.).   


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2. Study Objectives 
The primary objectives are: 
(i) Bioequivalence of rifaximin 200-mg tablets (the test product) and Xifaxan® 200 mg 
tablets (the reference product) with respect to the clinical cure rates on Study Day 5 
when administered 3 times a day (TID) for 3 days in subjects with TD.   
        Clinical cure is defined as either of the following: 
 No stools or only formed stools within a 48 hour period and no fever, with or 
without other enteric symptoms, OR 
 No watery stools or no more than two soft stools passed within a 24 hour period 
with no fever and no other enteric symptoms except for mild excess gas/flatulence. 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in 
≤ 3 days is a clinical failure. 
(ii) Superiority of test and reference products over placebo with respect to the clinical cure 
rates on Study Day 5, in the treatment of TD, using the mITT population with LOCF. 
 
The secondary objectives of this study are the following: 
• To compare the time to last unformed stool (TLUS) observed for rifaximin 200-mg 
tablets and Xifaxan® 200-mg tablets on test-of-cure (TOC) visit (Study Day 5, 6 or 7). 
TLUS is defined as the interval beginning with the first dose of study drug and ending 
with the last unformed stool passed.  
• To compare the microbiological cure rate of rifaximin 200-mg tablets and Xifaxan® 
200-mg tablets on test-of-cure (TOC) visit (Study Day 5, 6 or 7). Subjects are 
considered to have achieved microbiological cure if the pathogen identified at Visit 1 
is no longer found in the stool at the TOC visit. Microbiological cure rate will be a 
supportive evidence of similarity between the test product and the reference product 
treatment arms and not considered as evidence of clinical bioequivalence. 
 


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3. Investigational Plan 
This is a randomized, double-blind, placebo-controlled, parallel design, multicenter, 
multinational bioequivalence study. Subjects will be adult, non-indigenous travelers with 
naturally acquired acute diarrhea. Eligible subjects must have at least 3 episodes of 
unformed stools recorded within the 24 hours immediately preceding randomization 
(screening and randomization should occur as closely as possible on the same day, i.e. 
Day 1) and at least one of the following signs and symptoms of enteric infection:  
abdominal pain or cramps, nausea, vomiting, fecal urgency, excessive gas/flatulence, or 
tenesmus.  There will be 3 study visits: 2 visits on-site and 1 telephone visit (on Day 3 
after taking about 5 doses of study medication). At the first visit, subjects will be 
screened and eligible subjects will be randomized 
 to receive Rifaximin 
200-mg tablets, Xifaxan® 200-mg tablets, or placebo tablets, TID for 3 days, beginning 
not more than 72 hours after the onset of diarrhea.  The first dose of study drug should be 
preferably administered under the supervision of an unblinded study staff 
member/independent dispenser at the first study visit.  For the second visit, the study site 
will contact the subject by telephone to follow-up on Day 3, after taking about 5 doses of 
study medication. The third visit is the TOC visit, which will occur 24 to 72 hours after 
the last dose of study drug.  For 5 days after randomization/first dose, subjects will record 
dosing, stool information (date, time, consistency) and enteric symptoms in a daily Diary.  
Stool samples will be collected pre-treatment (screening) and post-treatment (TOC) to be 
cultured for pathogenic organisms. If the stool sample collection is not possible at visit 3, 
a rectal swab will be collected. Adverse events (AEs), concomitant medication details and 
safety laboratory samples will be collected at Visit 1 and Visit 3. AEs and concomitant 
medication details will also be obtained during Visit 2.  
Safety and efficacy assessments will be performed as noted in the Schedule of Procedures 
and Assessments (Section 6.1). 


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4. Selection of Study Population 
4.1 Inclusion Criteria  
Subjects must meet all of the following inclusion criteria: 
1. Be adult male or nonpregnant female aged ≥ 18 years non-indigenous travelers 
(e.g., visiting students/faculty or international tourists) affected by naturally 
acquired acute diarrhea. Diarrhea is defined as the passage of at least 3 episodes of 
unformed stools in a 24-hour period. Stools are classified as formed (retains 
shape), soft (assumes shape of container), or watery (can be poured). When using 
this classification, both soft and watery stools are unformed and abnormal. 
2. Have at least 3 episodes of unformed stools recorded within the 24 hours 
immediately preceding randomization (screening and randomization should occur 
as closely as possible on the same day, i.e. Day 1).  
3. Have at least one of the following signs and symptoms of enteric infection: 
a. abdominal pain or cramps 
b. nausea 
c. vomiting 
d. fecal urgency 
e. excessive gas/flatulence 
f. tenesmus 
4. Females of child bearing potential (WOCBP*) must not be pregnant or lactating at 
baseline visit (as documented by a negative urine pregnancy test with a minimum 
sensitivity of 25 IU/L or equivalent units of beta-human chorionic gonadotropin 
(Beta-HCG) at screening and urine pregnancy at baseline. *All female subjects will 
be considered to be of childbearing potential unless they are postmenopausal. 
WOCBP are defined as sexually mature women without prior hysterectomy, or 
who have had any evidence of menses in the past 12 months. However, women who 
have been amenorrheic for the past 12 or more months are still considered to be of 
childbearing potential, if the amenorrhea is possibly due to other causes, including 
prior chemotherapy, antiestrogens, or ovarian suppression. Postmenopausal 
women (defined as women who have been amenorrheic for at least 12 consecutive 
months, in the appropriate age group, without other known or suspected primary 
cause) or women who have been sterilized surgically or who are otherwise proven 
sterile (i.e., total hysterectomy, or bilateral oophorectomy with surgery at least 4 
weeks prior to randomization) are not considered WOCBP. Subjects who have 
undergone tubal ligation are NOT considered as surgically sterile. 
5. Female subjects of childbearing potential who are sexually active with males, must 
be willing to use an acceptable form of birth control from the day of the first dose 
administration to 30 days after the last administration of study drug. For the 
purpose of this study the following are considered acceptable methods of birth 
control: oral or injectable contraceptives, contraceptive patches, Depo-Provera® 


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(Medroxyprogesterone acetate- stabilized for at least 3 months); vaginal 
contraceptive; contraceptive implant; double barrier methods (e.g. condom and 
spermicide); Nuvaring vaginal hormonal birth control, intrauterine device (IUD), 
or abstinence with a second method of birth control should the subject become 
sexually active. A sterile sexual partner is NOT considered an adequate form of 
birth control.  Otherwise, they are not required to use a birth control method if they 
are in a same sex relationship. 
6. All male subjects who are sexually active with females, must agree to use accepted 
methods of birth control with their partners, from the day of the first dose 
administration to 7 days after the last administration of study drug. Please see 
acceptable forms for “Female” birth control above. Abstinence is an acceptable 
method of birth control for males.  Otherwise, they are not required to use a birth 
control method if they are in a same sex relationship. 
7. Subject must be willing and able to comply with study procedures for the duration 
of the study.  
8. Study subjects must have provided Local Ethics Committee (LEC)/ Institutional 
Review Board (IRB) approved written informed consent using the latest version of 
the LEC/IRB informed consent form.  In addition, study subjects must sign a 
Health Insurance Portability and Accountability Act (HIPAA) authorization, if 
applicable. 
9. Subject has to be literate and able to sign the informed consent form (ICF) and 
complete the Diary 
 
4.2 Exclusion Criteria  
Potential study subjects will be excluded if any of the following exclusion criteria are present: 
1. Is pregnant, breast feeding, or planning a pregnancy. 
2. Immediately prior to randomization has acute diarrhea for > 72 hours. 
3. Has : 
a. fever (≥ 100 °F or ≥ 37.8 °C), or 
b. hematochezia (blood in stool), or 
c. clinical findings suggesting moderate or severe dehydration. 
4. Has active, uncontrolled, or clinically significant diseases or disorders of the heart, 
lung, kidney, gastrointestinal (GI) tract (other than infectious diarrhea in travelers), or 
central nervous system. 
5. Administration of any of the following: 
a. any antimicrobial agents with an expected activity against enteric bacterial 
pathogens within 7 days preceding randomization. 


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b. more than two doses of a symptomatic antidiarrheal compound such as 
antimotility agents, absorbent agents, and antisecretory agents preceding 
randomization. 
c. any nonsteroidal anti-inflammatory drug or fever-reducing agent, such as 
aspirin or ibuprofen, which can cause GI bleeding within 8 hours preceding 
randomization. Acetaminophen or paracetamol is acceptable. 
d. Use of opioids (in any form) within 48 hours preceding randomization. 
6. Has a history or presence of allergic response to rifaximin or related drugs. 
7. People who have lived in or stayed in the country where they acquired travelers’ 
diarrhea for more than 6 months.  
 
8. Has a history of lactose or gluten intolerance. 
 
9. Consumed more than 2 alcoholic drinks within 12 hours before screening.  Alcohol 
consumption is not allowed during the study. 
 
10. Has a current or recent history (within 12 months of screening) of drug or alcohol 
abuse. 
11. A positive urine drug screen test in the absence of therapeutic use will exclude the 
subject from participating in the study at the investigator’s discretion. 
 
12. Family members of the investigator and the independent dispenser/unblinded staff 
member, nor site staff of this study. 
 
13. Subject currently enrolled in any other clinical investigation or who has participated in 
any clinical investigation within 30 days prior to starting this study. 
 
4.3 Restrictions  
The following are not allowed in this study: 
• 
Any antimicrobial agents with an expected activity against enteric bacterial pathogens 
within 7 days preceding randomization and during the study. 
• 
More than two doses of a symptomatic antidiarrheal compound such as antimotility 
agents, absorbent agents, and antisecretory agents preceding randomization and during 
the study. 
• 
Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding 
within 8 hours preceding randomization and during the study. Note: Acetaminophen 
(Tylenol) or paracetamol is acceptable for use during the study.  
• 
Opioids (in any form) within 48 hours preceding randomization and during the study. 
• 
Alcohol or probiotics consumption  


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4.4 Withdrawals and Replacement of Subjects 
Subjects may be discontinued from study treatment and assessments at any time.  
Subjects are also free to discontinue their participation in the study at any time, without 
prejudice to further treatment. 
Study completion or discontinuation and the reason for discontinuation will be 
documented.  Possible reasons for a subject discontinuing participation in the study are: 
• AE(s) that endanger the health of subjects, making it ethically unacceptable to 
continue 
• Deterioration of the subject’s clinical condition(s) that requires appropriate 
therapy/treatment during the study period 
• Lack of efficacy 
• Withdrawal of consent 
• Lost to follow up 
• Death. 
In case of an AE, the subject is to be followed up until resolution of the AE. Subjects who 
discontinue prematurely from the study will not be replaced. Investigational products and 
study materials should be returned by the subject. 


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5. Treatments 
5.1 Description of Treatment(s) 
The treatments used in this study are the following: 
• Rifaximin 200-mg tablets (test product) manufactured by Actavis Laboratories 
FL, Inc. 
• Xifaxan® 200-mg tablets (reference product) of Salix Pharmaceuticals, Inc. 
(Valeant Pharmaceuticals group of company) 
• Placebo tablets manufactured by Actavis Laboratories FL, Inc. 
 
Rifaximin is marketed under the tradename Xifaxan® (Salix Pharmaceuticals, Inc, recently 
acquired by Valeant Pharmaceuticals).  The investigational drug evaluated in this study is 
generic rifaximin.   
5.2 Selection and Timing of Dose for Each Subject 
Each subject will receive the same dosing regimen of 1 tablet TID (morning, noon and 
evening) for 3 days, which is the recommended dosing regimen for Xifaxan®.  
 
Subjects who take 3 doses of study drug on Day 1 (i.e., those randomized early in the day on 
Day 1) will complete study drug on Day 3; other subjects will receive the last dose of study 
drug on Day 4.  
5.3 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly allocated 
 to treatment groups to receive the Test 
product or the Reference Product or the Placebo control, respectively. The randomization 
schedule for this study will be generated by a third party vendor of the CRO such that a non-
study-assigned independent expert will allocate the subjects to one of the three treatment arms 
using a computer generated automated process i.e. Interactive Web Response System (IWRS). 
 
 
 
   
Study sites should have an unblinded dispenser/unblinded study staff member assigned to 
maintain blinding throughout the study.  Subject must return the study treatment bottle with 
original carton to the unblinded study staff member. 


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5.4 Unblinding 
In case of emergency, if the detail of study drug is required for management of emergency as 
per the opinion of investigator, investigator can unblind the product that is received by the 
patient during the study. In case of non- emergency condition that requires study drug 
information for management of condition as per investigator’s opinion, investigator should 
obtain sponsor or medical monitor approval in writing prior to breaking of the blind. 
 
 
 It is recommended that all attempts 
should be made to maintain the blind of the study. However, in case the unblinding is 
performed, the reason for breaking the blind must be clearly documented in the source 
documentation and electronic case report form (eCRF) and the patient must be discontinued 
from the study.   
5.5 Packaging and Labeling  
Packaging and labeling will be carried out in accordance with the requirements of the Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) requirements, sponsor approved standard operating procedures 
(SOPs) and all applicable country specific laws. A detailed packaging and labelling plan will 
be put in place with country specific requirements. 
Final labeling and packaging of the products will be performed by 
 
Actavis Laboratories UT, Inc. 
 
 
 
 
in accordance with their SOPs and international requirements. Product labels comply with 
United States (US) regulatory requirements and languages, and in the case of other 
participant countries will comply with applicable local regulatory requirements. 
5.6 Retention Sample Selection, Storage and Accountability 
Retention of Reserve Samples 
For every study product shipment received at the Investigator site, the Investigator (or 
designee) will randomly select at least one block of study product for retention, unless 
otherwise instructed by the Sponsor and/or CRO. The selection process will ensure a 
sufficient amount of retention samples are retained as per Sponsor requirement, and the same 
will be documented. 
 
