Conditions: Travelers' Diarrhea
Keywords: Travelers diarrhea rifaximin equivalence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
This study compared safety and efficacy of a generic rifaximin tablet to the reference listed drug in the treatment of travelers' diarrhea. Additionally both the generic and reference formulations were tested for superiority against a placebo tablet.

It was planned that 450 patients would be enrolled, but only 28 patients were randomized. Of these, 1 patient discontinued due to failure to meet the inclusion/exclusion criteria. The remaining 27 patients received study drug and 25 patients completed the study.

The study was terminated due to slow enrolment. The final analysis included only safety analysis in the Safety population, due to the low number of randomized patients. No efficacy analysis was performed.

Detailed description:

Arms:
arm 1: Patients received Rifaximin 200 mg tablet 3 times per day for 3 days. arm 2: Patients received Xifaxan 200 mg tablet 3 times per day for 3 days. arm 3: Patients received placebo tablet 3 times per day for 3 days.

Interventions: intervention 1: Rifaximin (Sandoz GmbH) tablet intervention 2: Rifaximin (Xifaxan) intervention 3: Placebo
Intervention descriptions: intervention 1: 200 mg tablet administered orally. intervention 2: 200 mg tablet administered orally intervention 3: Matching Placebo tablet administered orally

Protocol document:
Prot_000.pdf: 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A randomized, double-blind, parallel group, placebo-controlled, multi-center, therapeutic 
equivalence study to compare Rifaximin 200 mg tablets (Sandoz GmbH) to Xifaxan® 200 mg 
tablets (Salix Pharmaceuticals, Inc.) and placebo in patients with travelers’ diarrhea 
Protocol No.:  
Test Product: 
Indication: 
Development Phase: 
Sponsor: 
Sponsor Representative Signatory: 
Clinical Research Organization 
Date of the Protocol: 
Version of the Protocol: 
1526 RIF_2 / NCT02920242
rifaximin 
Travelers’ diarrhea 
Phase III 
Sandoz GmbH 
Biochemiestrasse 10 
6250 Kundl 
Austria 
 
 
 
 
 
 
 
 
 
October 29, 2015 
2.0 
The confidential information in this document is provided to you as an Investigator, potential Investigator or 
consultant for review by you, your staff and applicable Ethics Committee. It is understood that the information 
will not be disclosed to others without written authorization from Sandoz GmbH except to the extent necessary 
to obtain informed consent from those persons to whom the drug may be administered. 


Protocol No. 1526 RIF_2 
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Version 2.0, October 29, 2015 
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Version History 
 
 
Version 
Date 
Summary of Changes 
 
Final Version 1.0 
02 October 2015 
-- 
 
Final Version 2.0 
28 October 2015 
Appendix II Visual Scale for Patient Assessment of Stools 
deleted; reference to most recent version of Declaration of 
Helsinki updated; text edits for clarification of dosing; 
formatting 
Changes made prior to submission to any regulatory agencies 
 
 
 


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2 
SIGNATURE PAGES 
SPONSOR REPRESENTATIVE SIGNATURE PAGE 
 
PROTOCOL TITLE: A randomized, double-blind, parallel group, placebo-controlled, 
multi-center, therapeutic equivalence study to compare Rifaximin 200 mg tablets 
(Sandoz GmbH) to Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and placebo in 
patients with travelers’ diarrhea 
 
PROTOCOL NUMBER:  1526 RIF_2 
 
SPONSOR REPRESENTATIVE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date (day/month/year) 
 
 
 
 
 
 
 
 
 
 
 
Date (day/month/year) 
 
 


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Version 2.0, October 29, 2015 
Page 4 of 90 
 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: A randomized, double-blind, parallel group, placebo-controlled, 
multi-center, therapeutic equivalence study to compare Rifaximin 200 mg tablets 
(Sandoz GmbH) to Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and placebo in 
patients with travelers’ diarrhea 
I agree to conduct the study outlined above in accordance with the terms and conditions of 
the protocol, the latest version of the Declaration of Helsinki, ICH guidelines on GCP and 
with applicable regulatory requirements. All information pertaining to the study shall be 
treated in a confidential manner. 
I understand that I may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate Ethics Committee, except when 
necessary to eliminate immediate hazards to the patient. 
 
 
 
 
((Type name and job title))   
 
Date (day/month/year) 
 
 
 
(address) 
 
 
 
 
 
 
 
 
(phone number) 
 
 
 


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Version 2.0, October 29, 2015 
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CLINICAL RESEARCH ORGANIZATION SIGNATURE PAGE 
 
PROTOCOL TITLE:  A randomized, double-blind, parallel group, placebo-controlled, 
multi-center, therapeutic equivalence study to compare Rifaximin 200 mg tablets 
(Sandoz GmbH) to Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and placebo in 
patients with travelers’ diarrhea 
 
PROTOCOL NUMBER:  1526 RIF_2 
 
  
 
 
 
 
 
 
 
 
 
 
Date (day/month/year) 
 
 
 
 
 
 
 
 
 
 
Date (day/month/year) 
 
 
 
Date (day/month/year) 
 


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3 
GENERAL INFORMATION 
PROTOCOL TITLE: A randomized, double-blind, parallel group, placebo-controlled, 
multi-center, therapeutic equivalence study to compare Rifaximin 200 mg tablets 
(Sandoz GmbH) to Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and placebo in 
patients with travelers’ diarrhea 
Protocol No.: 
1526 RIF_2 
Protocol Version and Date: 
Version 2.0, October 29, 2015 
 
Sponsor: 
Sandoz GmbH 
 
Biochemiestrasse 10 
 
6250 Kundl 
 
Austria 
 
Clinical Research Organization: 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Signatory: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory: 
 
 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
 
 


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4 
STUDY SYNOPSIS 
Title of study: 
A randomized, double-blind, parallel group, placebo-controlled, multi-center, therapeutic equivalence 
study to compare Rifaximin 200 mg tablets (Sandoz GmbH) to Xifaxan® 200 mg tablets (Salix 
Pharmaceuticals, Inc.) and placebo in patients with travelers’ diarrhea 
Sponsor: Sandoz GmbH 
Study centers: It is planned that approximately 25 centers will be initiated in 3 countries. 
Publications: None. 
Planned Study Period: 
March 2016 to December 2017  
(first patient first visit to last patient last visit) 
Development Phase: 
Phase III 
Objectives: 
Primary objective: 
To demonstrate the therapeutic equivalence of rifaximin 200 mg tablets to Xifaxan 200 mg tablets in 
patients with travelers’ diarrhea (TD). In addition, the efficacy of rifaximin and Xifaxan will be 
compared to placebo to assess the assay sensitivity of the study.  
Secondary objective: 
To compare the safety and tolerability of rifaximin 200 mg tablets to Xifaxan 200 mg tablets and to 
placebo in patients with TD. 
Methodology:  
This is a randomized, double-blind, parallel group, placebo-controlled, multi-center, therapeutic 
equivalence study to compare rifaximin 200 mg tablets to Xifaxan and placebo. A total of 450 patients 
with TD will be randomized 2:2:1 (rifaximin:Xifaxan:placebo). 
The study will consist of a Screening and Randomization Visit (informed consent, history, physical 
examination, vital signs, laboratory, randomization, and distribution of drug and diary); 1 dose of 
self-administered treatment with rifaximin, Xifaxan or placebo approximately once every 8 hours for 72 
hours, for a total of 9 doses; phone call on Study Day 3; and a test of cure (TOC)/End of Study (EOS) 
visit at Study Day 5 (± 1 day). A follow-up phone call will be made on Study Day 30 (± 7 days) if there 
are any adverse events (AEs) ongoing at the time of the TOC/EOS Visit; any related AEs ongoing at the 
TOC/EOS Visit will be followed until resolution or until assessed by the Investigator to be permanent. 
Stool specimens for quantification and identification of enteric pathogens will be taken on Study Day 0 
and Study Day 5 (± 1 day). 
The Screening and Randomization procedures will be considered Study Day 0. The first administration 
of study drug will be immediately following randomization and will be considered Study Day 1; thus 
Study Day 0 will end and Study Day 1 will begin on the same calendar day. Subsequent days will be 
measured in 24 hour periods, not calendar days. Doses 1-3 of study drug will be self-administered on 
Study Day 1, doses 4-6 will be self-administered on Study Day 2 (beginning 24 hours after dose 1) and 
doses 7-9 will be self-administered on Study Day 3 (beginning 48 hours after dose 1); depending on the 
timing of the clinic visit on Study Day 0, the final doses taken on Study Day 3 may actually be taken on 
the 4th calendar day of the study.  
Patients will be randomized (2:2:1) to receive rifaximin 200 mg tablets, Xifaxan 200 mg tablets or 
matching placebo. Patients will take a total of 9 doses of study drug. 
The duration of participation for a patient is a maximum of 7 calendar days, including a maximum of 
4 days of treatment with study drug (depending on the number of doses taken on Calendar Day 1).  
Patients will maintain an electronic Patient Diary daily for recording the date, time and form (formed, 
soft, watery) of all stools passed; date and time of study drug administration; presence or absence and 
severity of signs and symptoms of enteric infection (abdominal pain/cramps, excessive gas/flatulence, 
nausea, vomiting, fecal urgency, tenesmus); body temperature; and presence or absence of blood in 


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stool. Patients will document administration of concomitant medications and occurrence of any AEs on 
a paper Supplemental Form. 
Number of patients: 
A total of 450 patients will be enrolled into the study. Patients will be randomized in a 2:2:1 ratio such 
that 180 eligible patients will receive rifaximin 200 mg tablets, 180 eligible patients will receive 
Xifaxan 200 mg tablets and 90 eligible patients will receive placebo. 
Diagnosis and main criteria for inclusion: 
Inclusion criteria 
Patients eligible for enrolment in the study must meet all of the following criteria: 
1. Patient is able to read and understand the language of the Informed Consent Form and Patient 
Information 
2. Patient has signed the Informed Consent Form 
3. Adult male or female aged ≥ 18 years 
4. International travelers (e.g., visiting students/faculty or international tourists) with a duration of 
stay 
in 
host 
country 
long 
enough 
to 
attend 
scheduled 
visits. 
 
 
 
 
5. Affected by naturally acquired acute diarrhea, defined as the passage of at least 3 unformed 
stools within the 24 hours immediately preceding randomization 
6. At least one of the following signs and symptoms of enteric infection present at Screening:  
a. abdominal pain or cramps  
b. nausea  
c. vomiting  
d. fecal urgency  
e. excessive gas/flatulence  
f. tenesmus  
7. Women of child-bearing potential (not post-menopausal or not surgically sterile) have a 
negative pregnancy test prior to beginning therapy and agree to use effective contraceptive 
methods during the study, as judged by the Investigator (including total abstinence from sexual 
intercourse) 
8. Patient must have adequate general health as determined by the Investigator 
9. Patient is willing and able (e.g., mental and physical condition) to participate in all aspects of 
the study, including providing an unformed stool sample at Screening and Randomization Visit, 
use of medication, completion of electronic Patient Dairy, attending scheduled visits, and 
compliance with protocol requirements as evidenced by providing signed written informed 
consent 
NOTE: the unformed stool provided at the Screening/Randomization Visit may be counted as 
1 of the 3 unformed stools specified in Inclusion Criteria 5. 
 
Exclusion criteria 
Patients meeting any of the following criteria must not be enrolled in the study: 
1. Hypersensitivity to rifaximin or any of the rifamycin antimicrobial agents or to any of the 
excipients of the study drug 
2. Pregnant, breast feeding, or planning a pregnancy 
3. Acute diarrhea for > 72 hours immediately prior to Randomization 


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4. Presence of:  
a. fever (≥ 100 °F/37.8 °C), or  
b. hematochezia (blood in stool; noted visually), or  
c. clinical findings suggesting moderate or severe dehydration  
5. 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 
which would, in the judgment of the Investigator, compromise the patient’s safety or successful 
participation in the clinical study 
6. Administration of any of the following:  
a. any antimicrobial agents with an expected activity against enteric bacterial pathogens 
(e.g., trimethoprim/sulfamethoxazole, quinolones, azithromycin) within 7 days 
preceding randomization  
b. more than 2 doses of a symptomatic antidiarrheal compound such as antimotility 
agents, absorbent agents, and antisecretory agents within 8 hours preceding 
randomization  
7. Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding  
NOTE: Acetaminophen (Tylenol) or paracetamol is acceptable for a maximum of 
2 consecutive days. 
If required, antimalarial prophylactic treatment, including doxycycline, is permitted prior to 
and during the study  
8. Presence of a medical condition with regular GI symptoms (e.g. Crohn’s disease, ulcerative 
colitis, indeterminate colitis, previous bowel surgery which impacts absorption long term, 
thyrotoxicosis, short bowel syndrome, etc.) 
9. Patient requires medication which alters GI function (e.g., prokinetic agents and other 
stimulants of GI contractility, laxatives and cathartics, antacids, or anti-diarrheal agents) 
10. Patient requires use of long term antibiotics (e.g. urinary tract infection prophylaxis, acne, etc.) 
11. Previous enrolment in trials involving rifaximin, previous enrolment in this study or 
participation in any other drug investigational trial prior to enrolment, within previous 6 months 
12. Active alcohol/drug dependence or abuse (excluding tobacco abuse), as determined by the 
Investigator 
13. Patient has an acute or chronic condition that, in the Investigator’s opinion, would limit the 
patient’s ability to complete or participate in this clinical trial 
14. Patient is involved in the conduct and administration of this trial as an Investigator, 
sub-Investigator, study coordinator, or other study staff member, or the patient is a first degree 
family member, or significant other of any person involved in the conduct of this study. 
Study drugs, dose and mode of administration: 
Patients will receive rifaximin or Xifaxan 200 mg tablets, or matching placebo. Patients will receive 
1 tablet of study drug approximately once every 8 hours for a total of 9 doses (3 tablets per day) starting 
immediately following the Screening and Randomization Visit on Study Day 0. Patients will participate 
in the study for a maximum of 7 calendar days.  
Variables:  
Efficacy: 
Primary endpoint 
The primary endpoint is clinical cure at the TOC/EOS Visit (Study Day 5 ± 1 day). Clinical cure is 
defined as either:  
• 
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 


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and no other enteric symptoms except for mild excess gas/flatulence.  
 
Secondary efficacy endpoints 
• 
Time to Last Unformed Stool (TLUS) defined as the interval beginning with the first dose of 
study drug and ending with the last unformed stool passed 
• 
proportion of patients with clinical failure defined as failure to achieve formed stool within 
≤ 3 days (72 hours) of the start of treatment with the study drug or clinical deterioration or 
worsening of symptoms by Study Day 5 
• 
Proportion of patients with improvement of diarrheal syndrome, defined as a reduction of 
≥ 50% in the number of unformed stools (soft or watery) passed during intervals 0-24 hours, 
24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of study drug, 
compared to the number of unformed stools passed during the 24 hours immediately preceding 
first dose of study drug 
• 
the number of unformed stools (soft or watery) passed during the intervals 0-24 hours, 
24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of study drug 
• 
the presence or absence and severity of signs and symptoms of enteric infection (abdominal 
pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus) – the 
proportion of patients with signs and symptoms of enteric infection during the intervals 
0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of 
study drug  
• 
microbiological cure rate defined as a post-treatment culture that was negative for the 
pre-treatment etiologic pathogen. 
Safety endpoints: 
• 
Incidence of reported AEs 
• 
Changes in vital signs and clinical laboratory parameters.  
Pharmacokinetics: There is no pharmacokinetic evaluation planned in this study. 