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a retention sample, in addition to the retention sample log. These retention samples should be 
stored under the appropriate storage conditions for a minimum of 5 years following the 
application approval or, if not approved, at least 5 years after the completion of the study.  
Retention samples should not be returned to the sponsor at any time. The retention samples 
can be shipped to a third party storage facility. A detailed investigational product plan will be 
provided to the study site. 
 
Product storage and dispensation 
All study material, together with necessary documentation, will be supplied to the study 
site before starting the trial. The study site will acknowledge receipt of all study material 
in IWRS. 
All supplies will be maintained under adequate security by the clinical investigator or 
unblinded study staff member/independent dispenser, who will be responsible for all 
supplies. 
The study drugs are to be stored at 20° to 25°C (68° to 77°F) with excursions permitted 
from 15° to 30°C (59° to 86°F). 
The study drugs are to be dispensed only under the restricted conditions defined in the 
present protocol. 
Any test materials remaining at the end of the study will be returned to the designated 
drug depots or destroyed in accordance with the guidelines provided by Sponsor. Before 
destruction, detailed product accountability has to be performed. An official document on 
what has been destroyed has to be issued and sent to the Sponsor/CRO. 
Product accountability 
Each center will be responsible for maintaining an accurate log and inventory of study 
material received and returned to the designated drug depot. 
At the end of the study, it must be possible to reconcile delivery records with records of 
used and returned study treatments. An account of any discrepancies has to be provided.  
The designated CRO will provide the framework for documenting study treatment 
accountability, without breaking the blind, throughout the study. CROs will assign 
unblinded CRAs to perform the drug accountability.   
The investigator has to maintain an accurate written record of the shipment, retention, 
dispensing, and return of study treatments using a drug accountability form. An accurate 
record of the date and amount of study drug dispensed to each subject has to be available 
for inspection at any time. The designated CRO representatives will verify drug 
accountability during routine site monitoring visits without breaking the blind. The total 
drug accountability will also be performed at the completion of the trial.   


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At the conclusion of the study and as appropriate during the course of the study, the 
investigator will return all used and unused drug containers, drug labels, and a copy of the 
completed drug accountability form to the Sponsor/designee. Some sites may destroy 
medications locally at an appropriate time point, if previously agreed with the sponsor.  
5.7 Treatment Compliance 
Subject compliance will be primarily monitored by counting the study tablets dispensed 
(Visit 1) and returned (Visit 3) compared to diary entries.  The medication dispensed 
and/or returned will be recorded by the independent dispenser/unblinded study staff 
member in the subject drug accountability log and eCRF.  Subjects will be asked to return 
all original packaging and unused study drug at Visit 3. Compliance calculation will be 
based on number of tablets taken (as recorded in the study diary) vs number of tablets 
subjects are expected to take. 
5.8 Concomitant Medications and Therapy 
All concomitant medications and therapies used during the trial will be documented in the 
eCRF including name of the medication, date of administration and its duration, and 
indication for use. 
Over-the-counter (OTC) anti-diarrheal medications, NSAIDs (with the exception of 
acetaminophen and paracetamol) and opioid analgesics are prohibited during the study.  
For further detail, please refer to Section 4.3 of the protocol. Use of prohibited 
concomitant medications will be considered a major protocol deviation and the subjects 
will be withdrawn from the study; and will be excluded from the per protocol (PP) 
analysis set.   


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6. Study Procedures 
6.1 Schedule of Events 
 
A schedule of study procedures is provided in Table 1.  
 
Table 1 
Schedule of Events 
Assessments 
Screening, 
Randomization 
and Treatment 
Treatment 
TOC 
Day 1 
Day 2 
Day 3a Day 4b 
5, 6 or 7c 
Visit 1 
 
Visit 2 
 
Visit 3 
Informed consent, I/E criteria 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Prior/concomitant medications 
X 
 
X 
 
X 
Physical examination  
X 
 
 
 
X 
Vital signs 
X 
 
 
 
X 
Stool sample for culture and O&P 
X 
 
 
 
Xf 
Hematology/chemistry panel 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
X 
Urine drug screen 
X 
 
 
 
 
Pregnancy test (urine)d 
X 
 
 
 
X 
Randomization  
X 
 
 
 
 
Telephone call  
 
 
X 
 
 
Study drug dosing 
X 
X 
X 
X 
 
Daily study diary completione 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
 
X 
TOC = test of cure; I/E = inclusion/exclusion; O & P = ova and parasites 
a Visit 2 assessment should be done by telephone (after the subject has taken about 5 doses); the subject should 
be contacted by a member of the study team. 
b If a subject takes 3 doses of study drug on Day 1, then study drug should be completed on Day 3, otherwise the 
final doses will be taken on Day 4.   
cVisit 3 should occur 24 to 72 hours after the last dose of study drug.  If a subject does not return for the 
scheduled TOC visit, a telephone call should be made and efficacy and safety data (same as Visit 2) should be 
collected for Visit 3. 
dFemale subjects of child-bearing potential only. 
eStudy drug diary completion will begin on Study Day 1 and end on last study visit.  Diary completion includes 
recording of temperature if a subject feels feverish; (a thermometer should be provided to each subject by the 
site), date/time of study drug each dose; date, time and consistency of stool; as well as enteric symptoms 
described in protocol 
fIn case stool sample collection not possible at visit 3, a rectal swab will be collected. 
6.2 Screening, Randomization and Treatment Visit 
Visit 1/Day 1: 
When a suitable candidate is identified, the investigator or designated healthcare 
professional will ask the subject about their willingness to be included in the clinical trial. 


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The subject is to be informed verbally and in writing about the nature, risks, benefits, and 
expectations of participating in the clinical trial and a copy of the subject informed consent 
form is to be given to the subject in the appropriate language. The subject informed consent 
form is to be signed by the subject and by the attending investigator/ designee, prior to 
proceeding with the screening activities. The subject number should be assigned at the time 
of starting the consent process.  
The following observations/procedures are to be performed/checked: 
• Check of inclusion/exclusion criteria 
• Gender, age, race 
• Complete medical history  
• Brief physical examination including vital signs (body temperature, blood pressure, 
and pulse) and body weight and height 
• Review of the use of previous/concomitant treatments for any other clinical 
condition(s)  
• Stool sample for culture (at a minimum, pathogenic E. coli) and O&P (Ova and 
Parasites) 
• Blood sample for hematology/chemistry panel 
• Urine sample for urinalysis and urine drug screen 
• Urine pregnancy test for WOCBP 
• Review of AEs 
 
Eligible subjects will be randomized and the first dose of study drug should be preferably 
administered under unblinded study staff/independent dispenser supervision at the clinic.  
Subjects should be suggested to start the first dose of the study drug only after providing 
the stool sample. 
 
 
  Subjects will be given a study 
drug diary, a thermometer and record the following for 5 days, beginning on Study Day 1:   
• Date and time of each dose 
• Date, time, and consistency of each stool  
• Temperature (if feeling feverish) 
• Enteric infection symptoms:  
o abdominal pain or cramps, 
o excessive gas/flatulence,  
o nausea,  


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o vomiting,  
o fecal urgency,  
o blood and/or mucus in the stool,  
o tenesmus  
Subjects will be observed for the occurrence of AEs after informed consent is signed. 
6.3 Treatment 
Days 2 to 4 
Subjects are to take 1 study drug tablet TID (morning, noon and evening) for 3 consecutive 
days for a total of 9 doses.  Subjects who take 3 doses of study drug on Day 1 (i.e., those 
randomized early in the day on Day 1) will complete study drug on Day 3; other subjects 
will receive the last dose of study drug on Day 4.  Subject will complete study diary until 
last study visit day, beginning on Day 1.  Subjects will record the following in the study 
diary: 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
  
 
  
  
6.4 Telephone Follow-Up 
Visit 2/Telephone Visit (Day 3) 
On study Day 3 (after about 5 doses), subjects should be contacted by a member of the study 
team to undergo a telephone follow-up.  Subjects will be asked about their AEs, concomitant 
medications and general health as well as their diary entries (see Section 6.3). 


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6.5  Test of Cure 
Visit 3 (Day 5, 6 or 7) 
Visit 3 will be the TOC visit and should be scheduled 24 to 72 hours after the last dose of 
study drug (i.e., after taking about 9 doses during the duration of the study).  The following 
procedures are to be performed/checked: 
• Stool sample for culture and examination 
• Blood sample for hematology/chemistry panel 
• Urine pregnancy test for WOCBP 
• Brief physical examination including vital signs (body temperature, blood pressure, 
and pulse) and body weight and height 
• Review of the use of concomitant treatments for any other clinical condition(s)  
• Review of AEs 
• Study medication compliance 
• Return of unused study medication.   
Subjects are to complete the study diary from day 1 until last study visit day.   
If the stool sample collection is not possible at Visit 3, a rectal swab will be collected. 
 
Note: If a subject does not return for the scheduled TOC visit (Visit 3; 24 to 72 hours after 
last dose of study medicine) then a telephone call should be made by the site and all the 
efforts should be made to collect efficacy and safety data for Visit 3. This data should be 
entered in eCRF for Visit 3 records. 
6.6  Unscheduled Visits and Early Discontinuation Visit 
An Unscheduled Visit is allowed at any time, for any reason, if in the Investigator’s opinion it 
is warranted. If the Unscheduled Visit is due to an AE, the Investigator will determine 
whether additional visits are needed.  
 
If a subject is discontinued from the study during an Unscheduled Visit, the Unscheduled 
Visit will be referred to as an Early Discontinuation Visit and all procedures scheduled for 
Visit 3 will be performed. If the Unscheduled Visit is not an Early Discontinuation Visit (i.e., 
the subject will continue to take part in the study), then study procedures will be performed at 
the discretion of the investigator, with the exception of the collection of IMP and subject 
diaries from subjects. 
 


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If the subject’s condition has worsened to the degree that it is unsafe for the subject to 
continue in the study, the subject may be discontinued from the study as treatment failure and 
a standard of care treatment may be advised at the Investigator’s discretion. 
 


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7. Efficacy and Safety Assessments 
7.1 Methods of Assessment 
All eligible subjects will be screened and randomized at Visit 1.  The first dose of study 
drug should be preferably administered under the supervision of unblinded clinical 
staff/independent study dispenser at the clinic immediately after randomization.  Subjects 
are provided with a study diary to record study drug doses; time and characteristics of 
each bowel movement; and enteric symptoms for 5 days.     
7.2 Primary Efficacy Parameter 
The primary efficacy endpoint will be clinical cure rate on TOC Visit (Study Day 5, 6 or 
7).  
Clinical cure is defined as either of the following: 
 No stools or only formed stools within a 48 hour period and no fever, with or without 
other enteric symptoms, OR 
 No watery stools or no more than two soft stools passed within a 24 hour period with 
no fever and no other enteric symptoms except for mild excess gas/flatulence. 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in ≤ 3 
days is a clinical failure. 
7.3 Secondary Efficacy Parameters 
Secondary efficacy endpoints are the following: 
1. Time to last unformed stool (TLUS). TLUS is defined as the interval 
beginning with the first dose of study drug and ending with the last unformed 
stool passed.  
Mathematically, TLUS will be calculated as follows. 
TLUS (hours) = date/time of last unformed stool – date/time of first dose  
2. Microbiological cure rate. Subjects are considered to have achieved 
microbiological cure if the pathogen identified at Visit 1 is no longer found in 
the stool at the TOC visit. Microbiological cure rate will be a supportive 
evidence of similarity between the test product and the reference product 
treatment arms and not considered as evidence of clinical bioequivalence. 


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7.4 Safety Parameters 
Safety parameters will include the following: 
1. Treatment emergent adverse events (TEAEs) 
2. Subjects with the following TEAEs of special interest 
a. Fever 
b. Moderate or severe dehydration 
c. Hematochezia (blood in stool) 
d. Abdominal pain or cramps 
e. Nausea 
f. Vomiting 
g. Fecal urgency 
h. Excessive gas/flatulence 
i. Tenesmus 
3. Changes in clinical laboratory tests, vital signs, and physical examinations from 
baseline 
7.5 Adverse Events 
All AEs that occur during the study after the subject has signed the informed consent are to 
be collected and reported on the eCRF, regardless of whether they are reported by the 
subject, observed by investigator/designee, or by any other means. All AEs are to be 
followed up till resolution or up to a maximum of 30 days from the date of occurrence. 
As far as possible, each AE is described by: 
• duration (start and end date) 
• start/end of study medication 
• severity grade (mild, moderate, severe) 
• investigator causality (relationship to the study product) 
• action(s) taken (concomitant medication, change of study medication etc.) including 
start and end of respective action 
• concomitant diseases and respective medication in general 
• outcome. 
 
AE 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 


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associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
TEAE 
TEAEs are those AEs occurring after first dose of study drug through the TOC or as noted 
in completed study diary, whichever is later.  TEAEs are also events that were present prior 
to the first dose of study drug, but increased in frequency or severity following initiation of 
study drug.  
SAE 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject is at risk of death at the time of the event; it does not refer to an event which 
hypothetically may cause death if it is more severe) 
• requires subject hospitalization or prolongation of existing hospitalization (for the 
purpose of this study, a hospitalization is defined as a hospital stay of at least 8 hours 
and/or an overnight stay) 
• results in persistent or significant disability/incapacity  
• is a congenital anomaly/birth defect 
or 
• other medically important condition 
Events that require intervention to prevent one or more of the outcomes listed in the 
definition above are also to be considered as serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsion that does not result in hospitalization, or development of drug dependency or 
drug abuse.  
However, medical judgment has to be exercised in deciding whether an event is serious in 
any other situations considered medically relevant. 
The evaluation of the AE as serious or not-serious is made independently of any attribution 
of causality. 
Events NOT considered to be SAEs are those that require: 
• treatment, which is elective or pre-planned, for a pre-existing condition that is unrelated 
to the indication under study and does not worsen 
• treatment on an emergency, outpatient basis for an event NOT fulfilling any of the 
definitions of serious given above and NOT resulting in hospital admission for the 


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purpose of this study, a hospitalization is defined as a hospital stay of at least 8 hours 
and/or an overnight stay). 
AE intensity 
AE intensity determined by the clinical investigator on the basis of his/her direct 
observations or the subject’s reporting: 
• Mild: causes no limitation of usual activities; the subject may experience slight 
discomfort 
• Moderate: causes some limitation of usual activities; the subject may experience 
annoying discomfort 
• Severe: causes inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
AE causality (relationship guide) 
Any AE has to be judged for causality (relationship to study medication and relationship to 
study procedure). 
The relationship of an AE to the study product is to be graded on the basis of the following: 
• Definite: 
a reaction that follows that follows a reasonable temporal sequence from 
study medication administration, abates upon discontinuation of the 
study medication (dechallenge), and is confirmed by reappearance of the 
reaction on repeat exposure 
• Probable: a reaction that follows a reasonable temporal sequence from 
administration of the product; that follows a known response pattern to 
the suspected product; that is confirmed by an improvement on stopping 
the product; and that cannot be reasonably explained by the subject’s 
clinical state 
• Possible: 
a reaction that follows a reasonable temporal sequence from 
administration of the product; that follows a known response pattern to 
the suspected drug; but that may have been produced by the subject’s 
clinical state or other therapeutic interventions on him/her 
• Unlikely: 
a reaction that occurs with an improbable temporal sequence from 
administration of the product; that can be explained by the clinical state 
of the subject/participant or by other therapeutic interventions or other 
drugs or underlying disease providing plausible explanations.  
• Unrelated: a reaction that occurs without a reasonable temporal sequence from 
administration of the product; that can be explained by the clinical state 
of the subject or by other therapeutic interventions on him/her and that 
does not improve or disappear following interruption of the product. 
Handling of AEs 
If an AE occurs, appropriate diagnostic and therapeutic measures are to be taken and the 
study product has to be discontinued if appropriate. Follow-up evaluations of the subject 


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are to be performed until the subject recovers or until the clinical investigator considers 
the situation to be no longer clinically significant. 
If clinically significant laboratory abnormalities appear at the final visit, appropriate 
additional tests may to be performed to clarify the nature of any clinically significant 
laboratory abnormalities that occur. 
AEs are monitored and registered on the AE form of the eCRF at each visit. In absence of 
a specific diagnosis, an individual AE form has to be filled in for each sign or symptom. 
Persistent AEs will be entered once in the eCRF until they are resolved or if a new event 
has to be documented due to deterioration. These AEs will be carefully monitored; further 
details of monitoring of persistent AEs will be provided in the monitoring plan. If an AE 
is still not resolved at the end of the study, this will documented as ongoing. 
For recurrent AEs, i.e., AEs of the same nature, but with a different date of onset, an 
individual AE form has to be completed for each of them. 
AEs occurring up to 30 days after the last dose of study drug (and when reported by the 
subject) will be collected by study sites and reported to Sponsor even after the clinical 
trial has been finished if, in the judgment of the investigator, there is an association 
between the event and the previous use of the product under investigation. 
If the AE is classified as serious, the clinical investigator has also to complete the SAE 
report form. It is the responsibility of the investigator or designee to send the SAE report 
form by fax or email to the CRO or designee within 24 hours and to retain the original 
copy of the form (keeping a photocopy in the Investigator Site File). At the earliest 
possible date, the SAE report form has to be followed by a detailed report and any 
documentation that may be available, e.g., hospital case records, autopsy reports, and/or 
other pertinent documents. 
All the above documents will be sent by fax or email to the CRO within 24 hours of 
occurrence. The investigator will be responsible for reporting the SAE to ethics 
committees; the sponsor will be responsible for reporting the SAE to the respective health 
authorities, according to the national regulatory requirements. 
Sponsor Medical Monitor for the study is: 
 
 
  
 
  
 
 
 


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The Safety Management Plan for specific countries will be written separately by 
respective CROs and the same will be followed. 
 
Reporting Serious Adverse Events 
Investigator Reporting of SAEs 
Adverse events which are evaluated by the Investigator as “Serious” will be reported to the 
CRO within 24 hours of notice whether or not they are considered expected or drug-related.  
All SAEs will be reported as per local regulations.  All Adverse Events encountered during 
the study will be reported on the appropriate form and summarized in the final report.  
Any serious or unexpected adverse events should be reported to Respective CRO within 
24 hours. For detailed safety information, refer to the safety plan or study manual.  The CRO 
will report any Serious Adverse Event to the following or as per the safety plan.  
Drug Safety Department 
 
 
 
 
 
With copy to 
 
Actavis Study Director  
 
 
Watson Laboratories, Inc., USA 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
 
 
 
Under 21 CFR 320.31(d)(3), the Sponsor or CRO must inform other investigators 
involved in the study plus the FDA within 15 days of becoming aware of the occurrence 
of the SAE. The CRO should report to the Medical Monitor and Sponsor within next 24 
hours. 


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7.6 Laboratory Safety Measurements and Variables 
The following laboratory variables will be analyzed at screening/Visit 1 and TOC/Visit 3: 
 
Clinical chemistry (serum) 
Hematology (whole blood) 
Creatinine 
Hemoglobin 
Glucose 
Platelet count 
Total Protein 
Total  white blood cell (WBC) count 
Sodium 
Differential blood counts 
Potassium 
 
Albumin 
 
Total bilirubin 
 
Alkaline phosphatase 
 
Aspartate aminotransferase 
 
Alanine aminotransferase 
 
 
A urinalysis will be performed per local practices; a urine pregnancy test (minimum 
sensitivity of 25IU/L) will be performed for female subjects of child-bearing potential at 
screening and at end of the study.  A urine test for drugs of abuse will also be performed at 
screening.   
 
Stool samples will be collected and analyzed for culture (at a minimum, E coli) and O&P 
(Ova and Parasites) at screening/Visit 1 and TOC/Visit 3 as described in the Study Manual or 
Lab Manual. 
 
Laboratory analyses will be performed at local laboratories or central laboratories based on 
site’s location.   
7.7 Vital signs and Physical Examination 
The investigator or designee will perform a brief physical examination at Visit 1 and Visit 
3. The examination will include evaluation of the heart, lungs, abdomen, and eyes, ears, 
nose, and throat. Height, weight, and vital signs will be recorded on the eCRF. Vital signs 
are to include sitting blood pressure, pulse, and body temperature. 
 
7.8 Procedures in Case of Medical Emergency 
The principal investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.   


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7.9 Procedures in Case of Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
However, the outcome of all pregnancies must be followed up and documented even if the 
subject was discontinued from the study.  
Spontaneous miscarriages should also be reported and handled as SAEs.   
If pregnancy is confirmed, the investigator must immediately terminate the study subject from 
the study but follow the study subject to determine the outcome and follow up the neonate for 
8 week post delivery to know the outcome and health status of the neonate. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
unless contraindicated by pregnancy. Appropriate pregnancy follow-up procedures should be 
considered if indicated. 
Reporting procedure 
Pregnancy reporting process will be followed for pregnancies as per the local regulatory 
requirements. The guidelines for pregnancy reporting will be provided in a separate document 
(safety plan/ or study manual) to the clinical trial sites. 
7.10 Appropriateness of Measurements 
All clinical and laboratory procedures that will be used in this study are standard and 
generally accepted.   All efficacy measurements are standard for studies of this indication.  


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8. Data Quality Assurance 
Detailed procedures will be separately provided in the data management, monitoring, and 
quality plans. 
 
Data Collection 
All clinical study data has to be recorded in the eCRFs.  
All subject data has to be reported on the eCRFs in an anonymous fashion. Subjects are 
identified only by subject number. 
The investigator will be responsible for the completeness, accuracy, and legibility of the 
information in the eCRF and other study documents. For documents other than eCRF, 
only ballpoint pen is to be used and any change of data is to be done by striking out the 
incorrect data with a single line and dating and initialing the changes made. 
The study monitors then have to check the eCRFs against the source documents for 
accuracy and validity as per the monitoring schedule, as applicable, including 
identification of any step in creation of source data such as when a computerized system 
is to be used to create, modify, maintain, archive, retrieve, or transmit source data. 
The subject diary will remain as source at site and will only be source data verified by the 
monitors, but not collected. Source data verification will include the subject visit notes, 
diary data, eCRF data, and drug accountability. CROs will assign unblinded CRAs to 
perform the drug accountability. 
Upon completion of the examination, eCRF completion is expected at each site to ensure 
quality of data and subject safety. Once eCRFs are completed, they will be available for 
review by the monitor and the designated CRO Clinical Data Management department. 
Completed eCRFs will be reviewed remotely for logical discrepancies. The monitor will 
ensure that all data queries and subsequent amendments in the eCRF documentation are 
made according to GCP guidelines.  
A copy of the eCRF is to be archived by the investigator together with the study 
documents, source data, and laboratory records for the time required by the national 
regulation.  
Site Audits 
The Sponsor (or designee) may carry out an audit at any time. Investigators will be given 
adequate notice before the audit occurs. The purpose of an audit is to confirm that the 
study is conducted as per protocol, GCP, and applicable regulatory requirements, that the 
rights and well-being of the subjects enrolled have been protected, and that the data 


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relevant for the evaluation of the study drug have been captured, processed and reported in 
compliance with the planned arrangements. The investigator will permit direct access to 
all study documents, drug accountability records, medical records, and source data.  
Regulatory authorities may perform an inspection of the study, even up to several years 
after its completion. If an inspection is announced, the Sponsor must be informed 
immediately. 
Database Management 
Lotus Labs will be responsible for the activities associated with the data management of 
this study, including the production of an eCRF, setting up a relevant database, along with 
appropriate validation of data and resolution of queries. All data will be entered into an 
eCRF. Automated and manual checks will be made against the data to ensure 
completeness and consistency. Resolution of queries will be implemented in the database. 
AEs will be standardized for terminology and classification, using Medical Dictionary for 
Regulatory Activities (MedDRA, using the latest available version). Concomitant 
medications will be classified by site of action and therapeutic and clinical characteristics 
using the World Health Organization (WHO) Drug Dictionary (WHO-DD, using the latest 
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9. Statistical Methods 
9.1 Statistical and Analytical Plans 
All items of the eCRF will be presented in individual subject data listings and in 
appropriate summary tables. Standard descriptive summary statistics will be calculated for 
continuous variables (i.e., arithmetic mean, standard deviation, minimum value, median, 
maximum value). Categorical data will be presented in frequency tables using counts and 
percentages. Individual subject data listings will be presented per parameter and will be 
sorted appropriately. Summary tables will be displayed by treatment group and visit (if 
applicable). Wherever appropriate, the presentation will include changes from baseline and 
shift tables. 
Further details of the planned analyses will be given in the statistical analysis plan (SAP), 
which will be developed separately using this protocol. The SAP will give detailed 
descriptions of the statistical methods, models, hypotheses, and analysis populations to be 
analysed along with mock-shells for tables, listings and figures (TLF). The SAP will serve 
as a companion to the protocol and will serve as the de facto documentation of the 
proposed statistical evaluation.  
9.2 Study Populations 
The following 3 analysis populations will be defined for this study: 
Safety Analysis Set: All randomized subjects who receive at least one dose of study drug 
will form the Safety Analysis Set. The Safety Analysis Set will be used for all analyses of 
safety, tolerability, and background characteristics. 
Modified intent-to-treat (mITT) Set:  
 
 
 
 
 
 
   
Per-Protocol (PP) Set: 
 
 
 
 
 
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The PP analysis set is the primary analysis set for the assessment of bioequivalence 
between the test and the reference products.  
 
 
 
 
 
 
. 
Note: If a subject does not return for the scheduled TOC visit (24 to 72 hours after last 
dose of study medication [Day 5, 6 or 7]), then a telephone call should be made by the site 
and all efforts should be made to collect efficacy and safety data for Visit 3. This data 
should be entered in the eCRF for Visit 3. 
9.3 Demography and Baseline Characteristics 
All screening and baseline summaries will be provided for the safety analysis set and 
randomized population. 
Ongoing and previous diseases in medical history will be summarized separately by 
system organ class (SOC) and preferred term. Coding will be based on MedDRA, using 
the latest available version. 
Previous and concomitant medications will be coded according to WHO-DD (using the 
latest available version) and the verbatim term will be displayed together with the WHO-
DD preferred term and the respective Anatomical Therapeutic Chemical (ATC) level 2 
classification. Previous and concomitant medications will be summarized separately by 
ATC level 2 and preferred name.  
Reasons for exclusion from each analysis set will be tabulated if warranted by results.  
Subject disposition status (randomized, treated, completed treatment, completed study) 
will be summarized by treatment group; reasons for discontinuation will be included in the 
disposition summary.  
9.4 Analysis of Efficacy Parameters 
9.4.1 Null Hypothesis for Primary Efficacy Parameter  
Two sets of null hypotheses will be used for the primary efficacy endpoint to evaluate the 
clinical bioequivalence between test product and reference products with respect to the 
clinical cure rate using PP population. The hypothesis for testing equivalence is stated as 
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(i) Null Hypothesis for Bioequivalence: 
H0 : pT – pR < -0.20 or  pT – pR > 0.20  
Versus  
H1: -0.20 ≤ pT –pR ≤ 0.20 
where pT = clinical cure rate of test treatment and pR = clinical cure rate of reference 
treatment. 
The null hypothesis for bioequivalence will be evaluated based on the PP analysis set 
using two one-sided Z-test test with Yates correction, each at the 0.05 significance level.  
In practice, this is equivalent to constructing 90% confidence intervals (CIs) for the 
difference (test – reference) using a statistical model appropriate for the study design. If 
both intervals fall completely within the cutoff limits of [-0.20, +0.20] for clinical cure 
rates in this study, then equivalence is declared.  Otherwise, equivalence is not declared.  
 