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Statistical Methods: 
Sample size and power: 
A sample size of 135 in the generic rifaximin and 135 in the reference listed drug (RLD) Xifaxan 
treatment groups achieve approximately 
 power to detect therapeutic equivalence when the 
margin of equivalence, given in terms of the difference, extends from -0.20 to 0.20.  
Concerning the assessment of study sensitivity, a sample size of 170 in the generic rifaximin group and 
RLD Xifaxan® group and 85 in the placebo group achieve approximately 
 power to detect a 
difference between the group proportions of 
  
Patients will be randomized 2:2:1 to generic rifaximin (n=180), Xifaxan (n=180), and placebo (n=90). A 
total of 450 patients will be randomized. As it can be anticipated that no more than 5% of patients will 
be excluded from the modified Intent to Treat (mITT) population, and no more than 20% of patients 
from the mITT population will be excluded from the PP population this sample size will have sufficient 
power to show therapeutic equivalence and study sensitivity.  
Efficacy: 
The primary endpoint will be clinical cure at the TOC/EOS Visit (Study Day 5 ± 1 day). Equivalence 
will be concluded if the 90% confidence interval of the difference of the success proportions between 
rifaximin and Xifaxan is completely contained within the interval [-0.20; 0.20]. Two, one-sided Z tests 
at the 5% significance level will be used. The PP population will be the primary analysis set. 
Study sensitivity will be evaluated by comparing the success proportions between rifaximin and placebo 
and Xifaxan and placebo. The two-sided Z test with pooled variance will be used. The significance level 
of the test is 0.05. The mITT population will be the primary analysis set. 
The primary endpoint will also be analyzed by subgroups according to the pathogen status at baseline. 
Secondary efficacy variables 
The analysis of all secondary endpoints will be performed in the mITT and PP populations.  
TLUS will be compared between the three treatment groups using a Cox proportional hazards model. 
The proportion of patients with clinical failure, with improvement in diarrheal syndrome and with signs 
and symptoms of enteric infection will be compared between the three treatment groups with two-sided 
Z tests. The significance level of these tests will be set to 0.05. For patients with a positive pre-treatment 
culture, the proportion of patients with microbiological cure will be compared between the three 
treatment groups with two-sided Z tests. The significance level of these tests will be set to 0.05. The 
number of unformed stools passed per unit time will be analyzed using repeated measures Poisson 
regression. 
Safety: 
All patients who are treated with any amount of study drug will be evaluated for safety. Adverse events 
will be summarized by the number and percentage of patients experiencing events by system organ 
class, preferred term and severity. Changes in vital signs and clinical laboratory measurements will be 
summarized descriptively by assessment time-points. Other safety variables will be summarized and 
listed. 
Version and date of the protocol synopsis: 2.0, October 29, 2015 


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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ....................................................................................................................... 1 
2 
SIGNATURE PAGES ......................................................................................................... 3 
3 
GENERAL INFORMATION .............................................................................................. 6 
4 
STUDY SYNOPSIS ............................................................................................................ 7 
5 
TABLE OF CONTENTS ................................................................................................... 12 
5.1 
List of Tables ......................................................................................................... 15 
5.2 
List of Figures ........................................................................................................ 15 
5.3 
List of Appendices and Supplements ..................................................................... 15 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................... 16 
7 
INTRODUCTION ............................................................................................................. 17 
7.1 
Background ............................................................................................................ 17 
7.1.1 Disease epidemiology ..................................................................................... 17 
7.1.2 Rifaximin Mechanism of Action .................................................................... 17 
7.1.2.1 Pre-clinical Data ............................................................................... 17 
7.1.2.2 Pharmacokinetic Data ....................................................................... 18 
7.1.3 Alternative Treatments.................................................................................... 18 
7.2 
Rationale ................................................................................................................ 18 
8 
STUDY OBJECTIVES ...................................................................................................... 20 
8.1 
Primary Objectives ................................................................................................. 20 
8.2 
Secondary Objective .............................................................................................. 20 
9 
INVESTIGATIONAL PLAN ............................................................................................ 21 
9.1 
Overall Study Design and Plan .............................................................................. 21 
9.1.1 Description ...................................................................................................... 21 
9.1.2 Study Assessments .......................................................................................... 26 
9.1.2.1 Screening and Randomization Visit (Day 0) .................................... 26 
9.1.2.2 Study Day 1 (Initiation of Study Treatment) .................................... 27 
9.1.2.3 Study Day 2 ...................................................................................... 27 
9.1.2.4 Study Day 3 ...................................................................................... 27 
9.1.2.5 Study Day 4 ...................................................................................... 28 
9.1.2.6 Study Day 5 (± 1 day), Test of Cure/End of Study Visit .................. 28 
9.2 
Discussion of Study Design ................................................................................... 29 
9.2.1 Risk/Benefit and Ethical Assessment ............................................................. 30 
9.2.2 Early Termination ........................................................................................... 30 
9.2.3 End of Study ................................................................................................... 31 
9.3 
Selection of Study Population ................................................................................ 31 
9.3.1 Inclusion Criteria ............................................................................................ 31 
9.3.2 Exclusion Criteria ........................................................................................... 32 
9.3.3 Withdrawal of Patients .................................................................................... 33 
10 TREATMENT OF PATIENTS ......................................................................................... 34 
10.1 Identity of Study Treatments.................................................................................. 34 
10.1.1 Administration of Study Treatments ............................................................... 34 
10.1.2 Missed Doses .................................................................................................. 35 
10.2 Study Treatment Packaging and Labelling ............................................................ 35 


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10.2.1 Packaging ........................................................................................................ 35 
10.2.2 Labelling  ........................................................................................................ 35 
10.2.3 Storage 
 ........................................................................................................ 35 
10.2.4 Blinding and Randomization of Study Treatments ......................................... 35 
10.3 Procedure for Breaking the Randomization Code ................................................. 35 
10.4 Patient Compliance ................................................................................................ 36 
10.5 Study Treatment Accountability ............................................................................ 36 
10.6 Concomitant Therapy ............................................................................................. 36 
10.7 Complaints Connected to Study Drugs .................................................................. 37 
10.7.1 Definitions....................................................................................................... 37 
10.7.2 Process 
 ........................................................................................................ 37 
11 ASSESSMENT OF EFFICACY ....................................................................................... 38 
11.1 Efficacy Endpoints ................................................................................................. 38 
11.1.1 Primary efficacy endpoint ............................................................................... 38 
11.1.2 Secondary efficacy endpoints ......................................................................... 38 
11.2 Efficacy Assessments ............................................................................................. 38 
11.2.1 Symptoms ....................................................................................................... 38 
11.2.2 Stool Frequency and Form .............................................................................. 39 
11.2.3 Microbiology................................................................................................... 39 
12 ASSESSMENT OF SAFETY ............................................................................................ 40 
12.1 Adverse Events ...................................................................................................... 40 
12.1.1 Definitions....................................................................................................... 40 
12.1.2 Intensity of Adverse Events ............................................................................ 41 
12.1.3 Relationship to the Investigational Product .................................................... 41 
12.1.4 Adverse Events Documentation ...................................................................... 41 
12.1.5 Serious Adverse Event (SAE) Reporting ........................................................ 43 
12.1.6 Pregnancies/Breastfeeding Cases .................................................................... 45 
12.1.7 Quality Complaints or Special Case Scenarios ............................................... 46 
12.1.8 Reconciliation ................................................................................................. 47 
12.1.9 Abnormal Laboratory Values/Vital Signs ...................................................... 47 
12.2 Physical Examination ............................................................................................. 47 
12.3 Vital Signs .............................................................................................................. 47 
12.4 Laboratory Assessments ........................................................................................ 48 
13 STATISTICAL EVALUATION ....................................................................................... 50 
13.1 Sample Size and Power .......................................................................................... 50 
13.2 Statistical Methods ................................................................................................. 50 
13.2.1 General Analysis and Coding ......................................................................... 51 
13.2.2 Analysis Populations ....................................................................................... 51 
13.2.3 Primary Endpoint Analysis ............................................................................. 52 
13.2.4 Secondary Endpoint Analysis ......................................................................... 53 
13.2.4.1 Time to Last Unformed Stool ........................................................... 53 
13.2.4.2 Clinical Failure ................................................................................. 53 
13.2.4.3 Diarrheal Syndrome .......................................................................... 53 
13.2.4.4 Unformed Stools ............................................................................... 54 
13.2.4.5 Signs and Symptoms of Enteric Signs  ............................................. 54 
13.2.4.6 Microbiological Cure ........................................................................ 54 
13.2.5 Handling Missing Data ................................................................................... 54 
13.2.6 Patient Disposition .......................................................................................... 54 


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13.2.7 Safety Analyses ............................................................................................... 54 
13.2.7.1 Adverse Events ................................................................................. 55 
13.2.7.2 Vital Signs ........................................................................................ 55 
13.2.7.3 Laboratory Parameters ...................................................................... 55 
13.2.7.4 Physical Examinations ...................................................................... 56 
14 DIRECT ACCESS TO SOURCE DATA/NOTES ............................................................ 57 
15 PATIENT CONFIDENTIALITY ...................................................................................... 58 
16 QUALITY CONTROL AND QUALITY ASSURANCE................................................. 59 
16.1 Conduct of the Study.............................................................................................. 59 
16.2 Study Monitoring ................................................................................................... 59 
17 ETHICS ............................................................................................................................. 60 
17.1 Ethics Committee ................................................................................................... 60 
17.2 Regulatory Authority ............................................................................................. 60 
17.3 Written Informed Consent ..................................................................................... 60 
18 DATA HANDLING AND RECORD KEEPING ............................................................. 62 
18.1 Case Report Forms/Source Data Handling ............................................................ 62 
18.2 Patient Diaries ........................................................................................................ 62 
18.3 Investigator File ..................................................................................................... 62 
18.4 Retention of Essential Documents/Materials ......................................................... 62 
18.4.1 Essential Documents ....................................................................................... 62 
18.4.2 Essential Materials .......................................................................................... 62 
19 FINANCING AND INSURANCE .................................................................................... 64 
20 PUBLICATION POLICY ................................................................................................. 65 
21 REFERENCE LIST ........................................................................................................... 66 
22 APPENDICES ................................................................................................................... 67 
 


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5.1 
List of Tables 
Table 9-1 
Schedule of Events ............................................................................................. 24 
Table 10-1 
Study Treatments................................................................................................ 34 
Table 12-1 
Serious Adverse Event Reporting Contacts ....................................................... 44 
Table 12-2 
Contacts for General Safety Questions .............................................................. 44 
 
5.2 
List of Figures 
Figure 9–1 
Study Design – Flow Chart ................................................................................ 23 
 
5.3 
List of Appendices and Supplements 
Appendix I 
Xifaxan Prescribing Information ........................................................................ 67 
Appendix II Commonly Used Medications, with Antimuscarinic Effects ............................. 90 
 


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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
ADR 
adverse drug reaction 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRO 
Clinical Research Organization 
CSR 
clinical study report 
EAEC 
enteroaggregative E.coli 
EC 
Ethics Committee 
E.coli 
Escherichia coli 
eCRF 
electronic Case Report Form 
EOS 
end of study 
ETEC 
enterotoxigenic E.coli 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IWRS 
Interactive Web Response System 
LOCF 
last observation carried forward 
LPPV 
Local Qualified Person for Pharmacovigilance 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat (Population) 
OGD 
(FDA’s) Office of Generic Drugs 
PP 
Per Protocol (Population) 
RLD 
reference listed drug 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TD 
travelers’ diarrhea 
TLUS 
time to last unformed stool 
TOC 
test of cure 
USA 
United States of America 
WHO 
World Health Organization 
 


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7 
INTRODUCTION 
7.1 
Background 
7.1.1 
Disease epidemiology 
Travelers’ diarrhea (TD) may be experienced by >60% of travelers from developed countries 
who visit developing countries, accounting for 40,000 travelers daily or > 15 million travelers 
annually1. Travelers’ diarrhea is usually contracted from contaminated food or water. 
Bacteria, in particular enterotoxigenic Escherichia coli (ETEC), are the most common cause 
of TD. Other bacteria implicated in travelers' diarrhea include enteroaggregative E.coli 
(EAEC), Shigella, Salmonella, and Campylobacter. Viruses (including Rotavirus) and 
protozoa (Giardia lamblia), make up the remainder of known causes2,3,4.  
The average duration of untreated travelers’ diarrhea is approximately 4 days, with 50% of 
patients being free of symptoms within 48 hours5,6. In a study of 1,455 Austrian tourists, 
abdominal cramps were reported in just over half of all patients, less than one third of 
patients reported nausea and/or vomiting and 13% of patients reported fever6. Travelers’ 
diarrhea tends to have a longer duration in patients with other symptoms in addition to 
diarrhea (suggestive of severe travelers’ diarrhea) and patients in whom pathogens are 
identified7. 
7.1.2 
Rifaximin Mechanism of Action 
The reference listed drug (RLD) in this study is the rifaximin 200 mg tablet marketed in 
United States of America (USA) by Salix Pharmaceuticals, Inc. under the trade name 
Xifaxan®. The investigational product produced by Sandoz GmbH also contains 200 mg of 
rifaximin.   
Rifaximin is a non-aminoglycoside semi-synthetic, non-systemic antibacterial drug derived 
from rifamycin SV, a structural analog of rifampin. Rifaximin acts by binding to the 
beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) 
polymerase, resulting in inhibition of bacterial RNA synthesis, consequently inhibiting the 
growth of bacteria. 
Rifaximin is approved in a number of countries (including the USA) for the treatment of TD. 
Rifaximin has been shown to be active against E.coli (enterotoxigenic and enteroaggregative 
strains) in both in vitro and clinical studies of infectious diarrhea8. 
Additional information regarding indications and usage, contraindications, warnings and 
precautions, and adverse reactions is provided in the prescribing information for rifaximin9. 
7.1.2.1 
Pre-clinical Data 
Teratogenic effects (ocular, oral and maxillofacial, cardiac, and lumbar spine malformations) 
were observed in animal reproduction studies following administration of rifaximin to 
pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 
0.7 to 33 times, respectively of the recommended human doses of 600 mg to 1650 mg per 
day. 


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7.1.2.2 
Pharmacokinetic Data 
Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects 
challenged with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin 
plasma concentrations and exposures were low and variable. There was no evidence of 
accumulation of rifaximin following repeated administration for 3 days (9 doses).  
A high-fat meal consumed 30 minutes prior to rifaximin dosing in healthy subjects delayed 
the mean time to peak plasma concentration from 0.75 to 1.5 hours and increased the 
systemic exposure (area under the curve, AUC) of rifaximin by 2-fold but did not 
significantly affect the maximum concentration (Cmax). 
Rifaximin is moderately bound to human plasma proteins. In vivo, the mean protein binding 
ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when 
rifaximin was administered. 
In an in vitro study, rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 
18% of radioactivity in plasma.  
In a mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy 
volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was 
recovered in feces mostly as the unchanged drug; 0.32% was recovered in urine mostly as 
metabolites with 0.03% as the unchanged drug.  
This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion 
of the unchanged drug.  
In a separate study, rifaximin was detected in the bile after cholecystectomy in patients with 
intact gastrointestinal (GI) mucosa, suggesting biliary excretion of rifaximin. 
7.1.3 
Alternative Treatments 
Alternatives to treatment with rifaximin include other antibiotics (e.g., ciprofloxacin, 
levofloxacin, azithromycin), or a combination of an anti-motility agent (e.g., loperamide) 
with an antibiotic. Adequate fluid intake with oral rehydration solutions are recommended, or 
foods which are relatively high in salt, such as crackers. 
7.2 
Rationale 
The rifaximin 200 mg tablet is currently approved in the USA for the treatment of travelers’ 
diarrhea caused by noninvasive strains of E.coli in adults and pediatric patients 12 years of 
age and older. This study is being carried out to demonstrate the therapeutic equivalence of 
rifaximin to the Xifaxan in patients with TD. 
 