The other null hypothesis will evaluate the differences between each active arm versus 
placebo as defined below: 
(ii) Null Hypothesis for Superiority: 
H0:  pT  = pP 
 
Versus 
H1:  pT  ≠ pP   
where pT = clinical cure rate of subjects treated with rifaximin or Xifaxan® and 
pP = clinical cure rate of subjects receiving placebo.  
 
The objective of superiority test is to demonstrate that the test product and the reference 
product performed as expected (i.e. statistically superior to placebo) in the study. Hence, 
this null hypothesis serves as a validity to check the study sensitivity, after establishing the 
clinical bioequivalence between the test product and the reference product. 
The null hypothesis for superiority analysis will be evaluated based on the mITT analysis 
set with LOCF for the missing data using a two-sided Z-test test with Yates correction 
with a significance level of α=0.05.  Differences between the treatment groups and 95% 
CIs for the difference will be presented.  
Note: Visit 2 data i.e. data from a telephone follow-up call on Day 3, after taking about 5 
doses of study medication, may be considered for applying LOCF for mITT population, 
for the cases where TOC data is missing. 
 


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9.4.2 Null Hypothesis for Other Efficacy Parameters 
Difference between groups in other efficacy endpoints will be examined as 
supportive/confirmatory analysis base on the following null hypothesis: 
For categorical variables: 
H0 : Pi = Pj  vs H1: Pi ≠ Pj 
Where P = proportion of subjects meeting the criteria, I and j = 1 (Test) , 
2 (Reference), or 3 (Placebo) and i ≠ j 
For continuous variables: 
H0 : µi = µj  vs H1: µi ≠ µj 
Where µ = group mean, i and j = 1 (Test), 2 (Reference), or 3 (Placebo) and i ≠ j 
All tests will be two-sided and performed at the 0.05 significance level.  No adjustments 
will be made for multiplicity testing since all secondary efficacy endpoints are 
supportive/confirmatory.  
9.4.3 Primary Efficacy Variable Analysis 
The primary efficacy variable is the proportion of subjects who achieve clinical cure at 
the TOC visit (i.e., Study Day 5, 6 or 7).   
To evaluate the null hypothesis (1) i.e., test for equivalence, the proportion of subjects 
meeting the clinical cure criteria will be tabulated by treatment group on the PP analysis 
set with LOCF*for missing data imputation.  The differences between the test product 
and reference product on the PP analysis set will be estimated and the 90% CIs for the 
difference will be presented.  The 90% CIs will be calculated using Z-test for proportion 
with Yates’ correction as presented below.   
L = (PT – PR) – 1.645 se – (1/NT – 1/NR)/2 
U = (PT – PR) + 1.645 se + (1/NT – 1/NR)/2 
PT = CT / NT   
PR = CR / NR 
se = SQRT [PT*(1-PT) / NT + PR*(1-PR)/NR]   
Where CT and CR are number of subjects meeting the clinical cure criteria in the test 
product and the reference product arm respectively; PT, PR are the proportions of clinical 
cure from the test product arm and the reference product arm, respectively; NT and NR are 
total number of subjects in the analysis set from the test product and the reference arm 
product, respectively; se = standard error; SQRT = square root.  


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If the upper and the lower CIs are within the range of [-0.20, +0.20], the null hypotheses 
for clinical bioequivalence will be rejected and it can be claimed that the test product and 
the reference product are clinically equivalent with respect to the clinical cure rates. 
Reasons for clinical failure will also be tabulated by treatment group showing the number 
and percentage of subjects failed by each criterion.     
*
 
 
 
 
 
 
  
 
To evaluate the null hypothesis (2) i.e., test of superiority, the proportion of subjects 
meeting the clinical cure criteria will be tabulated based on the mITT analysis set with 
LOCF for missing data imputation. The differences between each active arm (test and 
reference) and the placebo group will be tested separately using a two-sided Z-test for 
proportion using Yates correction; the estimated difference and 95% CIs will be 
presented.   
9.4.4 Secondary Efficacy Variables Analysis 
All secondary efficacy endpoints will be tabulated by treatment groups on the mITT and 
PP populations. 
For the secondary endpoint TLUS, defined as the interval beginning with the first dose of 
study drug and ending with the last unformed stool passed, summary tables will be 
presented along with p-values using appropriate statistical method. 
For microbiological cure rate, summary tables will include number and percentage of 
subjects in each category; differences between groups (test vs placebo, reference vs 
placebo, and test vs reference) will be derived along with the 95% CIs for the difference 
using the Z-test for proportion to test the difference between the treatment groups; the 
Yates’s correction will be applied for the calculation of 95% CIs. 
For variables related to number of formed and number of unformed stools by study day, 
summary tables will include number and percentage of subjects with 0, 1, 2 … etc. 
number of stools by treatment group and time point.  Stools occurred on Day 1 prior to 
receiving first dose of study drug will be included in the bowel movement at baseline; 
number of stools on Day 1 will include only those occurred on Day 1 after the first dose 
of study drug. 
 


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9.5 Analysis of Safety Parameters 
All adverse events (AEs) and treatment-emergent AEs (TEAEs) reported during the study 
will be summarized/reviewed in order to assess safety. Safety will be evaluated by 
incidence of TEAEs including incidence of selected TEAEs of special interest, incidence 
of SAEs; TEAEs by relationship to study drug and intensity; and TEAEs leading to 
discontinuation. Observed results and change from baseline in clinical laboratory tests, 
vital signs, and physical examinations will be tabulated by treatment group.   
MedDRA (using the latest available version) will be used to classify all AEs with respect 
to SOC and preferred term. All safety summaries will be performed on the safety analysis 
set by treatment group without inferential statistics. 
Total extent of exposure to study drug will be measured by total number of tablets taken 
and duration of exposure calculated as date of last dose minus date of first dose plus 1.  
Study drug compliance (%) will be calculated as number of tablets taken divided by 
number of tablets expected to take multiplied by 100.  Subjects are considered to have 
good compliance if the compliance (%) is within the range of ~75% to ~125%, 
corresponding to 7 to 11 doses.    
9.6 Sample Size Calculation 
The sample size calculation for this study is based on the published literature (CDER 
statistical review of NDA submission 21-361) and FDA’s current guidance (FDA Guidance, 
2004) on the clinical endpoint bioequivalence study of Rifaximin 200 mg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thus, approximately 618 patient(s) 
 will be 
enrolled and randomized 
 for Test vs. Reference vs. 
Placebo 
 


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 the overall dropout rate from the randomized patient population to mITT population 
does not exceed 15%.
 
 
he PP population when the 
lower and upper 90% CI falls within [-0.20, +0.20].   
9.7 Handling of Drop-outs and Discontinuations 
 
 
 
 
 
 
 
  
 
 
 
Missing data for other assessment (eg, safety assessment or baseline assessment) will not 
be imputed. However, for the purpose of summary, AEs with missing relationship to 
study drug assessment will be counted as “related”; AEs with missing intensity 
assessment will be counted as “severe”.  Missing intensity and relationship will be 
presented as is on the individual subject data listing. 
9.8 Interim Analyses 
No interim analysis is planned for this study. 
9.9 Data Monitoring Board 
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10. Study Administration 
10.1 Investigators and Study Administrative Structure 
The Investigator who is responsible for the conduct of this study, in compliance with this 
protocol, is identified on the Investigator Agreement page. The Investigator will also provide 
a completed United States Food and Drug Administration (US FDA) Form 1572 to the 
Sponsor or Sponsor’s representative prior to receipt of study drug and study initiation at that 
site. 
 
Sponsor:  
 
 
 
 
Actavis 
Study Director  
 
 
 
 
 
Contract Research  
Organization (CRO):  
 
 
 
Project Lead (Lotus Labs) 
 
 
 
Medical Monitor 
 
 
 
 
Lead Biostatistician (Lotus Labs) 
 
 
Contract Research  
Organization (CRO):  
 
 
 
Project Manager (TCTM): 
 
 
 
Contract Research  
Organization (CRO):  
 
 
 
Project Manager (Chiltern):   
 
 
10.2 Local Ethics Committee (LEC)/Institutional Review Board (IRB) Approval 
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent form, and all other forms of subject information related to the 
study and any other necessary documents be reviewed by an LEC/ IRB. 
 
It is required that a valid LEC/IRB approves in writing the conduct of this clinical study, 
together with the Investigator’s informed consent document, prior to study initiation. 
The trial protocol was developed in accordance with the Declaration of Helsinki, the ICH 
Guidance on GCP. 
 


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In performing this study, both the Investigator and Sponsor endorse, as a minimum, the 
standards for conduct of clinical research activities as set forth in the Declaration of Helsinki, 
ICH guidelines and local country laws and regulations. 
 
The Investigator will submit the protocol and informed consent for LEC/IRB acceptance. This 
will be appropriately documented. The LEC/IRB should be asked to give its acceptance in 
writing. The names and qualifications of the members of the review committee will be 
recorded and submitted to the Sponsor, together with the written acceptance for the conduct 
of the study. The members of the LEC/IRB accepting must be independent of the Sponsor and 
the Investigator. The written acceptance should consist of a completed LEC/IRB acceptance 
form or written documentation from the containing the same information. 
 
Until written acceptance by the LEC/IRB has been received by the Sponsor, no subject may 
undergo any procedures solely for the purpose of determining eligibility for this study. 
Protocol amendments must also be reviewed and accepted by the LEC/IRB and written 
acceptance from the committee or at least the chairperson (or a designated committee 
member) must be received by the Sponsor before implementation. This written approval will 
consist of a completed LEC/IRB acceptance form or written documentation from the 
LEC/IRB containing the same information. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, all ICH and GCP regulations 
governing clinical study conduct; ethical principles that have their origin in the Declaration of 
Helsinki and all applicable local laws and regulations. The investigator must assure that the 
study is conducted in accordance with the provisions as stated in the US FDA regulations and 
complies with prevailing local laws and customs. 
10.4 Subject Information and Consent 
The investigator or designee will explain the nature of the study to the subject, and answer all 
questions regarding this study, prior to obtaining informed consent.  
The Investigator or designee will obtain informed consent from each subject enrolled in the 
study, in accordance with the Declaration of Helsinki, the current version of the ICH 
guidelines and the laws and regulations of the country in which the investigation is being 
conducted.  In addition, study subjects must sign a HIPAA authorization, where required. 
The LEC/IRB must accept the informed consent document to be used by the Investigator. It is 
the responsibility of the Investigator to assure that the subject has signed the informed consent 
form before any activity or treatment is undertaken. This includes, but is not limited to, the 


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performance of diagnostic or therapeutic procedures and the administration of the first dose of 
study medication. 
10.5 Subject Confidentiality 
Adequate records have to be maintained for the study, including subject medical records, 
eCRFs, laboratory reports, worksheets, nursing notes, signed informed consent forms, 
product forms, SAE forms, and information regarding subject discontinuation and reasons 
for discontinuation. The confidentiality of each record with subject identification is to be 
guaranteed by the clinical investigator. 
This study protocol and other study documents contain trade secrets and commercial 
information that is privileged and confidential. Such information is not to be disclosed 
unless required by laws or regulations. The investigator agrees to use this information only 
in conducting this study and is not allowed to use it for other purposes without written 
consent from the Sponsor. Results obtained from this study are the property of the 
Sponsor. 
10.6 Study Monitoring 
For protocol monitoring and compliance, a site initiation visit will be held prior to subject 
enrolment. The protocol, eCRF, IWRS entries, study treatment supplies, and study procedures 
will be explained in detail.  
The purpose of monitoring is to verify the rights and well-being of human subjects are 
protected; that study data are accurate, complete, and verifiable with source data; and that the 
study is conducted in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
A monitor assigned by the designated CRO will conduct regular site visits for the purpose of 
study monitoring.  
The investigator must agree to allow the study monitor and authorized representatives of the 
designated CRO or the Sponsor to inspect all eCRFs and corresponding source documents 
(e.g., original medical records, subject records and laboratory raw data); to allow access to the 
clinical supplies, dispensing, and storage areas; and to agree to assist with their activities, if 
requested. The investigator should provide adequate time and space for monitoring visits. 
The monitor will query any missing or spurious data with the investigator, which should be 
resolved in a timely manner. A visit log will be maintained to record each visit, the reason for 
the visit, the monitor’s signature, and the investigator’s or designee’s confirmation signature. 