 
  
Rifaximin is recommended for the treatment of diarrhea caused by bacteria, and is noted to be 
effective at treating diarrhea caused by E.coli. 
 
 
Because appropriate treatment should be introduced as soon as possible, it is not 


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necessary to have laboratory confirmation of the presence of intestinal E.coli in the stool, 
prior to initiating treatment, since strong suspicion exists that infection is caused by rifaximin 
susceptible E.coli10. 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP). 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of this study is: 
• to demonstrate the therapeutic equivalence of rifaximin 200 mg tablets to 
Xifaxan 200 mg tablets in patients with TD.  
In addition, the efficacy of rifaximin and Xifaxan will be compared to placebo to assess the 
assay sensitivity of the study. 
 
8.2 
Secondary Objective 
The secondary objective of this study is: 
• to compare the safety and tolerability of rifaximin 200 mg tablets to Xifaxan 200 mg 
tablets and to placebo in patients with TD. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a randomized, double-blind, parallel group, placebo-controlled, multi-center 
therapeutic equivalence study to compare rifaximin 200 mg tablets to Xifaxan 200 mg tablets 
and placebo in patients with TD. 
The study design is summarized in Figure 9–1; Table 9-1 presents the Schedule of Events. 
Patients will undergo screening procedures at the study site and eligible patients will be 
randomized to treatment. The first dose will be self-administered immediately following 
randomization, thus initiating Study Day 1. Subsequent doses will be taken approximately 
once every 8 hours for 72 hours for a total of 9 doses. Study Day 1 will begin with the first 
administration of study drug and Study Day 2 will begin 24 hours after the first treatment. 
Study Day 3 will begin 48 hours after the first treatment. Depending on the timing of the first 
administration of study drug on Visit 1, a Study Day may extend across 2 calendar days. 
Thus, the final dose(s) of study drug taken on Study Day 3 may actually be taken on the 4th 
calendar day of the study.  
Treatments administered (randomized in a ratio of 2:2:1) will be: 
• rifaximin 200 mg tablets 
• Xifaxan 200 mg tablets 
• placebo tablets 
 
Patients will be contacted by telephone on Study Day 3 to determine if their condition has 
improved. Patients will return to the study site on Study Day 5 (± 1 day) for the test of cure 
(TOC)/End of Study (EOS) visit. Patients will participate in the study for a maximum of 
7 calendar days. 
Patients will maintain an electronic Patient Diary daily for recording the date, time and form 
(formed [retains shape], soft [assumes shape of container], watery [can be poured]) of all 
stools passed; the time and date of study drug administration; the presence or absence and 
severity of signs and symptoms of enteric infection (abdominal pain/cramps, excessive 
gas/flatulence, nausea, vomiting, fecal urgency, tenesmus); body temperature; and presence 
or absence of blood in the stool. The use of any concomitant medications and the occurrence 
of any AEs will be recorded on a paper Supplemental Form. Stool specimens for 
quantification and identification of enteric pathogens will be taken at Screening 
(Study Day 0) and Study Day 5. Clinical laboratory tests (hematology, chemistry and 
urinalysis), assessment of vital signs and physical examinations will be carried out at 
Screening (Study Day 0) and Study Day 5. 
Stool, blood and urine samples will be analyzed at a central laboratory; study treatment 
retention samples will be stored in national depots (Section 18.4.2). A separate laboratory 


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manual will provide details for sampling handling, storage and shipping of all biological 
samples. 
The primary efficacy endpoint is clinical cure at the TOC/EOS Visit, with clinical cure 
defined as either:  
• 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.  
 
Secondary efficacy endpoints are: 
• time to last unformed stool (TLUS) 
• proportion of patients with clinical failure 
• proportion of patients with improvement of diarrheal syndrome 
• number of unformed stools (soft or watery) passed during the intervals 0-24 hours, 
24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of study 
drug 
• presence or absence and severity of signs and symptoms of enteric infection 
(abdominal pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, 
tenesmus)  
• microbiological cure rate.  
 
Definitions of these endpoints are given in Section 11.1.2.  
Safety endpoints are the incidence of reported AEs and changes in vital signs and clinical 
laboratory parameters. 
There is no pharmacokinetic evaluation planned in this study. 
 


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Figure 9–1 
Study Design – Flow Chart 
Visit 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 22  
TOC/EOS 
 
 
 
 
 
Calendar Day 1/Calendar Day 2 (depending on timing of first dose) 
Calendar Day 2/3 
Calendar Day 3/4 
Calendar Day 4/5 
Calendar Day 5/6  
(±1 day) 
Study3 Day 0 
 
 
 
Study Day 1 
Study Day 2 
Study Day 3 
Study Day 4 
Study Day 5 (±1 day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
Randomization 
 
 
 
rifaximin 200 mg tablets, n=180 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xifaxan 200 mg tablets, n=180 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo, n=90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment administration4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment efficacy and safety 
assessments5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-treatment efficacy 
and safety assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE=adverse event; EOS=end of study; TOC=test of cure 
1. 
At Visit 1 (Study Day 0) patients will undergo screening and randomization and then eligible patients will self-administer their first tablet (initiating Study Day 1).  
2. 
Depending on the timing of the first dose, and given the window of ± 1 day for the TOC/EOS Visit, the TOC/EOS Visit can take place anywhere from Calendar Day 4 to Calendar Day 7. 
3. 
Study Days are measured in 24 hour periods, starting with the first dose of study drug. Depending on the timing of the first dose, 1 Study Day may extend across 2 calendar days. 
4. 
One tablet of the randomized treatment approximately every 8 hours, for a total dose of 9 tablets. 
5. 
Stool sample for diagnosis and culture; pre-enrollment stool form and frequency; physical examination; vital signs; clinical laboratory tests; urine pregnancy test (if appropriate); 
distribution and instructions on use of thermometer, electronic Patient Diary and paper Supplemental Form for documentation of concomitant medications and AEs. 
6. 
Stool sample for diagnosis and culture; physical examination; vital signs; clinical laboratory tests; urine pregnancy test (if appropriate); AE and concomitant medication assessment. 
Collection of Patient Diary. 


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Table 9-1 
Schedule of Events 
Procedure 
Study Day 0* 
Screening/ 
Randomization 
Study  
Day 1* 
Study  
Day 2 
Study  
Day 3 
Study  
Day 4 
Study Day 5*  
(± 1 day) 
TOC/EOS 
Day 30  
(± 7 days) 
Follow-up  
Phone Call 
Informed Consent1 
X 
 
 
 
 
 
 
Eligibility Verification 
X 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
Physical Examination2 
X 
 
 
 
 
X 
 
Vital Signs3 
X 
 
 
 
 
X 
 
Clinical Laboratory Tests4 
X 
 
 
 
 
X 
 
Signs and Symptom Assessment of TD 
X 
 
 
 
 
X 
 
Stool Culture/Fecal Leukocytes5 
X 
 
 
 
 
X 
 
Urine Pregnancy Test6 
X 
 
 
 
 
X 
 
Randomization, Study Drug Dispensing 
X 
 
 
 
 
 
 
Study Drug Administration7 
 
X 
X 
X 
 
 
 
Completion of Electronic Patient Diary8 
 
X 
X 
X 
X 
X 
 
Telephone Call to Patient 
 
 
 
X9 
 
 
 
Concomitant Medication Use10 
X 
X 
X 
X 
X 
X 
 
Adverse Event Assessment10 
X 
X 
X 
X 
X 
X 
X11 
Review of Diary/Supplemental Form 
 
 
 
X 
 
X 
 
Drug Accountability and Compliance 
 
 
 
 
 
X 
 
AE=Adverse Event; EOS=End of Study; ICF=Informed Consent Form; TD=travelers’ diarrhea; TOC=test of cure 
* 
Screening/Randomization (Study Day 0) and Study Day 1 are the same day. Study days are 24 hour periods. Study Day 1 will begin with the administration of the first 
dose of study drug, Study Day 2 will begin 24 hours after the administration of the first dose of study drug, and so on. Depending on the timing of the first dose of 
study drug, one Study Day may extend over two calendar days. Depending on the timing of the first dose, and given the window of ± 1 day for the TOC/EOS Visit, the 
TOC/EOS Visit can take place anywhere from Calendar Day 4 to Calendar Day 7. 
1 
Informed consent must be obtained before the patient undergoes any study-specific procedures. The Investigator must confirm that the patient is able to read and 
understand the language of the ICF, Patient Information, the electronic Patient Diary, and the Supplemental Form. 
2 
Weight and height will be measured at Screening; weight will be measured at the TOC/EOS visit. Body mass index (BMI) will be calculated at Screening and 
TOC/EOS. 
3 
Vital signs (respiratory rate, heart rate, blood pressure, and body temperature) will be performed at Screening and the TOC/EOS Visit. They will be obtained in the 
sitting position after the patient has rested for 5 minutes. The date and time of the assessment should be recorded. 
4 
To include hematology, clinical chemistry and urinalysis. 
5 
A stool sample will be obtained for fecal leukocyte testing and culture prior to randomization to study drug and on TOC/EOS. Stool culture for pathogenic organisms 
including: Enterotoxigenic Escherichia coli (ETEC); Enteroaggregative E.coli (EAEC); Shigella spp; Salmonella spp; Campylobacter jejuni; Plesiomonas spp; 
Aeromonas spp; Rotavirus; Giardia lamblia; Entamoeba histolytica, Cryptosporidium spp. 


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6 
For female patients of childbearing potential (not post-menopausal or have not undergone surgical sterilization), the results of the urine pregnancy test must be negative 
to confirm eligibility prior to randomization. 
7 
The first dose of study drug is considered to be on Day 1, and is to be taken as soon as possible following completion of the Screening/Randomization procedures. The 
remaining 8 doses are to be taken at even intervals for 3 doses per day – a total of 9 doses of study drug are to be taken. 
8 
At Screening/Randomization, the patient will be given an electronic Patient Diary in which to record his/her symptoms; time of study drug administration; and date, 
time and form of all stools passed. The Patient Diary will be reviewed by the Investigator during the call on Study Day 3 at the TOC/EOS Visit.  
9 
Site will contact patient on Study Day 3 to check on their clinical status (i.e., if their condition has improved) and review completion of Diary and Supplemental Form. 
Information on AEs and concomitant medication will also be collected. 
10 
Patients will be given a paper Supplemental Form for documentation of the administration of any concomitant medications or the occurrence of any AEs. The Form will 
be reviewed by the Investigator during the call on Study Day 3 and at the TOC/EOS Visit. 
11 
A follow-up phone call is to be performed should the patient have any ongoing AE at the TOC/EOS Visit. Any ongoing related AEs will be followed until resolution or 
until assessed by the Investigator to be permanent. 
 
 
.


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9.1.2 
Study Assessments 
Investigators will document data from all study assessments at each visit in the electronic 
Case Report Form (eCRF). Patients will complete their Patient Diary daily, and their 
Supplemental Form as required, from the time of first administration of study drug until they 
return to the study facility for the TOC/EOS Visit. 
9.1.2.1 
Screening and Randomization Visit (Study Day 0) 
Screening procedures are as follows: 
• ensure the patient is able to read and understand the Informed Consent Form (ICF) 
documents, and complete the Patient Diary and Supplemental Form 
• obtain signed and dated informed consent 
• check eligibility against study Inclusion and Exclusion Criteria (Sections 9.3.1 and 
9.3.2, respectively) 
• record medical and surgical history 
• record demographic information (age, race, ethnicity and gender; country of 
residence; date of arrival in host country; previous country[s] visited between 
residence and host country) 
• physical examination, including weight, height, and body mass index (BMI) 
(Section 12.2) 
• vital signs (body temperature; respiratory rate, heart rate, blood pressure in the sitting 
position after 5 minutes rest; Section 12.3)  
• clinical laboratory tests (hematology, chemistry, urinalysis; Section 12.4) 
• signs/symptoms of TD (Section 11.2.1) 
• baseline stool data (number and form of stools in the previous 24 hours; 
Section 11.2.2) 
• stool sample (unformed) to be used for diagnosis and culture (Section 11.2.3); this 
stool sample may count as 1 of the 3 unformed stools that must be passed in the 
24 hours prior to Randomization, as specified by the Inclusion Criteria 
• urine pregnancy test for females of childbearing potential (not post-menopausal or 
who have not undergone surgical sterilization), only 
• provide patients with Patient Diary to be completed during the study; patients will 
also receive instructions and practice in how to use Diary  
• provide patients with the (paper) Supplemental Form to document the administration 
of any concomitant medications or occurrence of any AEs 
• record prior medication taken within previous 4 weeks and occurrence of any AE 
(Section 12) 
• dispense thermometer for patient use, with instructions for use 
• documentation of any pre-treatment AEs 
 
Once all Screening procedures are complete, eligible patients will be randomized to treatment 
(rifaximin, Xifaxan, or placebo) and receive assigned study treatment. 


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9.1.2.2 
Study Day 1 (Initiation of Study Treatment) 
Randomized patients will self-administer their first dose of the study drug, initiating Study 
Day 1. The time of this dose will be recorded in the Patient Diary. After this, patients can 
leave the study site.  
Study days are measured in 24 hour periods, not calendar days. Because doses of study drug 
are to be taken approximately once every 8 hours, a study day may extend over 2 calendar 
days. Thus, depending on how many tablets were taken on Study Day 1, the final doses of 
study drug taken on Study Day 3 may be taken on the 4th calendar day of the study. 
From the time of the first study drug administration, patients will be asked to record the 
following in the Patient Diary: 
• date, time and form (formed, soft, watery) of all stools passed  
• date and time of study drug administration 
• presence or absence and severity of enteric symptoms (abdominal pain/cramps, 
excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus) 
• presence or absence of any blood in stool  
• body temperature. 
 
Patients will document the administration of any concomitant medication and occurrence of 
any AEs on the (paper) Supplemental Form. 
9.1.2.3 
Study Day 2  
Study Day 2 will begin 24 hours after the administration of the first dose of study treatment. 
On Study Day 2, patients will:  
• take the next 3 doses of their randomized study treatment, 1 tablet every 8 hours  
• complete the Patient Diary, recording: 
o date, time and form of all stools passed 
o date and time of study drug administration 
o the presence or absence and severity of enteric symptoms (abdominal 
pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus)  
o presence or absence of any blood in stool 
o body temperature. 
 