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10.7 Case Report Forms and Study Records 
Subject source documents are the physician’s records maintained at the study site. The 
information collected on the eCRF must match those charts. In some cases, a portion of the 
source for a given subject may be the eCRF. 
The eCRF data will be collected electronically. Instructions for entering data via internet will 
be provided in the eCRF Completion Guidelines and training will be provided to the study 
site staff prior to initiation of the site. 
Periodically, the Monitor or other authorized Sponsor personnel will visit the study site for 
the purpose of comparing the data on the eCRF with the source documents. The Investigator 
agrees to make source documents available for this purpose. The eCRF should be completed 
as soon as possible after the data are available. 
A minimum of the following set of documents will be received by the CRO prior to the 
initiation of the study: 
1. Fully executed protocol  
2. Debarment Letter 
3. Completed and signed FDA Form 1572  
4. Current curricula vitae, signed and dated for the Investigator and each Sub-
Investigator named in the FDA Form 1572 (current within 2 years) 
5. Current medical licenses of the Investigator and Sub-Investigators named in FDA 
Form 1572 
6. Documentation of “No Objection” to proceed from the local regulatory agency, where 
ever applicable. 
7. Documentation of LEC/IRB approval of this study protocol, Investigator and informed 
consent forms 
8. Current LEC/IRB membership list or roster and EC SOPs 
9. Financial Disclosure Statement for the Investigator and each Sub-Investigator named 
in FDA Form 1572  
10. Sites Clinical Laboratory Head’s current (within 2 years) curricula vitae and normal 
reference ranges of laboratory parameters 
11. Fully executed Clinical Trial Agreement 
 
10.8 Data Monitoring Committee 
Not applicable. 
 


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10.9 Protocol Violations/Deviations 
When a variation from the protocol is deemed necessary for an individual subject, the 
Investigator or other physician in attendance must contact the Sponsor’s Medical Monitor or 
sponsor representative through the CRO representatives. 
Such contact must be made as soon as possible to permit a decision as to whether or not the 
subject is to continue in the study. The deviation from the protocol will be authorized only for 
that subject. 
All deviations related to study inclusion and exclusion criteria and significant deviations to 
subject management and protocol procedures must be documented on the appropriate eCRF. 
Major protocol deviations/violations will include, but are not limited to, the following: 
• Did not meet any critical inclusion/exclusion criteria which may impact the 
assessment of treatment efficacy. 
• Did not receive randomized treatment (i.e., the actual treatment is not randomized 
treatment). 
• Use of prohibited concomitant medications (e.g., prescription or OTC anti-
diarrheal drug product, NSAIDs [with the exception of acetaminophen and 
paracetamol] or opioid analgesics).  
• Did not meet the drug compliance of taking ≥ 7 to ≤ 11 doses.  
• Did not come for Visit 3 within the visit window period of 24 to 72 hours of last 
dose. 
 
10.10 Access to Source Documentation 
Refer to Section 10.7. 
10.11 Data Generation and Analysis 
The majority of data is expected to be entered into the database via eCRF and any corrections 
will also be entered electronically. After completion of the entry process, computer logic 
checks will be run to check for such items as inconsistent study dates and outlying laboratory 
values. Any necessary corrections will be made to the database and documented via addenda 
or audit trail. A manual review of selected line listings will also be performed at the end of 
the study. 
10.12 Retention of Data 
The investigator agrees to retain copies of the eCRFs with other study documents (e.g., the 
protocol and any protocol amendments, the Summary of Product Characteristics, LEC 
approval, signed consent forms, and source documents for each subject in the study [e.g., all 
demographic and medical information, including laboratory data, electrocardiograms, 


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medication disposal and subject diaries) in a secure place as long as needed to comply with 
national and international regulations. These records have to be made available for inspection 
upon reasonable request by a representative of the Sponsor or regulatory authorities. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another Investigator, another 
institution, or to the Sponsor. The Investigator must obtain written permission from the 
Sponsor before disposing of any records. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
10.13 Termination of the Study 
The Sponsor reserves the right to terminate this study prematurely, either in its entirety or at a 
specific site, for reasonable cause provided that written notice is submitted a reasonable time 
in advance of the intended termination. The Investigator may also terminate the study at their 
site for reasonable cause, after providing written notice to the Sponsor a reasonable time in 
advance of the intended termination. Neither party requires advance notice if the study is 
stopped due to safety concerns. If the Sponsor chooses to terminate the study for safety 
reasons, it will immediately notify the Investigator and subsequently provide written 
instructions for study termination. Subjects who have not completed treatment in the trial at 
the time of termination will be advised and offered alternative treatment, as medically 
indicated. 
10.14 Financial Disclosure 
Consistent with Title 21 CFR Part 54, all investigators will complete a Financial Disclosure 
Form that permits Sponsor to demonstrate that an Investigator has no personal or professional 
financial incentive regarding study outcome or the future approval or disapproval of an 
investigational drug such that the Investigator’s research might be biased by such incentive. 
10.15 Publication and Disclosure Policy 
Any formal presentation or publication of data from this trial will be considered by the 
appropriate Sponsor personnel. For multicenter studies it is mandatory that the first 
publication is based on data from all centers, analyzed as stipulated in the protocol. 
Investigators agree not to present data gathered from one center or a small group of centers 
before the full publication. In this case, the Sponsor must receive and approve the copies of 
any intended communication in advance of publication (at least 30 working days for an 
abstract or oral presentation and 60 working days for a journal submission). In any case, the 
Sponsor will review the publications/communications/abstracts for accuracy (thus avoiding 


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potential discrepancies with submissions to health authorities), verify that proprietary, 
confidential information is not being inadvertently divulged, and provide any relevant 
supplementary information. 
10.16 Clinical Study Report 
The clinical study report will be prepared as per ICH E3 format. 
 


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11 References 
CDER Statistical review of NDA submission 21-361. 
Center for Disease Control. cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. 10 
February 2014. 
Food and Drug Administration, Draft Guidance on Rifaximin, November 2011. 
Food and Drug Administration, Guidance for Industry Handling and Retention of BA and 
BE Testing Samples, May 2004. 
Layer P, Andresen V. Review article. Rifaximin, a minimally absorbed oral antibacterial, 
for the treatment of travellers’ diarrhea. Aliment Pharmacol Ther 31, 1155–1164 
Xifaxan® (Rifaximin) tablets - 200 mg [package insert]. Raleigh, NC. Salix 
Pharmaceuticals, Inc; 2015. 
 


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12 Appendix - Detailed Protocol Summary of Changes 
 
Administrative changes: Minor changes involving grammar, wordsmithing, punctuation, and 
other editorial changes have been made throughout the document. All are clearly identified in the 
track-changes version of the amendment. 
 
Other changes:  Section numbers and titles in the table below refer to the current version of the 
protocol.  Language that has been added to the previous version of the protocol is indicated in red 
text (example text).  Language that has been deleted is indicated in red text with strikethrough 
(example text).   


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Section Number and Title; 
Rational for Change 
Old Version 
Amended Version 
Section 3. Investigational 
Plan 
 
Rationale for change: 
language added regarding 
stool collection if subject 
could not pass a stool 
sample at Visit 3 
Stool samples will be collected pre-
treatment (screening) and post-treatment 
(TOC) to be cultured for pathogenic 
organisms. 
Adverse 
events 
(AEs), 
concomitant medication details and safety 
laboratory samples will be collected at 
Visit 1 and Visit 3. 
Stool samples will be collected pre-treatment 
(screening) and post-treatment (TOC) to be 
cultured for pathogenic organisms. If the 
stool sample collection is not possible at visit 
3, a rectal swab will be collected. Adverse 
events (AEs), concomitant medication details 
and safety laboratory samples will be 
collected at Visit 1 and Visit 3. 
 
Section 4.2.  Exclusion 
Criteria 
 
Rationale for change:  
clarified use of opioids for 
criterion #5d. 
5d.  Use of opioids within 48 hours 
preceding randomization. 
5d.   Use of opioids (in any form) within 48 
hours preceding randomization. 
 


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Section Number and Title; 
Rational for Change 
Old Version 
Amended Version 
Section 4.2.  Exclusion 
Criteria 
 
Rationale for change:  
added three exclusion 
criteria to provide 
timeframe for visiting 
country, excluding subjects 
with lactose and gluten 
intolerance and adding 
alcohol restriction 
6. Has a history or presence of allergic 
response to rifaximin or related 
drugs. 
7. Has a current or recent history (within 
12 months of screening) of drug or 
alcohol abuse. 
 
6. Has a history or presence of allergic 
response to rifaximin or related drugs. 
7. People who have lived in or stayed in the 
country where they acquired travelers’ 
diarrhea for more than 6 months.  
8. Has a history of lactose or gluten 
intolerance. 
9. Consumed more than 2 alcoholic drinks 
within 12 hours before screening.  
Alcohol consumption is not allowed 
during the study. 
10. Has a current or recent history (within 12 
months of screening) of drug or alcohol 
abuse. 


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Section Number and Title; 
Rational for Change 
Old Version 
Amended Version 
Section 4.3 Restrictions 
 
Rationale for change: Added 
that alcohol and probiotics 
consumption would not be 
allowed; deleted the word 
“treatments” since alcohol 
consumption is not a 
treatment 
The following treatments are not allowed 
in this study:  
• Any antimicrobial agents with an 
expected 
activity 
against 
enteric 
bacterial pathogens within 7 days 
preceding randomization and during 
the study. 
• More than two doses of a symptomatic 
antidiarrheal 
compound 
such 
as 
antimotility agents, absorbent agents, 
and antisecretory agents preceding 
randomization and during the study. 
• Use of any drug such as aspirin or 
ibuprofen (Advil), which can cause GI 
bleeding within 8 hours preceding 
randomization and during the study. 
Note: Acetaminophen (Tylenol) or 
paracetamol is acceptable for use 
during the study.  
• Opioids within 48 hours preceding 
randomization and during the study. 
The following treatments are not allowed in 
this study:  
• Any 
antimicrobial 
agents 
with 
an 
expected activity against enteric bacterial 
pathogens within 7 days preceding 
randomization and during the study. 
• More than two doses of a symptomatic 
antidiarrheal 
compound 
such 
as 
antimotility agents, absorbent agents, and 
antisecretory 
agents 
preceding 
randomization and during the study. 
• Use of any drug such as aspirin or 
ibuprofen (Advil), which can cause GI 
bleeding within 8 hours preceding 
randomization and during the study. 
Note: 
Acetaminophen 
(Tylenol) 
or 
paracetamol is acceptable for use during 
the study.  
• Opioids (in any form) within 48 hours 
preceding randomization and during the 
study. 
• Alcohol or probiotics consumption. 
 


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Section Number and Title; 
Rational for Change 
Old Version 
Amended Version 
Section 6.1 Schedule of 
Events, Table 1 – Schedule 
of Events 
 
Rationale for change: Added 
footnote regarding stool 
collection if subject could 
not pass a stool sample at  
Visit 3 
N/A 
Stool sample for culture and  O & P:   
 
f.  In case stool sample collection not 
possible at visit 3, a rectal swab will be 
collected. 
Section 6.2 Screening, 
Randomization and 
Treatment Visit; Visit 1/ 
Day 1 
 
 
Rationale for change:  
Clarification that stool 
sample should be collected 
prior to study drug dosing 
Eligible subjects will be randomized and 
the first dose of study drug should be 
preferably administered under unblinded 
study 
staff/independent 
dispenser 
supervision at the clinic.  The unblinded 
study staff/independent will dispense a 
total of 12 tablets from the containers and 
instruct the subjects to only take 9 tablets, 
and that the extra 3 tablets are provided 
only in case subject loses tablets. 
 
Eligible subjects will be randomized and the 
first dose of study drug should be preferably 
administered 
under 
unblinded 
study 
staff/independent dispenser supervision at 
the clinic.  Subjects should be suggested to 
start the first dose of the study drug only after 
providing the stool sample. The unblinded 
study staff/ independent dispenser will 
dispense a total of 12 tablets from the 
containers and instruct the subjects to only 
take 9 tablets, and that the extra 3 tablets are 
provided only in case subject loses tablets. 
 


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Section Number and Title; 
Rational for Change 
Old Version 
Amended Version 
Section 6.5 Test of Cure; 
Visit 3 (Day 5, 6 or 7) 
 
Rationale for change: added 
language regarding stool 
collection if subject could 
not pass a stool sample at 
Visit 3 
Subjects are to complete the study diary 
from day 1 until last study visit day.   
 
 
Subjects are to complete the study diary from 
day 1 until last study visit day.   
If the stool sample collection is not possible 
at Visit 3, a rectal swab will be collected. 
 
 

SAP_000.pdf: 
Statistical Analysis Plan with Amendment 02 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multicenter, 
Bioequivalence Study with Clinical Endpoint Comparing Rifaximin 200-mg Tablets with 
Xifaxan® 200-mg Tablets in the Treatment of Travelers’ Diarrhea 
Study Number ACTA/RIFX/2015 
NCT02498418 
Statistical Analysis Plan with Amendment 02 Approval Date: 19 April 2017 


Protocol ACTA/RIFX/2015                     
 
 
Statistical Analysis Plan 
                                                     
 
 
 
 
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              Confidential 
         Page 1 of 28 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
PROTOCOL: ACTA/RIFX/2015 (Version 2, Amendment 2) 
 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multicenter, 
Bioequivalence Study with Clinical Endpoint Comparing Rifaximin 200-mg 
Tablets with Xifaxan® 200-mg Tablets in the Treatment of Travelers’ Diarrhea 
 
 
 
Sponsor 
Watson Pharma Pvt. Ltd. 
 
 
 
 
 
 
CRO 
 
 
 
 


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Statistical Analysis Plan 
                                                     
 
 
 
 
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         Page 2 of 28 
 
Author(s): 
 
 
 
CRO for 
Biostatistics: 
 
  
 
 
 
 
 
Sponsor:  
 
Watson Pharma Pvt. Ltd. 
 