Patients will document the administration of any concomitant medication or occurrence of 
any AEs on the Supplemental Form. 
9.1.2.4 
Study Day 3 
Study Day 3 will begin 48 hours after the administration of the first dose of study treatment. 
On Study Day 3, patients will: 
• take final 3 doses of study drug, 1 tablet every 8 hours 
• document the administration of any concomitant medication and occurrence of any 
AEs on the (paper) Supplemental Form 
• complete the Patient Diary, recording: 


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o date, time and form of all stools passed 
o date and time of study drug administration 
o the presence or absence and severity of enteric symptoms (abdominal 
pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus) 
o presence or absence of any blood in stool 
o body temperature. 
• receive a telephone call from the study site to allow the site to: 
o determine if the patient’s condition has improved.  
o confirm if the patient has noted the presence of any blood in the stool, as possibly 
indicative of infection with pathogens other than E.coli 
o confirm that patients are documenting any concomitant medications and AEs on 
the paper Supplement Form  
o record any concomitant medications noted in the Supplemental Form  
o record any AEs noted on the Supplemental Form 
o confirm that patients have completed the Patient Diary to date, and review Diary 
entries. 
 
If a patient’s condition has worsened, or if a patient has noted blood in the stool, the patient 
may be requested to return to the study facility. If in the opinion of the Investigator the 
patient requires alternate or supplemental therapy, the patient should be discontinued 
(Section 9.3.3), and provided with effective treatment.  
9.1.2.5 
Study Day 4 
Study Day 4 will begin 72 hours after the administration of the first dose of study treatment. 
On Study Day 4, patients will complete the Patient Diary, recording: 
• date, time and form of all stools passed 
• the presence or absence and severity of enteric symptoms (abdominal pain/cramps, 
excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus)  
• presence or absence of any blood in stool 
• body temperature. 
 
Patients will document the administration of any concomitant medication or occurrence of 
any AEs on the (paper) Supplemental Form. 
There should be no patient administration of study drug on Study Day 4. If however, study 
drug is administered the time and date of administration should be recorded in the Patient 
Diary. Any study administered as of Study Day 4 would be considered a protocol violation.  
9.1.2.6 
Study Day 5 (± 1 day), Test of Cure/End of Study Visit 
Depending on the timing of the first administration of the study drug, the TOC/EOS Visit 
may take place anywhere from Calendar Day 4 to Calendar Day 7. 


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Patients will complete the final entries of the Patient Diary, recording: 
• date, time and form of all stools passed 
• the presence or absence and severity of enteric symptoms (abdominal pain/cramps, 
excessive gas/flatulence, nausea, vomiting, fecal urgency, tenesmus)  
• any blood in stool 
• body temperature. 
 
Patients will document the administration of any concomitant medication or occurrence of 
any AEs on the (paper) Supplemental Form. 
Patients will also return to the study site on Study Day 5 for the TOC/EOS Visit. The 
following will be performed/documented: 
• physical examination, including weight and calculation of BMI  
• vital signs 
• clinical laboratory tests 
• signs/symptoms of TD 
• stool sample for culture 
• urine pregnancy test, if applicable 
• Investigator review of Patient Diary to ensure entries are complete 
• concomitant medications noted by the patient in the Supplemental Form 
• AEs noted by the patient on the Supplemental Form 
• drug accountability and patient compliance check. 
 
Once the above procedures have been carried out, patients will be considered to have 
completed the study. Patients with ongoing AEs on Day 5 will be followed up with a phone 
call on Day 30 (± 7 days); any related AE ongoing on Day 5 will be followed until the AE 
has resolved or until it is judged by the Investigator to be permanent (Section 12.1.4).  
9.2 
Discussion of Study Design 
The study was designed following the guidance published by the Food and Drug 
Administration’s (FDA) Office of Generic Drugs (OGD)11. The guidance requires a 
randomized, double blind, parallel, placebo controlled study in male and non-pregnant female 
patients with TD to demonstrate the therapeutic equivalence of rifaximin 200 mg tablets to 
Xifaxan 200 mg tablets. All the main design features of the study are in accordance with the 
OGD guidance (e.g. study population, efficacy endpoints, the controls used [Xifaxan and 
placebo] and statistical methodology).  
The equivalence margin for the primary endpoint was recommended by the OGD guidance 
(the 90% confidence interval [CI] of the test - reference difference between products for the 
primary endpoint has to be contained within [-0.20, +0.20] using the per protocol [PP] 
population). A placebo control arm was included to demonstrate that rifaximin and Xifaxan 
are active, and to establish that the study is sufficiently sensitive to detect differences 
between products.  


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9.2.1 
Risk/Benefit and Ethical Assessment 
Rifaximin is already approved by the FDA for use in the treatment of TD at the posology 
used in the present study.  
The risks associated with the treatment are well established and considered acceptable (see 
Xifaxan full prescribing information in Appendix I). In two placebo controlled trials 
comparing Xifaxan 200 mg three times daily (n=320) with placebo (n=228), discontinuations 
due to adverse reactions occurred in only 0.4% of patients (events of taste loss, dysentery, 
weight decrease, anorexia, nausea and nasal passage irritation). Of the adverse reactions that 
occurred at a frequency >2% in Xifaxan-treated patients, headache was the only event which 
occurred at a higher rate with Xifaxan (10%) than placebo (9%). 
As TD normally spontaneously resolves without treatments after approximately 4 days5, 
including a placebo arm (as recommended by the OGD) is considered to be ethically 
acceptable. The 2:2:1 randomization ensures that the maximum number of patients receive 
active treatment. In addition, patients will receive a phone call on Study Day 3 to identify 
patients who may need to receive an alternative or supplemental therapy. 
There are no adequate and well-controlled studies in pregnant women, however pregnant or 
lactating women will not be enrolled in this study. There is no information regarding the 
presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the 
effects of rifaximin on milk production. Any pregnancy that occurs during the study must be 
handled as described in Section 12.1.6. 
The safety and effectiveness of rifaximin has not been established in pediatric patients less 
than 12 years of age with TD. Patients less than 18 years of age will not be enrolled in this 
study. 
Because this study will enroll tourists who will not be local to the study facility, the 
Investigator will ensure that the prospective patient is able to understand the language of the 
study (Section 17.3) and is able to understand instructions for, and adequately complete, 
specified study activities (Section 18.2), prior to enrollment in the study. 
9.2.2 
Early Termination 
This study may be terminated at any time by the Sponsor to ensure patients’ safety, if the 
Investigator does not adhere to the protocol or if, in the Sponsor's judgment, there are no 
further benefits to be achieved from the study. In this event, the Sponsor will inform the study 
Investigators, institutions and all regulatory authorities. 
If, in the opinion of the Investigator, the clinical observations in the study suggest that it 
might not be justifiable for medical reasons to continue, he/she may terminate the study after 
consultation with the Sponsor. Reasons for discontinuation have to be documented 
appropriately and to be provided to the Sponsor and the Ethics Committee (EC).  
In case of premature discontinuation of the study a complete final examination must be 
performed for each patient as far as possible with regard to the patient’s health conditions and 
as far as necessary with regard to safety aspects and the validity of study results. 


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9.2.3 
End of Study 
The end of study will be at the time of last patient, last visit. 
When the last patient has completed the study, the remaining issues with eCRFs, study 
treatments, other study materials delivered to the study center, as well as archiving of study 
documents by the Investigator, will be dealt with. 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
Patients eligible for enrolment in the study must meet all of the following criteria: 
1. Patient is able to read and understand the language of the ICF and Patient Information 
2. Patient has signed the ICF 
3. Adult male or female aged ≥ 18 years 
4. International travelers (e.g., visiting students/faculty or international tourists) with a 
duration of stay in host country long enough to attend scheduled visits. 
 
 
 
 
 
5. Affected by naturally acquired acute diarrhea, defined as the passage of at least 
3 unformed stools within the 24 hours immediately preceding randomization 
6. At least one of the following signs and symptoms of enteric infection present at 
Screening:  
a. abdominal pain or cramps  
b. nausea  
c. vomiting  
d. fecal urgency  
e. excessive gas/flatulence  
f. tenesmus  
7. Women of child-bearing potential (not post-menopausal or not surgically sterile) have 
a negative pregnancy test prior to beginning therapy and agree to use effective 
contraceptive methods during the study, as judged by the Investigator (including total 
abstinence from sexual intercourse) 
8. Patient must have adequate general health as determined by the Investigator 
9. Patient is willing and able (e.g., mental and physical condition) to participate in all 
aspects of the study, including providing an unformed stool sample at Screening and 
Randomization Visit, use of medication, completion of electronic Patient Dairy, 
attending scheduled visits, and compliance with protocol requirements as evidenced 
by providing signed written informed consent 


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NOTE: the unformed stool provided at the Screening/Randomization Visit may be 
counted as 1 of the 3 unformed stools specified in Inclusion Criteria 5. 
 
9.3.2 
Exclusion Criteria 
Patients meeting any of the following criteria must not be enrolled in the study: 
1. Hypersensitivity to rifaximin or any of the rifamycin antimicrobial agents or to any of 
the excipients of the study drug 
2. Pregnant, breast feeding, or planning a pregnancy 
3. Acute diarrhea for > 72 hours immediately prior to Randomization 
4. Presence of:  
a. fever (≥ 100 °F/37.8 °C), or  
b. hematochezia (blood in stool; noted visually), or  
c. clinical findings suggesting moderate or severe dehydration  
5. Active, uncontrolled, or clinically significant diseases or disorders of the heart, lung, 
kidney, GI tract (other than infectious diarrhea in travelers), or central nervous system 
which would, in the judgment of the Investigator, compromise the patient’s safety or 
successful participation in the clinical study 
6. Administration of any of the following:  
a. any antimicrobial agents with an expected activity against enteric bacterial 
pathogens (e.g., trimethoprim/sulfamethoxazole, quinolones, azithromycin) 
within 7 days preceding randomization  
b. more than 2 doses of a symptomatic antidiarrheal compound such as 
antimotility agents, absorbent agents, and antisecretory agents within 8 hours 
preceding randomization  
7. Use of any drug such as aspirin or ibuprofen (Advil), which can cause GI bleeding  
NOTE: Acetaminophen (Tylenol) or paracetamol is acceptable for a maximum of 
2 consecutive days. 
If required, antimalarial prophylactic treatment, including doxycycline, is permitted 
prior to and during the study  
8. Presence of a medical condition with regular GI symptoms (e.g. Crohn’s disease, 
ulcerative colitis, indeterminate colitis, previous bowel surgery which impacts 
absorption long term, thyrotoxicosis, short bowel syndrome, etc.) 
9. Patient requires medication which alters GI function (e.g., prokinetic agents and other 
stimulants of GI contractility, laxatives and cathartics, antacids, or anti-diarrheal 
agents) 
10. Patient requires use of long term antibiotics (e.g. urinary tract infection prophylaxis, 
acne, etc.) 
11. Previous enrolment in trials involving rifaximin, previous enrolment in this study or 
participation in any other drug investigational trial prior to enrolment, within previous 
6 months 
12. Active alcohol/drug dependence or abuse (excluding tobacco abuse), as determined 
by the Investigator 


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13. Patient has an acute or chronic condition that, in the Investigator’s opinion, would 
limit the patient’s ability to complete or participate in this clinical trial 
14. Patient is involved in the conduct and administration of this trial as an Investigator, 
sub-Investigator, study coordinator, or other study staff member, or the patient is a 
first degree family member, or significant other of any person involved in the conduct 
of this study.  
 
9.3.3 
Withdrawal of Patients 
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
non-compliance or other administrative reasons. 
Patients whose condition worsens and in the opinion of the Investigator require alternate or 
supplemental therapy for the treatment of TD should be discontinued, and provided with 
effective treatment. A patient may also be removed, if necessary, to protect their health or the 
integrity 
of 
the 
study. 
This 
determination 
will 
be 
made 
by 
the 
Principal 
Investigator/Sub-Investigator. Every attempt will be made to record reasons for withdrawal. 
Patients whose participation in the study is discontinued (for any reason) will not be replaced. 
If a patient’s participation is terminated prematurely, the cause for the early termination and 
the date and time of the termination will be documented in the eCRF, on the source 
documents and in the final clinical study report (CSR). 
If a patient withdraws or is dismissed from the study, every effort will be made to see the 
patient and all procedures planned for the TOC/EOS Visit will be completed, where possible. 


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10 
TREATMENT OF PATIENTS 
10.1 
Identity of Study Treatments  
Details of the study treatments are presented in Table 10-1. 
Table 10-1 
Study Treatments 
Drug Name 
Rifaximin 
Xifaxan 
Placebo 
Active ingredient 
rifaximin 
rifaximin 
None 
Strength 
200 mg 
200 mg 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Dosage Form 
Tablet 
Route of administration 
Oral 
Mode of administration 
With or without food, to be taken with a glass of water 
Dose 
1 × 200 mg 3 times per day (approximately every 
8 hours, daily dose of 600 mg) for 72 hours  
1 tablet 3 times per day 
(approximately every 
8 hours) for 72 hours 
Manufactured by/for: 
 
 
  
 
 
Salix Pharmaceuticals, 
Inc. 
 
 
  
 
 
 
 
All tablets will be visually the same to ensure that all persons involved in the study remain 
blinded to treatment.  
10.1.1 
Administration of Study Treatments 
Patients will be randomized (2:2:1) to receive rifaximin 200 mg tablets, Xifaxan 200 mg 
tablets or matching placebo tablets. Treatment will be self-administered by the patients with a 
glass of water. The first study treatment will be taken at the study site, immediately following 
c randomization. Subsequent doses should be taken once approximately every 8 hours, for a 
total of 9 doses. 
Study drug can be taken with or without food. 