 
 
 
 
 
Version: 
03 
 
 
 
 
 
 


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REVISION HISTORY 
 
Date of this version: 19-APR-2017 
 
Version 
Number Version Date 
Previous 
Version Date 
Summary of Changes 
03 
19 FEB 2017 
09 FEB 2017 
 
 
 
 
 
 
 
 
 
 
02 
09 FEB 2017 
22 Aug 2016 
Section 3.1 Number of Study Sites: 
This study will be conducted at approximately 30 
study sites in approximately 3 countries. 
 
Section 5.4 Per-Protocol (PP) Population: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section  6 (d): 
 
 
 
 
 
  
 
Section  6 (e): 
 
 


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Section 7.5.1 Primary Efficacy Analysis: 
L = (PT – PR) – 1.645 se – (1/NT + 1/NR)/2 
U = (PT – PR) + 1.645 se + (1/NT + 1/NR)/2 
 
Section 8.8: Subjects Exclusion from the Efficacy 
Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix I: 14.2.2.5   Analysis of 
Microbiological Cure rates– Per protocol 
Population 
 
Appendix II: Per-protocol population, point #3 
Returned to the study site for Visit III after 24 
hrs from time of last dose. 
Consider the subjects who returned to visit III 
after 24 hours from the time of last dose; and had 
stool data up to 48 hours from the time of last 
dose. Subjects who did not enter any stool info in 
the diary after the last dose, but returned to visit 
III, will be considered as subjects did not have 
any stool sample for that particular period. Thus, 
subjects who did not report any stool sample 
within a period of 48 hours from the time of last 
dose with no fever, and with or without other 
enteric symptoms, will be considered in the 
clinical cure subjects list. 
01 
22 Aug 2016 
N/A 
N/A 
 
 


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APPROVALS 
 
 
This document requires the following approvals: 
 
Name 
Title  
Signature & Date 
 
 
  
. 
 
 
 
 
 
 
  
 
  
 
 
 
 
Actavis Inc  
 
 
 
*Signature by the Biostatistician responsible for development of the Plan and management of 
SAP activities for this study indicates: (1) study team validation of study requirements (2) 
approval, agreement, and commitment in support the plan for implementing these requirements. 
Signature by the Client/Sponsor appropriate personnel responsible for review and approval of the 
plan indicates: approval, agreement and commitment to support the plan.  
 
 


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TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN ............................................................................................ 1 
REVISION HISTORY ................................................................................................................. 3 
APPROVALS ............................................................................................................................... 5 
ABBREVIATIONS ...................................................................................................................... 8 
DEFINITIONS ............................................................................................................................. 9 
1. 
INTRODUCTION .......................................................................................................... 11 
2. 
STUDY OBJECTIVES .................................................................................................. 11 
2.1 
Primary Objective........................................................................................................... 11 
2.2 
Secondary Objective....................................................................................................... 11 
3. 
STUDY OVERVIEW .................................................................................................... 12 
3.1 
Study Design .................................................................................................................. 12 
3.2 
Investigational Medicinal Products ................................................................................ 12 
3.3 
Study Drug Dosing ......................................................................................................... 13 
3.4 
Number of Study Sites ................................................................................................... 13 
3.5 
Number of Subjects ........................................................................................................ 13 
3.6 
Estimated Study Duration .............................................................................................. 13 
3.7 
Randomization and Blinding .......................................................................................... 13 
3.8 
Schedule of Study Procedures ........................................................................................ 14 
4. 
STUDY ENDPOINTS ................................................................................................... 15 
4.1 
Efficacy Endpoints ......................................................................................................... 15 
4.1.1 Primary Efficacy Endpoint ............................................................................................. 15 
4.1.2 Secondary Efficacy Endpoint ......................................................................................... 16 
4.2 
Safety Endpoints............................................................................................................. 16 
5. 
ANALYSIS POPULATION .......................................................................................... 17 
5.1 
Randomized population .................................................................................................. 17 
5.2 
Safety Population ........................................................................................................... 17 
5.3 
Modified intent-to-treat (mITT) ..................................................................................... 17 
5.4 
Per-Protocol (PP) Population ......................................................................................... 17 
6. 
HANDLING MISSING VALUES ................................................................................. 17 
7. 
STATISTICAL METHODOLOGY............................................................................... 18 
7.1 
Hypotheses and Decision Rules ..................................................................................... 18 
7.1.1 Primary Efficacy Analysis.............................................................................................. 18 
7.1.2 Hypothesis for Other Efficacy parameters ..................................................................... 19 
7.2 
Sample Size Justification................................................................................................ 20 
7.3 
Exposure and Treatment Compliance ............................................................................ 21 
7.4 
Interim Analysis ............................................................................................................. 21 


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7.5 
Efficacy Analysis ........................................................................................................... 21 
7.5.1 Primary Efficacy Analysis.............................................................................................. 21 
7.5.2 Secondary Efficacy Analysis.......................................................................................... 22 
7.6 
Safety Analysis ............................................................................................................... 22 
7.6.1 Adverse Events .................................................................................................................. 22 
7.6.2 Physical Examination ........................................................................................................ 23 
7.6.3 Vital Signs ......................................................................................................................... 23 
7.6.4 Laboratory investigations .................................................................................................. 23 
7.6.5 Prior or Concomitant Medication ...................................................................................... 23 
7.6.6 Medical History ................................................................................................................. 24 
8. STUDY CONDUCT .............................................................................................................. 24 
8.1 
Subject Accountability and Disposition ......................................................................... 24 
8.2 
Demographics and Baseline Characteristics .................................................................. 24 
8.3 
Study diary Completion.................................................................................................. 24 
8.4 
Enteric Infection and Other Symptoms .......................................................................... 25 
8.5 
Stool Data and Results ................................................................................................... 25 
8.6 
Protocol deviations ......................................................................................................... 25 
8.7 
Analysis Conventions ..................................................................................................... 26 
8.8 
Subjects Exclusion from the Efficacy Analysis ............................................................. 27 
9 
REFERENCES ............................................................................................................... 27 
APPENDIX I .............................................................................................................................. 27 
APPENDIX II............................................................................................................................. 27 
APPENDIX III ........................................................................................................................... 28 
 
 
 


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ABBREVIATIONS 
 
Term 
Abbreviation 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body Mass Index  
eCRF 
Electronic Case Report Form 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
DBL 
Database Lock 
FDA 
Food and Drug Administration 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
Min 
Minimum 
mITT 
modified intent-to-treat  
PP 
Per Protocol 
P-Value 
Probability value 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class  
TEAEs 
Treatment Emergent Adverse Events  
TD 
Travelers’ Diarrhea  
TLF 
Table, Listing & Figure 
TID 
Three times a day 
TLUS 
Time to last unformed stool 
TOC 
Test of Cure 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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DEFINITIONS 
 
Adverse Event (AE): Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
 
Concomitant Medication: A concomitant medication (con-med) is a drug, other than a 
study drug, taken by a subject after initial dose of study drug. 
 
Database Lock: The point at which all clinical trial data has been reviewed, queries resolved, 
and issues addressed, and the database can no longer be changed in any manner; a locked 
database is ready to undergo statistical analysis. 
 
Double-blind Study: A study in which neither the subject nor the investigator nor the research 
team knows what treatment a subject is receiving. 
 
Dropout: A subject in a clinical trial who, for any reason, fails to continue in the trial until the 
last visit required of him/her by the study protocol. 
 
eCRF: Audible electronic record designed to record information required by the clinical trial 
protocol to be reported to the sponsor on each trial subject. 
 
Efficacy: The capacity of a drug or treatment to produce beneficial effects on the course or 
duration of a disease at the dose tested and against the illness for which it is designed.  
 
Endpoint: An indicator or outcome measured in a subject or biological sample to assess the 
safety, efficacy, or other objective of a trial. Variable that pertains to the efficacy or safety 
evaluations of a trial.  
 
p value: The lowest level of significance at which a given null hypothesis can be rejected; that 
is, the probability of observing a result as extreme or more extreme than that observed if the null 
hypothesis is true.  
 
Prior Medication: A prior medication is a drug taken prior to the initial dose of study drug. 
 
Randomization: The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine the assignments in order to reduce bias.  
 
Serious Adverse event (SAE): Any untoward medical occurrence that at any dose: results in 
death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect.  
 


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Statistical Analysis Plan: A statistical analysis plan is a document that contains a more 
technical and detailed elaboration of the principal features of the analysis described in the 
protocol, and includes detailed procedures for executing the statistical analysis of the primary 
and secondary variables and other data.  
 
Statistical Significance: State that applies when a hypothesis is rejected. Whether or not a given 
result is significant depends on the significance level adopted.  
 
Treatment-Emergent Adverse Event (TEAE):  An event that emerges during treatment, 
having been absent pretreatment, or worsens relative to the pretreatment state.  
 
Withdrawal: The act of reducing the degree of participation by a subject in a clinical trial. 
Subjects may withdraw permission for Sponsor use of data derived from study participation, 
privacy waivers, informed consent, or withdraw from active treatment component of a clinical 
trial but continue to be observed. Full withdrawal from participation in a study is called 
discontinuation.  
 


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1. 
INTRODUCTION 
 
The purpose of this document is to provide details about the statistical analyses methods 
specified in the study protocol of ACTA/RIFX/2015 (Version 2, Amendment 2), and dated 
06/Apr/2016. Detailed description of study objectives, study design, analysis populations, 
definitions of safety and efficacy endpoints, and details on statistical methods are provided in 
this document. Mock shells of tabulations and listings of efficacy and safety data will also be 
covered with this document as appendix. Any exploratory or additional analysis, apart from the 
methods specified in this document and the protocol, will be discussed in the clinical study 
report. 
The Biostatistician is responsible for updating the SAP throughout the life cycle of the study as 
and when required.  However, the first version of the SAP should be signed off before the 
database (DB) lock and any further changes should be addressed by the change control procedure 
such that the revised version of the SAP describes the change(s) along with rationale for those 
change(s) which are essential and would not compromise the quality and integrity of data or 
results. As this is a living document, changes will be made as needed.  The responsible 
representative at Actavis will be required to review and approve all versions of the SAP.  
 
2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
Following are the primary objectives of this study: 
 
(i) 
Bioequivalence of rifaximin 200-mg tablets (the test product) and Xifaxan® 200-mg 
tablets (the reference product) with respect to the clinical cure rate within a period of 24 to 
48 hr. from the time of last dose when administered 3 times a day (TID) for 3 days in 
subjects with Travelers’ Diarrhea (TD).   
Clinical cure is defined as either of the following: 
 No stools or only formed stools within a 48 hour period and no fever, with or without 
other enteric symptoms, OR 
 
 No watery stools or no more than two soft stools passed within a 24 hour period with 
no fever and no other enteric symptoms except for mild excess gas/flatulence. 
 
 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in ≤ 3 
days (i.e., within 72 hrs from the time of first dose) is a clinical failure. 
 
(ii) 
Superiority of test and reference products over placebo with respect to the clinical cure     
rate within a period of 24 to 48 hr. from the time of last dose, in the treatment of TD, using 
the mITT population with LOCF. 
 
2.2 
Secondary Objective 
 
Following are the secondary objectives of this study: 


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• 
To compare “Time to last unformed stool” (TLUS) observed for rifaximin 200-mg tablets 
and Xifaxan 200-mg tablets within a period of 120 hr. (last dose which is 72hrs, plus 
48hrs). TLUS is defined as the interval beginning with the first dose of study drug and 
ending with the last unformed stool passed till 48 hour from the time of last dose.  
 
• 
To compare the microbiological cure rate of rifaximin 200-mg tablets and Xifaxan 200-
mg tablets on test of cure (TOC) visit.  Subjects are considered to have achieved 
microbiological cure if the pathogen identified at Visit 1 is no longer found in the stool at 
the TOC visit. Microbiological cure rate will be a supportive evidence of similarity 
between the test product and the reference product treatment arms and not considered as 
evidence of clinical bioequivalence. 
 
3. 
STUDY OVERVIEW 
 
3.1 
Study Design 
 
This is a randomized, double blind, placebo controlled, parallel design, multicenter 
bioequivalence study, designed to demonstrate  
 
i. 
Bioequivalence of Test (Rifaximin 200-mg Tablets) to Reference (Xifaxan® 200-mg 
Tablets) in the treatment of Travelers’ Diarrhea. 
 
ii. 
Superiority of test and reference products over placebo with respect to the clinical cure     
rates within a period of 24 to 48 hr. from the time of last dose, in the treatment of TD, 
using the mITT population with LOCF. 
 
 
Approximately six hundred eighteen (618) adult, non-indigenous travelers with naturally 
acquired acute diarrhea will be enrolled up to 40 sites. Subjects will be participating in the study 
for approximately 7 days and will be randomized 
 to receive rifaximin 200-mg 
tablets, Xifaxan 200-mg tablets, or placebo tablets, TID for 3 days, beginning not more than 72 
hours after the onset of diarrhea.  
 
The scheduled study visits will include:  
 
Visit I:  
Screening, Randomization and Treatment Visit [Day 1 to Day 4] 
Visit II: 
Telephone Visit [Day 3] 
Visit III: 
Test of Cure Visit [>24 hrs from the time of last dose] 
 
3.2 
Investigational Medicinal Products 
 
Test Product: 
Name of the product: Rifaximin 
Pharmaceutical dosage form: Film-coated oral tablets 
Strength: 200-mg 


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Manufactured by: Actavis Laboratories FL, Inc. 
 
Reference Product: 
Name of the product: Xifaxan   
Pharmaceutical dosage form: Film-coated oral tablets 
Strength: 200-mg  
Manufactured by: Salix Pharmaceuticals, Inc. (Valeant Pharmaceuticals group of 
company) 
 
Placebo: 
Placebo tablets manufactured by Actavis Laboratories FL, Inc. 
 