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10.1.2 
Missed Doses  
Missed doses should be taken as soon as possible, and all subsequent doses should be taken at 
their regular time. 
10.2 
Study Treatment Packaging and Labelling 
The packaging and labelling of all 3 study drugs (rifaximin, Xifaxan, and placebo) will be the 
same to ensure that all persons involved in the study remain blinded to treatment. 
10.2.1 
Packaging 
All study tablets will be packaged in bottles. Each bottle will contain 12 tablets, which 
includes 3 extra tablets to allow for loss of a tablet. 
Patients will be instructed to take only 9 tablets (1 tablet approximately every 8 hours for 
72 hours). 
10.2.2 
Labelling 
Bottles will be labeled to clearly identify that the contents are for investigational use only, 
and with appropriate study details, including storage instructions.  
10.2.3 
Storage 
Tablets should be stored on site and by the patient at room temperature not above 25°C/77°F, 
in a dry location.  
10.2.4 
Blinding and Randomization of Study Treatments 
 At each study center, patients who are eligible to enter the double-blind treatment period will 
be randomized to generic rifaximin 200 mg, Xifaxan 200 mg or matching placebo according 
to a 2:2:1 randomization ratio through an Interactive Web Response System (IWRS). Prior to 
randomization via IWRS, the IWRS will send an initial shipment that confirms sufficient 
inventory to treat each randomized patient. 
The staff at the study center, the Sponsor and its representatives, and all patients will be 
blinded to the identity of the investigational product. The study blinding may only be broken 
for an individual patient in the case of an emergency and when the knowledge of the 
investigational product is essential for the clinical management of the safety of this patient as 
described in Section 10.3. 
10.3 
Procedure for Breaking the Randomization Code 
The treatment code may be broken for an individual patient in the case of an emergency and 
when the knowledge of the investigational product is essential for the clinical management of 
the safety of this patient. The Investigator must make every effort to contact the Medical 
Monitor before breaking the treatment code. The Investigator will be able to access the IWRS 
database to receive the treatment code, 24 hours a day and 7 days a week. A record will be 
kept at each study center of all broken treatment codes, of the person who broke the treatment 
code, date, time and of the reasons for breaking the treatment code. This will also be 


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documented in the eCRF. The treatment code must not be recorded on the patient’s eCRF. In 
the case of a code break, the Investigator must inform the Sponsor or its representative 
immediately, without revealing to the Sponsor or its representative personnel the result of the 
code break. 
The Sponsor will have a designated Safety Manager at the Central Case Processing Site that 
has access to the randomization codes via the IWRS who may unblind a case if it is deemed 
medically appropriate.  
10.4 
Patient Compliance 
Patients will enter the time and date of each treatment administration in the Patient Diary. 
This information will be reviewed by the Investigator at the TOC/EOS Visit to assess 
treatment compliance. 
Patients will be required to return the bottle containing 3 remaining doses of study treatment 
to the study site at the TOC/EOS Visit on Study Day 5. The number of remaining doses 
returned to the study site will be recorded on the patient’s eCRF. 
10.5 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatments to the study centers, the 
inventory at the study centers, distribution to and use of study drug by each patient and the 
return to the Sponsor, as well as the destruction of any study drug. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study drug and to the study patients. 
The Investigator shall be responsible for ensuring that the records adequately document that 
the patients were provided the doses specified in the protocol and that all study drug received 
from the Sponsor is reconciled.  
10.6 
Concomitant Therapy 
Concomitant medication will be allowed, with the exception of the prohibited medications 
noted below, or unless deemed otherwise by the Principal Investigator/Sub-Investigator. 
The following concomitant medications are prohibited from the signing of informed consent 
until the TOC/EOS Visit on Study Day 5: 
• any drug such as aspirin or ibuprofen (Advil) which can cause GI bleeding 
• any medication considered “traditional” by the Investigator and that has an influence 
of GI function 
• antimicrobial agents with an expected activity against enteric bacterial pathogens 
(e.g., trimethoprim/sulfamethoxazole, quinolones, azithromycin)  
• oral antibiotic medications 
• antimuscarinic drugs (e.g., Tolterodine, Solifenacin, Darifenacin, Trospium chloride), 
Oxybutynin. A complete list of commonly used medications with antimuscarinic 
effects is provided in Appendix II. 


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• drugs effecting GI motility such as antimotility agents, adsorbent agents, prokinetic 
agents and other stimulants of GI contractility, laxatives and cathartics, antacids, or 
anti-diarrheal agents 
• analgesic 
drugs 
(opioids 
or 
non-steroidal 
anti-inflammatory 
drugs) 
NOTE: Use of paracetamol is allowed for a maximum of 2 consecutive days 
• fiber products  
• probiotics 
• herbal products/dietary supplements with effect on the GI system (i.e., Rue [rude], 
wormwood, estafiate, Espazote de zorrillo, chamomile [manzanilla]). 
 
The administration of any concomitant medication or herbal/dietary supplements during the 
study (from signing of informed consent until the TOC/EOS Visit) will be recorded by 
patients on the Supplemental Form provided at the Screening/Randomization Visit. The start 
and stop date should be recorded along with the reason for the medication use. 
10.7 
Complaints Connected to Study Drugs 
10.7.1 
Definitions 
Quality complaints are complaints connected to the investigation’s medicinal product (test 
product, reference product or placebo) and include: 
• technical complaints are complaints connected to the quality of the products and 
include the following cases: 
o any fault of quality and/or effectiveness, e.g., change of visual appearance, 
change of amount, damaged tablets, presence of foreign matter 
o any fault of the labeling, e.g., missing or illegible label 
o any falsification of the medicinal product, e.g., suspected product mix-up, 
tampering or counterfeiting. 
• transport complaints are complaints connected to the transport of the product, such as 
damaged transport carton, damaged packaging upon receipt of the shipment, missing 
drugs from the shipment package, unsuitable transport conditions. 
 
10.7.2 
Process 
In case any of the above quality complaints are detected or received the completed Quality 
Complaint Report form must be sent to the Sponsor (study manager) within 24 hours. In 
parallel the local monitor or Clinical Research Associate of the respective study must be 
informed about the complaint. If possible, a photo of the affected material should be attached 
to the report. Affected material should be retained and stored according to the storage 
conditions label and/or returned to Sponsor if requested by the Sponsor. 


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11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy Endpoints 
11.1.1 
Primary efficacy endpoint 
The primary endpoint is clinical cure at the TOC/EOS Visit (Study Day 5 ± 1 day). Clinical 
cure is defined as either:  
• 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.  
 
11.1.2 
Secondary efficacy endpoints 
• TLUS defined as the interval beginning with the first dose of study drug and ending 
with the last unformed stool passed 
• proportion of patients with clinical failure defined as failure to achieve formed stool 
within ≤ 3 days (72 hours) of the start of treatment with the study drug or clinical 
deterioration or worsening of symptoms by Study Day 5 (± 1 day) 
• proportion of patients with improvement of diarrheal syndrome, defined as reduction 
of ≥ 50% in the number of unformed stools (soft or watery) passed during the 
intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after 
the first dose of study drug, compared to the number of unformed stools passed during 
the 24 hours immediately preceding first dose of study drug 
• the number of unformed stools (soft or watery) passed during the intervals 0-24 hours, 
24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of study 
drug 
• the presence or absence and severity of signs and symptoms of enteric infection 
(abdominal pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal urgency, 
tenesmus) – the proportion of patients with signs and symptoms of enteric infection 
during the intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, and 
96-120 hours after the first dose of study drug 
• microbiological cure defined as a post-treatment culture that was negative for the 
pre-treatment etiologic pathogen. 
 
11.2 
Efficacy Assessments 
11.2.1 
Symptoms 
Symptoms of TD to be noted include the presence or absence and severity of enteric 
symptoms (abdominal pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal 
urgency, tenesmus).  
Patients will record the presence or absence and severity of any of these symptoms in the 
Patient Diary once daily, from the time of the Screening Visit until the TOC/EOS Visit on 
Study Day 5 (± 1 day).  


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11.2.2 
Stool Frequency and Form 
Patients will record in the Patient Diary the date, time and form of all stools passed, from the 
time of the first drug administration until the end of the study on Study Day 5 (± 1 day). 
Patients will receive detailed instructions, with diagrams, on how to rate the stool form.  
Stools will be recorded as follows:  
• formed (retains shape)  
• soft (assumes shape of container)  
• watery (can be poured). 
 
Both soft and watery stools are to be considered unformed. 
11.2.3 
Microbiology 
Stool specimens for quantification and identification of enteric pathogens will be taken on 
Study Day 0 as soon as possible after inclusion, prior to randomization and PRIOR to the first 
administration of study drug, and again on Study Day 5 (± 1 day).  
Stool samples will be assessed in a central laboratory in order to determine the 
microbiological status of this acute diarrhea episode. Details on sample handling, collection, 
storage and shipping are provided in the laboratory manual. 
Stools will be analyzed for the following: 
• fecal leukocyte 
• ETEC  
• EAEC 
• Shigella spp 
• Salmonella spp 
• Campylobacter jejuni 
• Plesiomonas spp 
• Aeromonas spp 
• Rotavirus 
• Giardia lamblia 
• Entamoeba histolytica 
• Cryptosporidium spp. 
 


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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 9.1.2; the 
assessments are detailed in Sections 12.1 through 12.4. 
Safety endpoints include incidence of reported AEs (Section 12.1), changes in vital signs 
(Section 12.3), and changes in clinical laboratory parameters (Section 12.4). 
12.1 
Adverse Events 
12.1.1 
Definitions 
An adverse event/experience (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• results in persistent or significant disability/incapacity  
• is a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing inpatient hospitalization 
• is medically significant: Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as 
important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject (patient) or may require 
intervention to prevent one of the other outcomes listed above. These should also 
usually be considered serious. 
 
For further details, please refer to the Quick Reference Guide for completing the Serious 
Adverse Event Form. 
An AE is defined as an adverse drug reaction (ADR) if the following applies: 
• A response to a medicinal product which is noxious and unintended. Response in this 
context means that a causal relationship between a medicinal product and an AE is at 
least a reasonable possibility. 
• ADRs may arise from use of the product within or outside the terms of the marketing 
authorization or from occupational exposure. Conditions of use outside the marketing 
authorization include overdose, misuse, abuse and medication errors. 
• Adverse events with a suspected relationship to non-investigational medicinal product 
or other concomitant medication (for both Sandoz and non-Sandoz products), even if 
non-serious, need to be reported by the Investigator to the respective Local Qualified 
Person for Pharmacovigilance (LPPV; Table 12-1). 


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12.1.2 
Intensity of Adverse Events 
In the course of the study, the Investigator will determine whether any AEs have occurred 
and will grade their intensity as follows: 
• Mild:  
awareness of symptoms but easily tolerated 
• Moderate: 
discomfort enough to cause interference with usual activity 
• Severe: 
incapacitating with inability to work or carry out usual activity. 
 
12.1.3 
Relationship to the Investigational Product 
Assessment of AEs will be made by the Investigator after having evaluated all accessible data 
and, if necessary, re-evaluation of the case as new information becomes available. 
Investigational product includes the test product under evaluation and the reference product 
or placebo that is given during any phase of the study. 
The Investigator will make a judgment considering whether or not, in his/her opinion, the AE 
was related to the drug according to the following classification: 
Suspected: 
The temporal relationship of the clinical event to study treatment 
administration makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a 
sufficient explanation for the observed event. 
Not suspected: 
The temporal relationship of the clinical event to study treatment 
administration makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the observed event. 
 
Causality assessments are critical and must be provided for each unique event reported and 
for each study treatment or concomitant medication, if applicable. Missing causality 
assessments will be handled by the Sponsor as “suspected” to study treatment. 
12.1.4 
Adverse Events Documentation 
Any AE (non-serious and serious) occurring after the patient has provided study-specific 
informed consent until the last study visit of the patient has to be recorded on the AE pages of 
the eCRF. The following information is to be recorded: 
• verbatim/AE description 
• time and date for AE start and stop 
• maximum intensity 
• seriousness 
• causality rating 
• action taken to treat AE 
• action taken with study drug 


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• whether or not the AE caused the patient to discontinue  
• outcome. 
 
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test or other 
assessments. All AEs should be treated appropriately. Treatment may include one or more of 
the following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this AE; 
concomitant medication given; non-drug therapy given, patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the AE should be documented in the 
eCRF. In addition, the action taken with the study drug should be documented and be 
assigned to one of the following categories: not changed, withdrawn, reduced, increased, 
interrupted, unknown and not applicable. Concomitant medication, other treatments or 
changes in the administration of the study drug should be defined and be also documented. 
Medical conditions/diseases present before starting study drug are only considered AEs if 
they worsen after enrolment. Abnormal laboratory values or test results constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent. The outcome should be documented and be assigned to one of the following 
categories: 
not 
recovered/unchanged, 
condition 
deteriorating, 
recovered/resolved, 
improving/recovering, recovered/resolved with sequelae, fatal or unknown. The assessment 
of an AE should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship with the investigational product, the interventions 
required to treat it, and the outcome. 
AE/SAE between informed consent and first dosing 
Any AE/SAE occurring between study-specific informed consent and first dosing will be 
documented as screening event with a study drug causality assessment “IMP not yet 
administered”. 
AE/SAE after first dosing  
All AEs/SAEs which occurred during the study are followed-up at the latest until the last visit 
of the patient. Then the last outcome assessment will be performed and documented in the 
eCRF. 
For any ongoing AEs/SAEs at the time of last visit, the Investigator is obliged to follow-up 
with patient for safety reasons. All AEs ongoing at the time of the last patient visit should be 
followed up for 30 days after the last administration of study drug, with the exception of any 
ongoing study drug-related AEs, which should be followed until resolution, unless in the 
Investigator's opinion, the AE is unlikely to resolve due to the patient's underlying disease. 
The follow-up information (including the attempt to follow-up) is documented in source data 
(i.e., patient files). See also Section 12.1.5 for SAE follow-up reporting. 


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SAE after first dosing 
If the outcome of a SAE is not resolved during the last visit of the patient, it is followed up by 
Sandoz on an individual basis until its resolution or until it is judged to be permanent. 
AE at the final examination 
Clinically relevant abnormal laboratory values detected at the final examination are to be 
documented as AEs, even when they cannot be attributed to treatment A or B, etc. 
12.1.5 
Serious Adverse Event (SAE) Reporting 
It is vitally important that the Investigator immediately reports any AE which by the 
definitions given above would be considered serious, even if the Investigator does not 
consider the AE to be drug-related. 
All SAEs must be reported, whether or not considered causally related to the investigational 
product or to the study procedure(s). All SAEs will be recorded in the eCRF. The Investigator 
is responsible for informing the EC of the SAE as per local requirements. 
For reporting of a SAE, the Investigator should use the “Serious Adverse Event Report 
Form” (Novartis form). During the study the original of the SAE Report Form and all related 
correspondence (e.g. email print-out, fax confirmation sheet) must be kept with the eCRF at 
the study site. 
Any SAE has to be reported by the Investigator immediately within 24 hours of learning 
of its occurrence, in the form of an initial report via fax or email to the LPPV, Sandoz and in 
copy to the responsible Study Manager (Sponsor) and the 
 
maintaining a delivery notification for either system, as noted in Table 12-1. 
 


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Table 12-1 
Serious Adverse Event Reporting Contacts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
LPPV=Local Qualified Person for Pharmacovigilance 
 
The responsible contact persons for questions are provided in Table 12-2. 
Table 12-2 
Contacts for General Safety Questions 
Sponsor 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
As soon as new information about the SAE becomes known, the Investigator has to forward it 
within 24 hours to the LPPV and in copy to the Study Manager (Sponsor), using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE. The follow-up 
information should describe whether the event has resolved or continues, if a diagnosis is 
available, if and how it was treated, and whether the patient continued or withdrew from 
study participation. Also queries on SAE reports should be answered by the Investigator 


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within 24 hours. For more detailed information refer to the “Quick Reference Guide for 
Completing the SAE Form” and the Manual for Completing the Novartis SAE Form for 
Clinical Trials” (Novartis documents). 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. 
A SAE that is considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
Any SAE experienced after the final visit of the patient should be reported to the LPPV and 
in copy to the responsible Study Manager (Sponsor), only if the Investigator suspects a causal 
relationship to the investigational product. 
The unblinding of single cases by the Investigator in the course of the clinical trial should 
only be performed if relevant for the subsequent treatment of the patient in emergency 
situations (see also Section 10.3 on unblinding). 
Investigator Notification and 6-Monthly Line Listings 
If a SAE is not previously documented in the Reference Safety Information (Investigator’s 
Brochure) and is thought to be related to the study drug, Sandoz may urgently require further 
information from the Investigator for Health Authority reporting. Sandoz may need to issue 
an Investigator Notification and, if applicable, 6 monthly line listings to inform all 
Investigators involved in any study with the same drug that this SAE has been reported. 
Sandoz will notify all reportable cases within the requested timelines to national authorities in 
order to fulfil the Sponsor´s reporting obligation. 
The announcement of Investigator Notifications and 6-monthly line listings, if applicable, to 
local ECs is the responsibility of the Investigator as stipulated in the study contract. The 
announcement of Investigator Notifications and 6-monthly line listings to national EC is the 
responsibility of the Clinical Research Organization (CRO), if applicable. 
Investigator Training 
By his/her signature of the study protocol, the Investigator certifies that he/she has been 
trained in the Sandoz SAE/AE and pregnancy reporting obligations by the CRO as defined in 
the study protocol. 
12.1.6 
Pregnancies/Breastfeeding Cases 
In general, all cases of drug exposure during pregnancy or drug use during lactation in 
patients exposed to Sandoz products, regardless of seriousness criteria or outcome, must be 
reported. Therefore, pregnancy cases of female patients or breastfeeding cases, which emerge 
during a clinical study between first dosing and the final visit, have to be reported by the 
Investigator to the Sponsor. 
If a pregnancy of the female partners of male patients becomes known to the Investigator, 
which is likely to have started during study participation of the male patient (paternal 
exposure), this pregnancy will also need to be reported. 


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To ensure patient safety, each pregnancy or breastfeeding case in a patient participating in the 
study must be reported by the Investigator immediately within 24 hours of learning of its 
occurrence to the LPPV, Sandoz and in copy to the Study Manager (Sponsor), as described in 
Section12.1.5. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy or breastfeeding case should be recorded on a “Clinical Trial Pregnancy Form” 
(Novartis form) Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the investigational product of any 
pregnancy outcome. For more detailed information refer to the “Clinical Trial Pregnancy 
Quick Reference Guide” (Novartis document). 
Any SAE experienced during pregnancy must be reported on the SAE Report Form and 
reported as described in Section 12.1.5. 
12.1.7 
Quality Complaints or Special Case Scenarios 
In case of quality complaints (technical or transport complaints), the Investigator within 
24 hours of learning of its occurrence informs the Sponsor as described in Section 10.7. Any 
AE associated with a quality complaint needs to be documented and reported in addition by 
the Investigator as described in Sections 12.1.4 and 12.1.5. 
Special case scenarios are always treated like AE cases, even if no other AEs have been 
reported. Special case scenarios can be assessed as serious or non-serious cases.  
Some special case scenarios have to be reported within 24 hours from the Investigator to the 
LPPV, even if assessed as non-serious: 
• pregnancy/breastfeeding (Section 12.1.6) 
• withdrawal syndrome/reaction 
• drug dependency, misuse, abuse or addiction (always serious) 
• suspected transmission of infectious agents (always serious) 
• use of a falsified product/counterfeit 
• death (including without other event, always serious). 
 
In cases where the Investigator suspects one of the following events (special case scenarios), 
the Sponsor has to be contacted likewise (within 24 hours for serious cases): 
• medication error (including maladministration, accidental exposures and dispensing 
errors) 
• occupational exposure 
• pediatric or elderly exposure 
• overdose (including suicide attempts; suicide attempt is always serious) 
• lack of efficacy or vaccine failure (vaccine failure is always serious) 
• drug/drug interactions 
• disease progression or aggravation 


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• off-label use 
• treatment non-compliance 
• environmental issues (i.e. reported effects of pharmaceuticals on the environment, e.g. 
water contamination by pharmaceuticals). 
 
12.1.8 
Reconciliation 
Reconciliation between the safety database of the Sponsor and the clinical database at the 
CRO will be done periodically as described in a reconciliation plan by comparing line listings 
from the safety database with the data in the clinical database. 
The data management will review the eCRFs/clinical database for potentially unreported 
SAEs or other individual safety cases. For any Individual Safety Case Report, the following 
parameters need to match exactly between the clinical and the safety database: trial number, 
site number, patient number, randomization number (if applicable), investigational drug, 
seriousness, date of death (if applicable) and Investigator causality. All other parameters only 
need to be plausibly and medically consistent. For any SAE assessed as suspected, a more 
detailed reconciliation should be conducted, including treatment dates and medical history. 
12.1.9 
Abnormal Laboratory Values/Vital Signs 
Laboratory/vital signs abnormalities should be reported as AEs if any one of the following 
criteria is met: 
• any criterion for an SAE is fulfilled 
• the laboratory/vital signs abnormality causes the patient to discontinue from the study 
treatment. 
• the laboratory/vital signs abnormality causes the patient to interrupt the study 
treatment 
• the laboratory/vital signs abnormality causes the patient to modify the dose of study 
treatment 
• the Investigator believes that the abnormality should be reported as an AE 
• if an abnormal laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom should be reported as an AE and the associated 
laboratory result or vital sign should be considered additional information that must 
be collected on the relevant eCRF. 
12.2 
Physical Examination 
 A full physical examination, including calculation of BMI, will be carried out at Study Day 1 
and on Study Day 5 (± 1 day) at the TOC/EOS Visit. This examination will include 
assessment of the cardiovascular, GI and respiratory systems.  
12.3 
Vital Signs 
Vital signs (respiratory rate, heart rate, blood pressure, and body temperature) will be 
assessed at the visits on Study Day 0 and Study Day 5 (± 1 day) according to the 
investigational sites standard of practice. Assessments will be carried out on patients in the 


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sitting position after the patient has rested for 5 minutes. The date and time of the assessment 
will be recorded. 
12.4 
Laboratory Assessments 
Urine pregnancy tests will be done on all females of child bearing potential (not 
post-menopausal or not surgically sterile) prior to randomization at Study Day 1 and again on 
Study Day 5 (± 1 day). Urine pregnancy tests will be done locally. 
Microbiological assessments of stool samples are detailed in Section 11.2.3. 
All hematology, blood chemistry and urine samples will be analyzed at the central laboratory; 
details for handling, storage and shipping will be provided in the laboratory manual. Blood 
and urine samples will be collected for the following analyses: 
• Hematology 
o hemoglobin 
o hematocrit 
o red blood cell count 
o platelet count 
o white blood cell count with differential 
• Serum Chemistry 
o glucose 
o calcium 
o sodium 
o chloride 
o albumin 
o protein 
o bilirubin 
o blood urea nitrogen 
o lactate dehydrogenase 
o aspartate aminotransferase 
o alanine aminotransferase 
o potassium 
o alkaline phosphatase 
o uric acid 
o creatinine 
o creatine kinase 
• Urinalysis 
o bilirubin 
o blood 
o glucose 
o pH 
o ketones 


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o leukocytes 
o nitrites 
o protein 
o specific gravity 
o urobilinogen 
 


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13 
STATISTICAL EVALUATION 
13.1 
Sample Size and Power 
According to the FDA Draft Guidance on rifaximin11 sample sizes should be chosen such that 
the power is sufficient to establish therapeutic equivalence between generic and RLD 
rifaximin (Xifaxan) and sufficient to show that both are active compared to placebo (study 
sensitivity). Therapeutic equivalence is to be shown for the PP population whereas study 
sensitivity is to be shown for the modified Intent-to-Treat (mITT) population 
(Section 13.2.2). 
A sample size of 135 in the generic rifaximin and 135 in the Xifaxan treatment groups 
achieve approximately 
 power to detect therapeutic equivalence when the margin 
of equivalence, given in terms of the difference, extends from -0.20 to 0.20. The calculations 
assume that: 
• two one-sided Z tests (pooled) at the 0.05 significance level are used (corresponding 
to a 90% CI for the difference of success proportions); 
• 
 
• 
 
 
Concerning the assessment of study sensitivity, a sample size of 170 in the rifaximin group, 
170 in the Xifaxan group and 85 in the placebo group achieve approximately 
 
power to detect a difference between the group proportions of 
, assuming that:  
• 
 
• two-sided Z tests (pooled) at the 0.05 level will be used.  
 
Patients will be randomized 2:2:1 to rifaximin (n=180), Xifaxan (n=180), and placebo 
(n=90). A total of 450 patients will be enrolled. As it can be anticipated that no more than 5% 
of patients will be excluded from the mITT population and no more than 20% of patients will 
be excluded from the PP population12 this sample size will have sufficient power to show 
therapeutic equivalence and study sensitivity. 
13.2 
Statistical Methods 
A detailed description of all statistical analyses to be performed for this study will be given in 
a statistical analysis plan (SAP). Any deviations from the analysis detailed in the protocol 
will be described in the SAP. 
No interim analysis is planned. 
Any deviations from the original SAP will be described and justified in the final CSR, as 
appropriate.  


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13.2.1 
General Analysis and Coding 
The statistical analysis will be performed using the software package SAS version 9.3 or 
higher (SAS Institute Inc., Cary, NC 27513, USA). All individual data as well as results of 
statistical analyses, whether explicitly discussed in the previous sections or not, will be 
presented in individual patient data listings and statistical summary tables. 
In general, continuous variables will be summarized using the following standard descriptive 
summary statistics: number of observations, arithmetic mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Categorical data will be described using 
count and frequency. Shift tables will be provided, where appropriate. Confidence intervals 
will be two-sided 95% CIs if not otherwise specified. 
All analyses and summary tables will be displayed by treatment group. Data to be used for 
comparability between treatment groups will be specified in the SAP. 
The following international dictionaries (in latest available version) will be used for medical 
coding: 
• Diagnoses: Medical Dictionary for Regulatory Activities (MedDRA) 
• Medications: World Health Organization (WHO) Drug Dictionary including 
Anatomical Therapeutic Chemical (ATC) classification 
• AEs: MedDRA 
 
13.2.2 
Analysis Populations 
The following analysis populations will be defined for the statistical analyses: 
• The Safety population will include all randomized patients who received at least 
1 dose of the study product. 
• The mITT population will include all randomized patients who met all 
inclusion/exclusion criteria, received at least 1 dose of the study drug and recorded the 
number of formed and unformed bowel movements during Study Day 1. 
• The PP population will include all randomized patients from the mITT population 
who do not have a major protocol deviation that would affect treatment evaluation. 
Patients who discontinue the study due to lack of treatment effect after completing 
3 days of treatment or whose condition worsens and who require alternate or 
supplemental therapy for the treatment of TD should be included in the PP population 
(see Section 13.2.5 for the handling of missing values).  
 
Major protocol deviations include but are not limited to: 
• lack of compliance defined as having administered <75% or >125% of the scheduled 
doses for the specified duration of the study 
• completion of the TOC/EOS Visit outside the specified visit window (Study Day 5 
±1 day) (if patient did not discontinue the study due to lack of treatment effect or 
worsening of the underlying condition requiring alternate or supplemental therapy). 
 
Further major protocol deviations will be defined in the SAP. 


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The PP population will be the primary population for establishing equivalence of rifaximin 
and Xifaxan regarding the primary efficacy endpoint (clinical cure). The mITT population 
will be the primary population for evaluation of the study sensitivity comparing the 
proportions of clinical cure between rifaximin and placebo and Xifaxan and placebo. 
13.2.3 
Primary Endpoint Analysis 
The primary endpoint is clinical cure at the TOC/EOS Visit (Study Day 5 ± 1 day). Clinical 
cure is defined as either:  
• 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.  
 
Patients will assess stool consistency and document it in the patient’s diary; stools will be 
classified, as formed (retains shape), soft (assumes the shape of container), or watery (can be 
poured). When using this classification, both soft and watery stools are unformed and 
abnormal. 
Therapeutic equivalence will be concluded if the 90% CI of the difference of the success 
proportions between rifaximin and Xifaxan is completely contained within the interval [-0.20; 
0.20]. This approach can be alternatively formulated as a statistical test problem where the 
compound hypothesis to be tested is: 
 
against the alternative 
. 
 
Here 
 denotes the probability of clinical cure at the TOC/EOS Visit for rifaximin and 
 
denotes the respective probability for Xifaxan.  
Two one-sided Z tests at the 0.05 significance level will be used for the above test problem. 
The PP population will be the primary analysis set for the assessment of therapeutic 
equivalence. 
Study sensitivity will be evaluated by comparing the success proportions between rifaximin 
and placebo and Xifaxan and placebo. Two two-sided Z tests with pooled variance will be 
used. The significance level of each of these tests will be set to 0.05. The mITT population 
will be the primary analysis set for assessing study sensitivity. 
The primary endpoint will also be analyzed by subgroups according to the pathogen status at 
baseline: 
• inflammatory/invasive pathogens (i.e. Campylobacter jejuni, Shigella species, and 
Salmonella species) 
• diarrheagenic E Coli group without evidence of inflammatory/invasive pathogens 
• Other pathogens without evidence of inflammatory/invasive pathogens. 


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All p-values resulting from these subgroup analyses will be interpreted in the exploratory 
sense. 
13.2.4 
Secondary Endpoint Analysis 
The analysis of all secondary endpoints will be performed in the mITT and PP populations. 
13.2.4.1 
Time to Last Unformed Stool 
TLUS is defined as the interval beginning with the first dose of study drug and ending with 
the last unformed stool passed. 
TLUS will be calculated for each patient in the following manner: 
Step 1: Identify when the patient achieves clinical cure (definition see Section 13.2.3). 
Step 2: Moving backwards from this time, identify the time of the last unformed stool. 
Step 3: The TLUS equals the time from the first dose of study drug to the time of the last 
unformed stool identified in Step 2. 
 
Patients who met the criteria for clinical cure (Section 13.2.3) immediately after the start of 
study drug and prior to passing any unformed stools will be defined as having a TLUS of 
0 hours. Patients for whom TLUS cannot be calculated because they terminated early due to 
clinical failure (Section 13.2.4.2) will have censored TLUS of 120 hours. Patients who 
terminate early due to reasons other than clinical failure (AE, patient request, intercurrent 
illness) or because they completed the study without achieving clinical cure will have 
censored TLUS at the time of the last available information on unformed stools. 
Rifaximin will be compared to Xifaxan, and the rifaximin groups to placebo using a Cox 
proportional hazards model with treatment group and center as independent variables. A 
treatment by center term will also be included to assess potential treatment by center 
interactions. Centers with 5 or fewer patients per treatment arm will be pooled with 
geographically related centers to form analysis centers.  
13.2.4.2 
Clinical Failure 
Clinical failure is defined as failure to achieve formed stool within ≤ 3 days (72 hours) of the 
start of treatment with the study drug or clinical deterioration or worsening of symptoms by 
Study Day 5 (± 1 day, TOC/EOS Visit). The proportion of patients with clinical failure will 
be compared between the three treatment groups with two-sided Z tests. The significance 
level of these tests will be set to 0.05. 
13.2.4.3 
Diarrheal Syndrome 
Improvement of diarrheal syndrome is defined as reduction of ≥ 50% in the number of 
unformed stools (soft or watery) passed during a 24-hour post-enrolment interval (the 
intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first 
dose of study drug) compared to number of unformed stools passed during the 24 hours 
immediately preceding the first dose of study drug. The proportion of patients with 


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improvement of diarrheal syndrome will be compared between the three treatment groups 
with two-sided Z tests. The significance level of these tests will be set to 0.05. 
13.2.4.4 
Unformed Stools 
The number of unformed stools (soft or watery) passed during the intervals 0-24 hours, 
24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first dose of study drug 
will be compared between the three groups using repeated measures Poisson regression with 
treatment, time, and interaction as fixed effects, and with the baseline number of unformed 
stools as a covariate In the event that the data are overdispersed, a negative binomial model 
will be used.  
13.2.4.5 
Signs and Symptoms of Enteric Infection  
The proportion of patients with the presence or absence and severity of signs and symptoms 
of enteric infection (abnormal pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal 
urgency, tenesmus) during the intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, 
and 96-120 hours after the first dose of study drug will be compared between the three 
treatment groups with two-sided Z tests. The significance level of these tests will be set to 
0.05. 
13.2.4.6 
Microbiological Cure  
Microbiological cure is defined as a post-treatment culture that is negative for the 
pre-treatment etiologic pathogen. For those patients with a positive pre-treatment culture the 
proportion of patients with microbiological cure will be compared between the three 
treatment groups with two-sided Z tests. The significance level of these tests will be set to 
0.05. This test will be considered as supportive of the similarity of populations in each arm of 
the study and not considered as evidence of equivalence. 
13.2.5 
Handling Missing Data 
Patients who are discontinued early from the study due to lack of treatment effect after 
completing 3 days of treatment should be included in the PP population using the last 
observation carried forward (LOCF). Patients whose condition worsens and who require 
alternate or supplemental therapy for the treatment of TD should be discontinued, included in 
the PP population analysis using LOCF, and provided with effective treatment. Patients 
discontinued early for other reasons should be excluded from the PP population, but included 
in the mITT population, using LOCF.  
13.2.6 
Patient Disposition 
The primary reason for withdrawal will be summarized by treatment group in the safety 
population. 
13.2.7 
Safety Analyses 
The safety evaluations will include analyses of AEs, vital signs, safety laboratory 
measurements, and physical examinations. The analysis of safety will be based on the safety 
population. 