3.3 
Study Drug Dosing 
 
Each subject will receive the same dosing regimen of 1 tablet TID (morning, noon and evening) 
for 3 days, which is the recommended dosing regimen for Xifaxan.  
 
Subjects who take 3 doses of study drug on Day 1 (i.e., those randomized early in the day on Day 
1) will complete study drug on Day 3; other subjects will receive the last dose of study drug on 
Day 4.  
 
3.4 
Number of Study Sites 
 
This study will be conducted at approximately 30 study sites in approximately 3 countries. 
 
3.5 
Number of Subjects 
 
Approximately 618 
 will be randomized 
 
 
 
 assuming that the overall dropout rate from the 
randomized population to mITT population is about 15%. 
 
3.6 
Estimated Study Duration 
 
Treatment duration for a subject is 3 days.  A subject’s participation in the study could be for 
duration of approximately 7 days.  
 
3.7 
Randomization and Blinding 
 
All the study subjects will be randomly assigned 
 to 
receive either the test or the reference or Placebo. The original randomization schedule for this 
study is generated by CRO’s third party vendor- 
, by a non-study-assigned 
independent expert using a computer generated automated process i.e. Interactive Web Response 
System (IWRS). All the IMPs will be handled by an independent dispenser at the site who will 
be unblinded with treatment arm, the subject is receiving. The study statistician and 


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programmers or other study personnel will have no access to the treatment codes until the final 
database is locked (DBL).  
 
A dummy randomization will be used to program the TLFs before the DBL. Once the database is 
locked, original randomization schedule will be requested, after sponsor’s approval, and utilized 
to create the final TLFs by meeting all the standard procedures. Unblinding the treatment code 
for any subject in middle of the study by investigator for safety reasons will not affect the 
creation of TLFs.  
 
3.8 
Schedule of Study Procedures 
 
The schedule of study procedures is as presented in Table 1. 
 
Table 1: Schedule of Study Procedures 
Assessments 
Screening, 
Randomization 
and Treatment 
Treatment 
TOC 
Day 1 
Day 2 Day 3a Day 4b 
5, 6 or 7c 
Visit 1 
 
Visit 2 
 
Visit 3 
Informed consent, I/E criteria 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Prior/concomitant medications 
X 
 
X 
 
X 
Physical examination  
X 
 
 
 
X 
Vital signs 
X 
 
 
 
X 
Stool sample for culture and 
O&P 
X 
 
 
 
Xf 
Hematology/chemistry panel 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
X 
Urine drug screen 
X 
 
 
 
 
Pregnancy test (urine)d 
X 
 
 
 
X 
Randomization  
X 
 
 
 
 
Telephone call  
 
 
X 
 
 
Study drug dosing 
X 
X 
X 
X 
 
Daily study diary completione 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
 
X 
 
TOC = test of cure; I/E = inclusion/exclusion; O & P = ova and parasites 
a. Visit 2 assessment should be done by telephone (after the subject has taken about 5 doses); the 
subject should be contacted by a member of the study team. 
b. If a subject takes 3 doses of study drug on Day 1, then study drug should be completed on Day 3, 
otherwise the final doses will be taken on Day 4.   
c. Visit 3 should occur after 24 hours from the time of last dose of study drug.  If a subject does not 
return for the scheduled TOC visit, a telephone call should be made and efficacy and safety data 
(same as Visit 2) should be collected for Visit 3. 
d. Female subjects of child-bearing potential only. 
e. Study drug diary completion will begin on Study Day 1 and end on last study visit.  Diary 
completion includes recording of temperature if a subject feels feverish; (a thermometer should be 


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provided to each subject by the site), date/time of study drug each dose; date, time and consistency 
of stool; as well as enteric symptoms described in protocol 
f. In case stool sample collection not possible at visit 3, a rectal swab will be collected 
 
4. 
STUDY ENDPOINTS 
 
4.1 Efficacy Endpoints 
 
4.1.1 Primary Efficacy Endpoint 
 
As per protocol, the primary efficacy endpoint is clinical cure rate on TOC Visit (Study Day 5, 
6 or 7). Clinical cure is defined as either of the following: 
 
 No stools or only formed stools within a 48 hour period and no fever, with or without other 
enteric symptoms, OR 
 No watery stools or no more than two soft stools passed within a 24 hour period with no fever 
and no other enteric symptoms except for mild excess gas/flatulence. 
 
In addition, clinical deterioration by Study Day 5 or failure to achieve formed stool in ≤ 3 days 
(i.e., within 72 hrs from the time of first dose) is a clinical failure. 
 
As per FDA’s OGD guidance, the primary endpoint is clinical cure at the test of cure (TOC) 
visit on study Day 5, with a window period of +/- one day. In line with OGD, the protocol was 
designed such that the TOC visit should occur 24 to 72 hours after the last dose of study drug 
administration. After the study initiation, it was observed that some subjects were not able to 
complete the TOC visit within the above defined window period and a protocol deviation was 
filed to redefine the cut-off time point for evaluation of primary efficacy endpoint. Since, all the 
subjects were completing their diaries until the TOC visit and all the sites entered all diary data 
in the EDC that includes the data beyond the upper limit of window period for some subjects, 
decision was taken to consider 24 to 48 hour data for efficacy analysis. Thus, clinical cure rate 
was assessed on Visit-3 using subject’s diary data from 24 to 48 hour period from the time of last 
dose when the drug is administered 3 times a day (TID) for 3 days in subjects with Travelers’ 
Diarrhea (TD). Accordingly, clinical cure is re-defined as either of the following: 
 
 No stools or only formed stools within a 48 hour period from the last dose with no 
fever, and with or without other enteric symptoms, OR 
 
 No watery stools or no more than two soft stools passed within a 24 hour period from 
the time of last dose with no fever and no other enteric symptoms except for mild 
excess gas/flatulence. 
 
This above decision was taken to standardize the data to be used for efficacy analysis and 
therefore there is no impact on the quality, safety & integrity of data due to the following 
reasons- 
  
1. The evaluation of primary efficacy endpoint will be based on patient reported data and 
not the visit dependent clinician’s evaluation. 


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2. This is a planned deviation for efficacy evaluation and will be applied to all the 
subjects. 
 
 
4.1.2 Secondary Efficacy Endpoint 
 
Secondary efficacy endpoints are the following: 
 
• Time to last unformed stool (TLUS) 
TLUS is defined as the interval beginning with the first dose of study drug and ending with 
the last unformed stool passed within a period of 120 hr. (last dose which is 72hrs, plus 
48hrs). 
Mathematically, TLUS will be calculated as follows: 
TLUS (hours) = date/time of last unformed stool within 48hrs from the time of last dose – 
date/time of first dose  
 
• Microbiological cure rate 
Subjects are considered to have achieved microbiological cure if the pathogen identified at 
Visit 1 is no longer found in the stool at the TOC visit. Microbiological cure rate will be a 
supportive evidence of similarity between the test product and the reference product treatment 
arms and not considered as evidence of clinical bioequivalence. 
 
4.2 Safety Endpoints 
 
The safety endpoints are: 
 
1. Number and proportion of subjects reporting adverse events 
2. Changes in clinical laboratory tests, vital signs, and physical examinations from baseline 
3. Prior or Concomitant Medication 
4. Medical History 
5. Enteric symptoms 
 
 
 


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5. 
ANALYSIS POPULATION 
 
4.3 
Randomized population 
 
Randomized population includes all the subjects who satisfies the inclusion and exclusion 
criteria and randomized into the study. This population may contain subjects who were 
randomized and have not consumed any drug. The assigned treatment group is used for the 
analysis.  
 
4.4 
Safety Population 
 
All randomized subjects who receive at least one dose of study drug will form the Safety 
Analysis Set. The Safety Analysis Set will be used for all analyses of safety, tolerability, and 
background characteristics. 
 
4.5 
Modified intent-to-treat (mITT) 
 
The modified intent-to-treat (mITT) is a subset of the safety analysis set consisting of all 
randomized subjects who meet all inclusion and none of the exclusion criteria, received at least 
one dose of study drug and provided efficacy and safety data after one dose of study drug.  The 
mITT set is the basis for testing superiority of each active arm compared to the placebo with 
respect to primary efficacy endpoint i.e. clinical cure rate. 
 
4.6 
Per-Protocol (PP) Population 
 
 
 
 
 
  
The PP analysis set is the primary analysis set for the assessment of bioequivalence between the 
test and the reference products. 
  
 
 
 
 
 
Subjects discontinued early for other reasons will be excluded from the PP population, 
but included in the mITT population, using LOCF. 
 
6. 
HANDLING MISSING VALUES  
 
LOCF will be used to impute missing efficacy data for the following situations. 
a. 
 
 
 


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b. 
 
 
 
  
c. Subjects discontinued early for other reasons will be excluded from the PP population 
d. 
 
 
 
.  
e. 
 
 
. 
 
Missing data for other assessment (e.g., safety assessment or baseline assessment) will not be 
imputed. However, for the purpose of summary, AEs with missing relationship to study drug 
assessment will be counted as “related”; AEs with missing intensity assessment will be counted 
as “severe”.  Missing intensity and relationship will be presented as is on the individual subject 
data listing. 
 
7. 
STATISTICAL METHODOLOGY 
 
Unless otherwise explicitly stated, descriptive statistics for continuous variables are: n, mean, 
median, standard deviation, minimum and maximum.  Descriptive statistics for categorical 
variables are: percentage, and the numerator (n) and the denominator (N) used in the percentage 
calculation. 
 
7.1  Hypotheses and Decision Rules 
 
Two sets of null hypotheses will be used for the primary efficacy endpoint to evaluate the 
clinical bioequivalence between test product and reference products with respect to the clinical 
cure rate using Per-Protocol (PP) population. The hypothesis for testing equivalence is stated as 
below: 
 
7.1.1 Primary Efficacy Analysis 
 
(i)    Hypothesis for Bioequivalence: 
H0 : pT – pR < -0.20 or  pT – pR > 0.20 
Versus 
H1: -0.20 ≤ pT –pR ≤ 0.20 
 
Where pT = clinical cure rate of test treatment and pR = clinical cure rate of reference treatment. 
 


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The null hypothesis for bioequivalence will be evaluated based on the PP analysis set using two 
one-sided Z-test with Yates correction, each at the 0.05 significance level.  In practice, this is 
equivalent to constructing 90% confidence intervals (CIs) for the difference (test – reference) 
using a statistical model appropriate for the study design. If both intervals fall completely within 
the cut-off limits of [-0.20, +0.20] for clinical cure rates in this study, then equivalence is 
declared.  Otherwise, equivalence is not declared. 
 
(ii) 
Hypothesis for Superiority: 
H0:  pT  =  pP 
Versus 
H1:  pT  ≠  pP 
Where pT = clinical cure rate of subjects treated with rifaximin or Xifaxan and pP = clinical cure 
rate of subjects receiving placebo.  
 
The objective of superiority test is to demonstrate that the test product and the reference product 
performed as expected (i.e. statistically superior to placebo) in the study. Hence, this null 
hypothesis serves as a validity to check the study sensitivity, after establishing the clinical 
bioequivalence between the test product and the reference product. 
The null hypothesis for superiority analysis will be evaluated based on the mITT analysis set 
with LOCF for the missing data using a two-sided Z-test test with Yates correction with a 
significance level of α=0.05.  Differences between the treatment groups and 95% CIs for the 
difference will be presented. 
 
The tests for superiority will be conducted independently for test and reference products and 
superiority will be claimed if the two-sided p-value is found to be <0.05 at 5% level of 
significance for both, test and reference products separately; and the clinical cure rate is higher 
for the active drug(s) when compared with the placebo arm. 
 
7.1.2 Hypothesis for Other Efficacy parameters  
  
Difference 
between 
groups 
in 
other 
efficacy 
endpoints 
will 
be 
examined 
as 
supportive/confirmatory analysis base on the following null hypothesis: 
 
For categorical variables: 
H0 : Pi = Pj  vs H1: Pi ≠ Pj 
Where P = proportion of subjects meeting the criteria, I and j = 1 (Test) , 2 (Reference), or  
3 (Placebo) and i ≠ j 
 
For continuous variables: 
H0 : µi = µj  vs H1: µi ≠ µj 
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All tests will be two-sided and performed at the 0.05 significance level.  No adjustments will be 
made for multiplicity testing since all secondary efficacy endpoints are supportive/ confirmatory.  
 
7.2   Sample Size Justification 
 
The sample size calculation for this study is based on the published literature (CDER statistical 
review of NDA submission 21-361) and FDA’s current guidance (FDA Guidance, 2004) on the 
clinical endpoint bioequivalence study of Rifaximin 200 mg. 
 
 
 
 
 
Superiority to be concluded when the lower bound of 
the two-sided 95% CI is greater than zero i.e. the 95% CI does not contain zero.  
 
achieve at least 85% power to detect equivalence 
when the margin of equivalence for clinical cure rate extends from -0.20 to 0.20 (i.e. ± 20%). 
 
 
 
 
 
Thus, approximately 618 patient(s) 
 will be 
enrolled and randomized 
 
 
the overall dropout rate from the randomized patient population to mITT population does not 
exceed 15%.
 
 
subjects in the PP population when the lower and upper 90% CI 
falls within [-0.20, +0.20].   
 