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13.2.7.1 
Adverse Events 
The incidence of treatment-emergent AEs will be summarized for each treatment group by 
MedDRA system organ class (SOC) and preferred term. An AE is defined as 
treatment-emergent if its onset date/time is on or after the date/time of the first intake of study 
mediation or if a pre-existing condition becomes worse after the date/time of first intake of 
study drug. An AE is defined as pre-treatment if its onset date/time is before the date/time of 
the first intake of study mediation. AEs will be summarized according to the following:  
• An overview of the absolute and relative frequencies of patients with at least one AE 
will be given for the categories pre-treatment and treatment-emergent by seriousness, 
severity, and causality. 
• Further tables will present the absolute and relative frequencies of patients with at 
least one treatment-emergent AE classified by SOC and preferred term and, in 
addition, by seriousness and causality. 
• The absolute and relative frequencies of patients with at least one related treatment-
emergent AE will be summarized by SOC and preferred term. An AE will be defined 
as related if its causality is either probable or possible. 
• The absolute and relative frequencies of patients with at least one SAE will be 
summarized by SOC and preferred term. 
• The absolute and relative frequencies of patients with at least one AE leading to 
discontinuation of study drug will be summarized by SOC and preferred term. 
• Individual patient data listings will be provided for all deaths, patients with other 
SAEs, and discontinuation of study drug due to AEs. 
 
Regarding the summaries by severity and causality the following rule will be applied: if a 
patient experiences more than one AE within the same SOC or with the same preferred term, 
the AE with the highest severity (closest relationship to study treatment) will be used for the 
analysis. 
13.2.7.2 
Vital Signs 
Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be analyzed in 
the following way: 
• Standard descriptive summary statistics will be calculated at each scheduled time 
point and the last individual time point. 
• Further, standard descriptive summary statistics will be computed for the absolute 
change from baseline to each scheduled time point after baseline and the last 
individual time point. 
• A patient data listing of all clinically significant abnormal vital signs will be provided. 
 
13.2.7.3 
Laboratory Parameters 
Laboratory data will be subjected to both a quantitative analysis (descriptive summary 
statistics) and qualitative analysis where frequencies of normal, abnormal low, and abnormal 
high values will be computed. 
The following analyses will be performed: 


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• Standard descriptive summary statistics will be calculated at each scheduled 
measuring time point and the last individual measuring time point. 
• Standard descriptive summary statistics will be calculated for the absolute and relative 
change from baseline to each scheduled measuring time point after baseline and the 
last individual measuring time point. 
• Shift tables displaying changes with respect to the normal range between baseline and 
each scheduled measuring time point after baseline and the last individual measuring 
time point will be provided. 
• A listing of all patients with abnormal values at any time point will be given. 
 
13.2.7.4 
Physical Examinations 
The results of physical examinations will be presented in individual patient listings. 
 


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14 
DIRECT ACCESS TO SOURCE DATA/NOTES 
Information on the eCRF should be verifiable to source documents. Other records that will be 
considered source documents include, but are not limited to, electronic Patient Diary, hospital 
records, clinic charts, radiographic data, laboratory reports and pathology reports. Copies of 
source documents that should be sent to the Sponsor or Sponsor’s authorized representative, 
if requested, include operative summaries and discharge reports. Other source documents 
may include hospital discharge summaries, if available, or information in lieu of a discharge 
summary, such as discharge orders or progress notes; any relevant notes pertaining to AEs, 
additional surgical procedures, or deaths and autopsy reports. 
The Investigator must maintain a copy of all data collected for each patient treated (including 
eCRF, eDiary and source data). In order to assure the accuracy of data collected in the eCRF, 
it is mandatory that the representatives of the Sponsor (or designee) as well as representatives 
of the regulatory authorities and the ECs have direct access to original source documents 
(e.g., patient records, patient charts, laboratory reports). During the review of these 
documents, the anonymity of the patient will be respected with strict adherence to 
professional standards of confidentiality and regulatory requirements. 
The Investigator shall arrange the retention of the patient identification codes and 
Investigator’s trial files for at least 15 years after the completion or discontinuation of the 
study. Patient files and other source data shall be retained in accordance with national 
legislation and in the accordance with the maximum period of time permitted by the hospital, 
institution or private practice. The Investigator must retain essential documents as specified 
in Section 18.4. No study document will be destroyed without prior written agreement 
between the Sponsor and the Investigator. Should the Investigator wish to assign the study 
records to another party or move them to another location, written agreement must be 
obtained from the Sponsor. 
The Sponsor reserves the right to terminate the study for refusal of the Investigator to supply 
source documentation of work performed in the study. 
 
 


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15 
PATIENT CONFIDENTIALITY 
Patient names shall not be revealed to the Sponsor or Sponsor’s authorized representatives. 
Only the patient identifier and initials will be recorded in the eCRF, and if the patient’s name 
appears on any other document, it must be redacted and replaced with the patient identifier 
before a copy of the document is supplied to the Sponsor or Sponsor’s authorized 
representatives. In the event of accidental communication of such information, immediate 
steps to redact the information from all study files will be implemented, with appropriate 
documentation in the patient study file. 
Study findings stored on a computer will be stored in accordance with local data protection 
laws. 
By signing the ICF, patients give explicit permission for representatives of the Sponsor, 
regulatory authorities, and the EC to have direct access to their medical records to verify the 
information collected. Patients will be informed that all personal information made available 
for inspection will be handled in the strictest confidence and in accordance with laws and 
regulations. 
All personnel involved in the study will observe and work within the confines of local data 
protection regulations. 


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16 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1 
Conduct of the Study 
 shall implement and maintain quality control and quality assurance procedures with 
written standard operating procedures (SOPs) to ensure that the study is conducted and data 
are generated, documented and reported in compliance with the protocol, ICH GCP and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 2013) and all revisions thereof, and in accordance with FDA regulations 
(Code of Federal Regulations [CFR], Sections 312.50 and 312.56) and with ICH GCP 
(CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate EC, except when necessary to 
eliminate immediate hazards to the patient. Any deviations may result in the patient having to 
be withdrawn from the study and render that patient non-evaluable. 
16.2 
Study Monitoring 
The Investigator shall permit the Site Monitor to review study data as frequently as deemed 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The Investigator shall access medical records for the Monitor in order that entries in the 
eCRF may be verified. The Investigator, as part of his/her responsibilities, is expected to co-
operate with 
 in ensuring that the study adheres to GCP requirements. 
Monitors will perform 100% source data verification to confirm that the data recorded in the 
eCRF reported data are accurate, complete and verifiable from the medical/study records of 
each patient; the presence of appropriately signed and dated ICF; adherence to 
inclusion/exclusion criteria; and documentation of all SAEs. 
The Investigator may not recruit patients into the study until such time that a visit, or with the 
agreement of the Sponsor, attendance at the Investigator meeting, has been made by a 
Sponsor/
 monitor to conduct a detailed review of the protocol and eCRF. 


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17 
ETHICS 
17.1 
Ethics Committee 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant EC. The EC shall be 
appropriately constituted and perform its functions in accordance with FDA ICH GCP and 
local requirements as applicable. 
The EC shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures (e.g., advertisements), written information to be provided to the patients, 
Investigator's Brochure, available safety information, information about payment and 
compensation available to patients, the Investigator's curriculum vitae and/or other evidence 
of qualifications and any other documents requested by the EC and Regulatory Authority 
(Competent Authority) as applicable. 
17.2 
Regulatory Authority 
Beside other study relevant documents, the appropriate information about the active 
compound (e.g., Investigator’s Brochure); the protocol; name and site of the Investigators; 
and the vote of the ECs will be submitted to the relevant competent authorities before starting 
the study in compliance with the Declaration of Helsinki, the ICH-GCP guidelines and the 
national laws and regulations. In accordance with the national law all approvals needed for 
conduction of the trial in this country will be obtained. The trial can start after the approval is 
granted. 
17.3 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each patient in a form 
understandable to them; the Investigator must confirm that the patient is able to understand 
the language of the ICF and Patient Information. The process of obtaining informed consent 
will be in compliance with relevant regulatory guidance, ICH requirements and local laws. 
The consent documents to be used for the study shall be reviewed and approved by the 
appropriate EC prior to use. 
Signed and dated informed consent must be obtained from each patient prior to any study 
procedures being performed. The Investigator or Investigator’s designee will provide 
background information on the study, including the benefits and risks of both the 
investigative treatment, control treatment and the implications of possible enrolment to 
placebo; scope of the study; procedures to be done at each visit; and responsibility of the 
patient (e.g., completion of the Patient Diary). The Investigator or Investigator’s designee 
will also encourage the prospective patient to ask questions about the study and will provide 
the prospective patient with sufficient opportunity to consider whether or not to participate. 
Original signed and dated ICFs must be filed in the patient records at the site. A copy of the 
signed and dated consent must also be provided to the patient or to his/her legal 
representative. 


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If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to all new patients and repeat the consent process with the amended 
ICF for any ongoing patients, if appropriate. 


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18 
DATA HANDLING AND RECORD KEEPING 
18.1 
Case Report Forms/Source Data Handling 
The Investigator shall be provided with standardized eCRFs and shall ensure that all data 
from patient visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The Investigator must sign each eCRF to verify the integrity of the data 
recorded. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. It is essential that all samples be analyzed at 
the central laboratory. 
The Investigator must maintain source documents, such as laboratory reports, consultation 
reports, and complete medical history and physical examination reports (Section 14). 
18.2 
Patient Diaries 
Patients will be provided with electronic Diaries, and instructed in how to use and complete 
the Diary entries at Visit 1 (Screening and Randomization). Investigators must ensure that the 
patient is able to understand the instructions, and be able to read the language of the Diary 
provided. Patients who are not able to understand the instructions, or complete the Diary 
entries, will not be enrolled into the study. 
18.3 
Investigator File 
The Investigator/institution should maintain an Investigator Trial File specific for the study 
and clinical center. The Investigator/institution must maintain trial-related documents per 
ICH E6§8 and 21CRF 312.57, and must take measures to prevent accidental or premature 
destruction of these documents. Sites should archive Investigator Files at least for 15 years 
after study close-out at the site. 
18.4 
Retention of Essential Documents/Materials 
18.4.1 
Essential Documents 
Essential documents should be retained for at least 15 years after the end of study. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer need to 
be retained. 
Details and instructions for collection, handling, shipping and storage of retention samples 
(Section 18.4.2) will be provided in the laboratory manual. 
18.4.2 
Essential Materials 
Retention samples of all study treatments will be stored in national depots, per 21 CFR 
320.38, 320.63; 21 CFR 320.36; 21 CFR 58; Guidance for Industry, “Handling and Retention 
of BA and BE Testing Samples”; and ICH E6, “Good Clinical Practice: Consolidated 


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Guideline”, for retention of study records and data in order to conduct their studies in 
compliance with Good Laboratory Practices (GLP) and Good Clinical Practices (GCP). 
Retention samples will be randomly selected from the drug supplies received prior to 
dispensing to study centers.  
Details and instructions for collection, handling, shipping and storage of retention samples 
will be provided in the laboratory manual. The samples will be stored until the Sponsor 
confirms storage is no longer required and regulatory requirements for storage times have 
been met.  Each reserve sample shall be retained for a period of at least 5 years following the 
date on which the application or supplemental application is approved, or, if such application 
or supplemental application is not approved, at least 5 years following the date of completion 
of the bioavailability study in which the sample from which the reserve sample was obtained 
was used (21 CFR 320.38). 
Retention samples will not be returned to the Sponsor at any time. 


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19 
FINANCING AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement. 
The Sponsor will provide clinical trial liability insurance for study patients in all participating 
countries according to the local regulations. 
 
 


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20 
PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data.  
When the study is complete the Sponsor shall arrange the analysis and tabulation of data. A 
CSR shall then be prepared, which may be used by the Sponsor for publication, presentation 
at scientific meetings or submission to regulatory authorities.  
Individual Investigators and/or their associates subsequently may publish additional findings 
of the study. All publications (manuscripts, abstracts or other modes of presentation) shall be 
submitted at a time determined by the Sponsor and must be reviewed and approved in writing 
by the Sponsor, in advance of submission. Co-authorship with any Sponsor personnel will be 
discussed and mutually agreed upon before submission of a manuscript to a publisher.  
 
 


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21 
REFERENCE LIST 
1. Steffen R. Epidemiology of traveler’s diarrhea. Clin Infect Dis. 2005;41:S536–40. 
2. Merson MH, Morris GK, Sack DA, Wells JG, Feeley JC, Sack RB, Creech WB, Kapikian 
AZ, Gangarosa EJ. Travelers’ diarrhea in Mexico. A prospective study of physicians and 
family members attending a congress. N Engl J Med 1976;294:1299–1305. 
3. Taylor DN, Houston R, Shlim DR, Bhaibulaya M, Ungar BL, Echeverria P. Etiology of 
diarrhea among travelers and foreign residents in Nepal. JAMA 1988;260:1245-1248. 
4. Adachi JA, Jiang ZD, Mathewson JJ, Verenkar MP, Thompson S, Martinez-Sandoval F, 
Steffen R, Ericsson CD, DuPont HL. Enteroaggregative Escherichia coli as a major 
etiologic agent in traveler’s diarrhea in 3 regions of the world. Clin Infect Dis. 2001;32: 
1706-1709. 
5. Steffen R, Van der Linde F, Gyr K, Schär M. Epidemiology of diarrhea in travelers. 
JAMA. 1983;249:1176–80. 
6. Kollaritsch H. Traveller’s diarrhea among Austrian tourists to warm climate countries. II. 
Clinical features. Eur J Epidemiol. 1989;5:355–62. 
7. Mosavi A, DuPont HL, Selwyn BJ, Hsi B, Mathewson JJ, Ericsson CD. Prognostic 
factors related to recovery from diarrhea among U.S. students with diarrhea in Mexico. J 
Travel Med. 1997;4:161–6. 
8. Koo HL, DuPont HL, Huang, BD. The role of rifaxmin in the treatment and 
chemoprophylaxis of travelers’ diarrhea. Ther Clin Risk Manag. 2009; 5:841-848. 
9. Prescribing information for Xifaxan. 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Last accessed 29 September 
2015. 
10. Jiang ZD, DuPont HL, Brown EL, Nandy RK, Ramamurthy T, Sinha A, Ghosh S, Guin 
S, Gurleen K, Rodrigues S, Chen, J, McKenzie R, Steffen, R. Microbial Etiology of 
Travelers’ Diarrhea in Mexico, Guatemala, and India: Importance of Enterotoxigenic 
Bacteroides fragilis and Arcobacter Species. J Clin Microb. Apr 2014; 1417-1419. 
11. Draft 
Guidance 
on 
Rifaximin, 
recommended 
February 
2012. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM291392.pdf. Last accessed 26 August 2015. 
12. Taylor DN, Bourgeois AL, Ericsson CD, Steffen R, Jiang Z-D, Halpren J, Haake R, 
Dupont HL. A randomized, double-blind, multicenter study of rifaximin compared with 
placebo and with ciprofloxacin in the treatment of travelers’ diarrhea. Am J Trop Med 
Hyg. 2006;74:1060–66. 