1:1:1 Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
Thus, a total of 618 
 subjects need to be enrolled and randomized
 
 
 
 assuming that the dropout rate from the randomized to mITT population does not 
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7.3 Exposure and Treatment Compliance 
 
Subject compliance will be primarily monitored by counting the study tablets dispensed (Visit 1) 
and returned (Visit 3) compared to diary entries. Compliance calculation will be based on 
number of tablets taken (as recorded in the study diary) vs number of tablets subjects are 
expected to take. 
 
Total extent of exposure to study drug will be measured by total number of tablets taken and 
duration of exposure calculated as date of last dose minus date of first dose plus 1.  Study drug 
compliance (%) will be calculated as number of tablets taken divided by number of tablets 
expected to take multiplied by 100.  Subjects are considered to have good compliance if the 
compliance (%) is within the range of ~75% to ~125%, corresponding to 7 to 11 doses.    
 
7.4 Interim Analysis 
 
No interim analyses are planned in this study. 
 
7.5 Efficacy Analysis 
 
The following primary and secondary variables will be investigated in the evaluation of efficacy: 
 
7.5.1 Primary Efficacy Analysis 
 
The primary efficacy variable is the proportion of subjects who achieve clinical cure within 24 to 
48 hours from the time of last dose.   
 
To evaluate the null hypothesis (i) i.e., test for equivalence, the proportion of subjects meeting 
the clinical cure criteria will be tabulated by treatment group on the PP analysis set with LOCF* 
for missing data imputation.  The differences between the test product and reference product on 
the PP analysis set will be estimated and the 90% CIs for the difference will be presented.  The 
90% CIs will be calculated using Z-test for proportion with Yates’ correction as presented below.   
 
L = (PT – PR) – 1.645 se – (1/NT + 1/NR)/2 
U = (PT – PR) + 1.645 se + (1/NT + 1/NR)/2 
PT = CT / NT 
PR = CR / NR 
se = SQRT [PT*(1-PT) / NT + PR*(1-PR)/NR] 
 
Where CT and CR are number of subjects meeting the clinical cure criteria in the test product and 
the reference product arm respectively; PT, PR are the proportions of clinical cure from the test 
product arm and the reference product arm, respectively; NT and NR are total number of subjects 
in the analysis set from the test product and the reference arm product, respectively; se = 
standard error; SQRT = square root.  
 
If the upper and the lower CIs are within the range of [-0.20, +0.20], the null hypotheses for 
clinical bioequivalence will be rejected and it can be claimed that the test product and the 
reference product are clinically equivalent with respect to the clinical cure rates. 


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Reasons for clinical failure will also be tabulated by treatment group showing the number and 
percentage of subjects failed by each criterion.     
 
 
 
 
 
  
 
To evaluate the null hypothesis (ii) i.e., test of superiority, the proportion of subjects meeting the 
clinical cure criteria will be tabulated based on the mITT analysis set with LOCF for missing 
data imputation. The differences between each active arm (test and reference) and the placebo 
group will be tested separately using a two-sided Z-test for proportion using Yates correction; the 
estimated difference and 95% CIs will be presented.   
 
7.5.2 Secondary Efficacy Analysis 
 
All secondary efficacy endpoints will be tabulated by treatment groups on the mITT and PP 
populations. 
 
For the secondary endpoint TLUS, defined as the interval beginning with the first dose of study 
drug and ending with the last unformed stool passed within 48hrs from the time of last dose, 
summary tables will be presented.  
 
A nonparametric test, Wilcoxon Rank-Sum Test, will be used for comparing the median TLUS 
difference between two treatment arms at 5% level of significance, without any adjustment for 
multiplicity. Additionally, Hodges-Lehmann estimate of location shift and Moses 95% 
confidence intervals will be calculated to assess the magnitude of median TLUS difference 
between two treatment arms at 5% level of significance. 
 
For microbiological cure rate, summary tables will include number and percentage of subjects in 
each category; differences between groups (test vs. placebo, reference vs. placebo, and test vs. 
reference) will be derived along with the 95% CIs for the difference using the Z-test for 
proportion to test the difference between the treatment groups; the Yates’s correction will be 
applied for the calculation of 95% CIs. 
 
7.6 Safety Analysis 
 
All Safety analysis will be summarized based on safety population and all safety summaries will 
be provided by treatment group. 
 
7.6.1 Adverse Events 
 
All AEs that occur during the study will be recorded.  AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 18.1 or higher. Descriptions of 


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reactions or complaints will include the approximate time of onset, the time the AE ended, the 
severity of the AE, and the outcome. The Adverse Events (AEs) will be summarized by System 
Organ Class, preferred term, severity, and relationship to study drug.   
 
All Adverse Event summary tables will list each event, the number of subjects in each treatment 
group in which the event occurred, and the rate of occurrences.  The events will be grouped by 
System Organ Class and Preferred Term.  Frequencies and percentages of patients experiencing 
TEAEs (Treatment Emergent Adverse Events) will be summarized by system organ class (SOC) 
and by preferred term within SOC for each treatment group. Additional summaries of AEs by 
severity and by relation to treatment will be tabulated by SOC and by MedDRA preferred term 
within SOC.  
 
For AE summary tables, percentages would be based on the number of subjects in safety 
population in that particular treatment group.  If a subject experienced more than one episode of 
an adverse event, the subject would be counted once for that event. If a patient had more than 
one adverse event in a system organ class, then the patient would be counted only once in that 
system organ class. 
 
Serious Adverse Events (other than death but including the Serious Adverse Events temporally 
associated with or preceding the deaths) will be displayed in a summary table and listed. All 
Adverse Events or Serious Adverse Events which lead to withdraw from the study will be 
displayed in a summary table and listings.  
 
7.6.2 Physical Examination 
 
The number (%) of patients with screening physical examination abnormalities will be tabulated 
for the safety population and all physical examination data will be displayed in a listing by 
treatment group. 
 
7.6.3 Vital Signs 
 
Vital signs from each visit and the change from the baseline to each post-baseline visit will be 
summarized using descriptive statistics for the safety population. No formal inferential tests of 
significance will be performed. All vital signs data will be listed by treatment group and patient. 
 
7.6.4 Laboratory investigations 
 
Laboratory investigations of hematology, biochemistry and urine analysis tests performed for the 
safety population at screening (Visit I) will be repeated at TOC to ensure study subject safety and 
will be summarized accordingly.  
 
7.6.5 Prior or Concomitant Medication 
 
Incidence of prior or concomitant medications will be summarized by treatment group, and by 
the number and percentage of patients taking each medication, and will be classified using World 
Health Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) 
classes and preferred terms. 


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7.6.6 Medical History 
 
Medical history will be captured at baseline and will be tabulated and listed by treatment group. 
 
8. STUDY CONDUCT 
 
This section details general conventions to be used for the statistical analyses. Departures from 
these general conventions may be given in the specific detailed sections of this analysis plan. 
 
8.1 Subject Accountability and Disposition 
 
The subject accountability and disposition information will be summarized for each treatment 
group.  The subject accountability may include and not limited to number of subjects screened, 
enrolled, randomized, treated, discontinued before study completion and study completed. The 
subject disposition may include number of subjects in each population, study completion status 
and primary reason for discontinuation from the study. These summary reports will be generated 
using all randomized population and grouped by randomized treatment with total as a separate 
column.  
 
8.2 Demographics and Baseline Characteristics 
 
Demographic characteristics including age, gender, race, ethnicity, height, weight and body mass 
index (BMI) will be summarized by treatment groups for the safety, mITT & Per-Protocol 
population.  
 
The comparability of treatment groups with regard to patient demographic characteristics will be 
evaluated using descriptive statistics. No inferential analyses are planned.  
 
Gender, race, ethnicity will be summarized as frequency distribution by treatment group. 
 
Patient’s age in years at the time of consent will be derived as follows: 
 Age = [(Date of Consent - Date of Birth) +1]/365.25 and truncated to completed years. 
 
Baseline patient characteristics will include medical history and will be coded and tabulated by 
body system and preferred term using MedDRA, version 18.1 or higher. 
 
Baseline and post-baseline patient characteristics will include physical examination, vital signs, 
and lab data, prior and concomitant medications.  
 
Investigational product administration will be summarized for each patient and include total 
duration of exposure. Descriptive statistics including the mean, SD, minimum, and maximum 
will be provided by treatment group for safety population. 
8.3 Study diary Completion 
 
Study drug diary completion will begin on Study Day 1 and end on last study visit.  Diary 
completion includes recording of temperature if a subject feels feverish; date/time of study drug 


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each dose; date, time and consistency of stool; as well as enteric infection symptoms (abdominal 
pain or cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, blood and/or mucus in 
the stool, tenesmus) 
 
8.4 Enteric Infection and Other Symptoms 
 
The number of subjects with enteric infection symptoms (abdominal pain or cramps, excessive 
gas/flatulence, nausea, vomiting, fecal urgency, blood and/or mucus in the stool, tenesmus) from 
the study diary and other symptoms (Fever, Moderate or severe dehydration) will be summarized 
and percentage will be calculated on mITT and per-protocol populations on all visits by 
treatment group.    
 
8.5 Stool Data and Results 
 
Number of formed and unformed bowel episodes will be listed per subject by treatment group 
and time on randomized population.  
 
The number of subjects will be distributed to the corresponding frequency of formed and 
unformed bowel episodes by treatment group. The percentage will be calculated based on safety 
population. 
 
Stool Culture Results of E.coli (ETEC & EAEC), Other Microorganism (example: 
Campylobacter, Salmonella, Shigella), Stool microscopy for ova and parasites will be 
summarized on the values of present or absent by treatment in Day 1 and TOC visits on mITT & 
Per-Protocol Population. 
    
8.6 Protocol deviations 
 
The following describes the protocol deviations that relate to statistical analyses or Per-protocol 
population. 
 
All deviations related to study inclusion and exclusion criteria and significant deviations to 
subject management and protocol procedures must be documented on the appropriate eCRF. 
Major protocol deviations/violations will include, but are not limited to, the following: 
 
• Did not meet any critical inclusion/exclusion criteria which may impact the assessment of 
treatment efficacy. 
• Did not receive randomized treatment (i.e., the actual treatment is not randomized treatment). 
• Use of prohibited concomitant medications (e.g., prescription or OTC anti-diarrheal drug 
product, NSAIDs [with the exception of acetaminophen and paracetamol] or opioid 
analgesics).  
• Did not meet the drug compliance of taking ≥ 7 to ≤ 11 doses.  
• Did not come for Visit 3 or did not provide efficacy data for 24 hour to 48 hour period after 
the last dose. 
 
A list of protocol deviations will be compiled prior to database closure for the primary analysis 


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and be updated prior to the analysis. The deviations will be listed on randomized population and 
also will be summarized on randomized population by treatment group.   
 
Further, all the protocol deviations will be manually reviewed by the medical monitor of the 
study to determine whether any deviation is significant with respect to per-protocol population. 
Such deviations which may affect the treatment evaluation would be declared as “significant” 
protocol deviation by the medical monitor, and consequently these subjects will also be excluded 
from the per-protocol population for the primary efficacy analysis, in addition to above 
mentioned protocol deviations.  
 
The medical monitor will send the significant protocol deviations to Biostatistics team in an 
excel sheet through email before DB lock. All these significant protocol deviations will also be 
submitted to regulatory in the form of XPT file along with the protocol deviations captured in the 
eCRF. The additional list of these protocol deviations will be prepared with respect to per-
protocol population criteria and will be listed on randomized population by treatment group.   
   
8.7 Analysis Conventions 
 
The following conventions will be applied to all data presentations and analyses. 
 
• Summary statistics will consist of the number and percentage of responses in each level for 
categorical variables, and the sample size (n), mean, standard deviation (SD), median, 
minimum and maximum values for continuous variables. 
 
• All mean and median values will be formatted to one more decimal place than the measured 
value. Standard deviation values will be formatted to two more decimal places than the 
measured value. Minimum and maximum values will be presented with the same number of 
decimal places as the measured value. 
 
• The number and percentage of responses will be presented in the form xx (xx.x) where the 
percentage is in the parentheses. 
 
• All summary tables will include the analysis population sample size (i.e., number of subjects). 
 
• Change from baseline will be calculated as follows: 
Change = (baseline value)–(post-baseline value). 
 
• All listings will be sorted for presentation by treatment and subject. 
 
• Date variables will be formatted as DDMMMYYYY and time format is HH:MM for 
presentation. 
 
• SAS Version 9.4 or higher will be the statistical software package used for all data analysis. 
 
• A separate document with programming instructions will be prepared that will describe the 
derivation of these populations, before the database lock (DBL) or treatment unblinding for 


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the study. This document will also include specifications and programming instructions for 
creating analysis datasets. An analysis dataset is a dataset created to answer specific analysis 
purposes which will include all the variables from raw dataset, population flags, treatment 
flags and some derived variables as per requirement. 
 
8.8 Subjects Exclusion from the Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 REFERENCES 
1. Clinical Protocol of Rifaximin 200-mg Tablets [Protocol Number: ACTA/RIFX/2015, 
Protocol Version: Version 2 Amendment 2 dated 06/Apr/2016] 
 
2. Food and Drug Administration, Draft Guidance on Rifaximin, November 2011. 
 
3. CDER Statistical review of NDA submission 21-361. 
 
4. Statistical Principles For Clinical Trials (ICH E9) 
 
 
APPENDIX I 
 
Mock Shells: The TFL templates will be provided in a separate document. 
 
APPENDIX II 
 
PP Logic: Specifications and logic for the derivation of per-protocol population. 
 
 
 
 


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APPENDIX III 
 
Analysis Data Specification: Detailed plan for derived variables (have specified attributes and 
definitions) to create TFLs on Subject-Level data and Basic Data Structure of domain wise 
analysis data will be prepared in a separated spread sheet document.