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22 
APPENDICES 
Appendix I 
Xifaxan Prescribing Information 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI G H LI G H T S O F P R E S C RI BI N G I N F O R M A TI O N 
T hese hi g hli g hts d o n ot i ncl u d e a ll t he i nf or m ati o n n ee de d t o use 
XI F A X A N s afel y a n d effecti vel y.  S ee f ull prescri bi n g i nf or m ati o n f or 
XI F A X A N. 
XI F A X A N ® (rif a xi mi n) t a blets, f or or al use 
I niti al U. S. A p pr o v al: 2 0 0 4 
T o re d uce t he de vel o p me nt of dr u g- resist a nt b acteri a a n d m ai nt ai n t he 
effecti ve ness of XI F A X A N a n d ot h er a nti b acteri al d r u gs, XI F A X A N 
s h o ul d be use d o nl y t o tre at or pre v e nt i nfecti o ns t h at are pr o ve n or 
str o n gl y s us pecte d t o be c a use d b y b acteri a. 
--------------------------  R E C E N T M A J O R C H A N G E S  --------------------------
I n dicati o ns a n d Usa ge 
Irrita ble B o wel S y n dr o me wit h Diarr hea ( 1. 3)  
5/ 2 0 1 5 
D osa ge a n d A d mi nistrati o n 
Irrita ble B o wel S y n dr o me wit h Diarr hea ( 2. 3)  
5/ 2 0 1 5 
---------------------------  I N DI C A TI O N S A N D U S A G E  --------------------------
XI F A X A N is a rifa m yci n a nti bacteri al i n dicate d f or: 
•   
Treat me nt of tra velers’ diarr hea ( T D) ca use d b y n o ni n vasi ve 
strai ns of Esc heric hi a c oli  i n a d ult a n d pe diatric patie nts 1 2 years 
of a ge a n d ol der ( 1. 1) 
•  
Re d ucti o n i n ris k of o vert he patic  e nce p hal o pat h y ( H E)  rec urre nce 
i n a d ults ( 1. 2) 
•  
Treat me nt of irrita ble b o wel s y n dr o me wit h diarr hea (I B S- D) i n 
a d ults ( 1. 3) 
Li mitati o ns of Use 
•   
T D: D o n ot use i n patie nts wit h diarr hea c o m plicate d b y fe ver or 
bl o o d i n t he st o ol or diarr hea d ue t o pat h o ge ns ot her t ha n 
Esc heric hi a c oli ( 1. 1, 5. 1) 
----------------------  D O S A G E A N D A D MI NI S T R A TI O N ---------------------- 
C o n diti o n 
Rec o m me n de d D os a ge Re gi me n 
T D ( 2. 1) 
O ne 2 0 0 m g ta blet 3 ti mes a da y f or 
3 da ys 
H E ( 2. 2) 
O ne 5 5 0 m g ta blet 2 ti mes a da y 
I B S- D ( 2. 3) 
O ne 5 5 0 m g ta blet 3 ti mes a da y f or 
1 4 da ys. Patie nts w h o e x perie nce 
rec urre nce ca n be retreate d u p t o t w o 
ti mes wit h t he sa me re gi me n. 
•   
XI F A X A N ca n be ta ke n wit h or wit h o ut f o o d. ( 2. 4) 
---------------------  D O S A G E F O R M S A N D S T R E N G T H S  --------------------
2 0 0 m g a n d 5 5 0 m g ta blets ( 3) 
 ------------------------------ C O N T R AI N DI C A TI O N S  -----------------------------
Hist or y of h y perse nsiti vit y t o rifa xi mi n, rifa m yci n a nti mi cr o bial a ge nts, or 
a n y of t he c o m p o ne nts of XI F A X A N ( 4) 
-----------------------  W A R NI N G S A N D P R E C A U TI O N S  ----------------------
•   
Tra velers’ Di arr hea N ot Ca use d b y E. c oli : XI F A X A N was n ot 
effecti ve i n diarr hea c o m plicate d b y fe ver a n d/ or bl o o d i n t he st o ol 
or diarr hea d ue t o pat h o ge ns ot her t ha n E. c oli . If diarr hea 
s y m pt o ms get w orse or persist f or m ore t ha n 2 4 t o 4 8 h o urs, 
disc o nti n ue XI F A X A N a n d c o nsi der  alter nati ve a nti bi otics ( 5. 1) 
•   
Cl ostri di u m difficile - Ass ociate d Diarr hea: E val uate if di arr hea 
occ urs after t hera p y or d oes n ot i m pr o ve or w orse ns d uri n g t hera p y 
( 5. 2) 
•  
He patic I m pair me nt: Use wit h ca uti o n i n patie nts wit h se vere 
( C hil d- P u g h Class C) he patic i m p air me nt ( 5. 4, 8. 7) 
•   
C o nc o mita nt P- gl yc o pr otei n i n hi bit o r: Ca uti o n s h o ul d be e xercise d 
w he n c o nc o mita nt use of XI F A X A N a n d a P- gl yc o pr otei n 
i n hi bit or is nee de d ( 5. 5, 7. 2). 
------------------------------  A D V E R S E R E A C TI O N S  -----------------------------
M ost c o m m o n a d verse reacti o ns: 
•  
T D ( > 2 %): Hea dac he ( 6. 1) 
•  
H E ( > 1 0 %): Peri p heral e de ma, na usea, dizzi ness, fati g ue, a n d 
ascites ( 6. 1)  
•  
I B S- D (> 2 %): A L T i n crease d, na usea ( 6. 1)  
T o re p ort S U S P E C T E D A D V E R S E R E A C TI O N S, c o nt act S ali x 
P h ar m ace utic als at 1- 8 0 0- 5 0 8- 0 0 2 4 a n d w w w. S ali x.c o m or F D A at 1- 8 0 0-
F D A- 1 0 8 8 or w w w.f d a. g o v/ me d w atc h . 
----------------------- U S E I N S P E CI FI C P O P U L A TI O N S  ----------------------
Pre g na nc y: Ma y ca use fetal har m ( 8. 1) 
See 1 7 f or P A TI E N T C O U N S E LI N G I N F O R M A TI O N  
 
Re vise d: 0 5/ 2 0 1 5 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N: C O N T E N T S* 
1 I N DI C A TI O N S A N D U S A G E 
1. 1  Tra velers’ Di arr hea 
1. 2  He patic E nce p hal o pat h y 
1. 3  Irrita ble B o wel S y n dr o me wit h Diarr hea 
2 D O S A G E A N D A D MI NI S T R A TI O N 
2. 1  D osa ge f or Tra velers’ Di arr hea 
2. 2  D osa ge f or He patic E nce p hal o pat h y 
2. 3 D osa ge f or Irrita ble B o wel S y n dr o me wit h Diarr hea 
2. 4  A d mi nistrati o n 
3 D O S A G E F O R M S A N D S T R E N G T H S 
4 C O N T R AI N DI C A TI O N S 
5 W A R NI N G S A N D P R E C A U TI O N S 
5. 1  Tra velers’ Di arr hea N ot Ca use d b y Es c heric hi a c oli 
5. 2 Cl ostri di u m difficile- Ass ociate d Diarr hea 
5. 3  De vel o p me nt of Dr u g- Resista nt Bacteria 
5. 4  Se vere ( C hil d- P u g h Class C) He p atic I m pair me nt 
5. 5  C o nc o mita nt use wit h P- gl yc o pr otei n I n hi bit ors 
6 A D V E R S E R E A C TI O N S 
6. 1  Cli nical St u dies E x perie nce 
6. 2  P ost mar keti n g E x perie nce 
7 D R U G I N T E R A C TI O N S 
7. 1  Effects of XI F A X A N o n Ot her Dr u gs 
7. 2  Effects of Ot her Dr u gs o n XI F A X A N 
8 U S E I N S P E CI FI C P O P U L A TI O N S 
8. 1  Pre g na nc y 
8. 2  Lactati o n 
8. 4  Pe diatric Us e 
8. 5  Geriatric Use 
8. 6  Re nal I m pair me nt 
8. 7  He patic I m pair me nt 
1 0 O V E R D O S A G E 
1 1 D E S C RI P TI O N 
1 2 C LI NI C A L P H A R M A C O L O G Y 
1 2. 1  Mec ha nis m of Acti o n 
1 2. 3  P har mac o ki netics 
1 2. 4  Micr o bi ol o g y 
1 3 N O N C LI NI C A L T O XI C O L O G Y 
1 3. 1  Carci n o ge nesis, M uta ge nesis, I m p air me nt of Fertilit y 
1 4 C LI NI C A L S T U DI E S 
1 4. 1  Tra velers’ Diarr hea 
1 4. 2  He patic E nce p hal o pat h y 
1 4. 3  Irrita ble B o wel S y n dr o me wit h Diarr hea 
1 5 R E F E R E N C E S 
1 6 H O W S U P P LI E D/ S T O R A G E A N D H A N D LI N G 
1 7 P A TI E N T C O U N S E LI N G I N F O R M A TI O N 
* Secti o ns or s u bsecti o ns o mitte d fr o m t he f u ll prescri bi n g i nf or mati o n are n ot liste d. 
1 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
FULL PRESCRIBING INFORMATION   
1 INDICATIONS AND USAGE 
To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial 
drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or 
strongly suspected to be caused by susceptible bacteria.  When culture and susceptibility information are available, they 
should be considered in selecting or modifying antibacterial therapy.  In the absence of such data, local epidemiology and 
susceptibility patterns may contribute to the empiric selection of therapy. 
1.1 Travelers’ Diarrhea 
XIFAXAN is indicated for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli in 
adults and pediatric patients 12 years of age and older. 
Limitations of Use 
XIFAXAN should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to 
pathogens other than Escherichia coli [see Warnings and Precautions (5.1), Clinical Pharmacology (12.4), Clinical 
Studies (14.1)]. 
1.2 Hepatic Encephalopathy 
XIFAXAN is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults. 
In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly.  Differences in the treatment 
effect of those patients not using lactulose concomitantly could not be assessed. 
XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores >25, and only 8.6% 
of patients in the controlled trial had MELD scores over 19.  There is increased systemic exposure in patients with more 
severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical 
Pharmacology (12.3)]. 
1.3 Irritable Bowel Syndrome with Diarrhea 
XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. 
2 DOSAGE AND ADMINISTRATION 
2.1 Dosage for Travelers’ Diarrhea 
The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days. 
2.2 Dosage for Hepatic Encephalopathy 
The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times a day. 
2.3 Dosage for Irritable Bowel Syndrome with Diarrhea 
The recommended dose of XIFAXAN is one 550 mg tablet taken orally three times a day for 14 days.  Patients who 
experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen.  
2.4 Administration 
XIFAXAN can be taken with or without food [see Clinical Pharmacology (12.3)]. 
2 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
3 DOSAGE FORMS AND STRENGTHS  
XIFAXAN is a pink-colored biconvex tablet and is available in the following strengths: 
• 
200 mg – a round tablet debossed with “Sx” on one side. 
• 
550 mg – an oval tablet debossed with “rfx” on one side. 
4 CONTRAINDICATIONS 
XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or 
any of the components in XIFAXAN.  Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic 
edema, and anaphylaxis [see Adverse Reactions (6.2)]. 
5 WARNINGS AND PRECAUTIONS 
5.1 Travelers’ Diarrhea Not Caused by Escherichia coli 
XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or 
diarrhea due to pathogens other than Escherichia coli. 
Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic 
therapy should be considered. 
XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in 
travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven.  XIFAXAN should not be used in 
patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens [see 
Indications and Usage (1.1)]. 
5.2 Clostridium difficile-Associated Diarrhea 
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including 
XIFAXAN, and may range in severity from mild diarrhea to fatal colitis.  Treatment with antibacterial agents alters the 
normal flora of the colon which may lead to overgrowth of C. difficile. 
C. difficile produces toxins A and B which contribute to the development of CDAD.  Hypertoxin producing strains of C. 
difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may 
require colectomy.  CDAD must be considered in all patients who present with diarrhea following antibiotic use.  Careful 
medical history is necessary since CDAD has been reported to occur over two months after the administration of 
antibacterial agents. 
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. 
Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical 
evaluation should be instituted as clinically indicated. 
5.3 Development of Drug-Resistant Bacteria 
Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a 
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-
resistant bacteria. 
3 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.4 Severe (Child-Pugh Class C) Hepatic Impairment 
There is increased systemic exposure in patients with severe hepatic impairment.  The clinical trials were limited to 
patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with 
severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7), Clinical Studies (14.2)]. 
5.5 Concomitant use with P-glycoprotein Inhibitors 
Concomitant administration of drugs that are P-glycoprotein inhibitors with XIFAXAN can substantially increase the 
systemic exposure to rifaximin.  Caution should be exercised when concomitant use of XIFAXAN and a P-glycoprotein 
inhibitor such as cyclosporine is needed.  In patients with hepatic impairment, a potential additive effect of reduced 
metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin [see Drug 
Interactions (7.2), Pharmacokinetics (12.3)]. 
6 ADVERSE REACTIONS 
6.1 Clinical Studies Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials 
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed 
in practice. 
Travelers’ Diarrhea 
The safety of XIFAXAN 200 mg taken three times a day was evaluated in patients with travelers’ diarrhea consisting of 
320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with 
XIFAXAN. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were >65 years 
old, 53% were male and 84% were White, 11% were Hispanic. 
Discontinuations due to adverse reactions occurred in 0.4% of patients.  The adverse reactions leading to discontinuation 
were taste loss, dysentery, weight decrease, anorexia, nausea and nasal passage irritation. 
The adverse reaction that occurred at a frequency >2% in XIFAXAN-treated patients (n=320) at a higher rate than 
placebo (n=228) the two placebo-controlled trials of TD was: 
• 
headache (10% XIFAXAN, 9% placebo) 
Hepatic Encephalopathy 
The data described below reflect exposure to XIFAXAN in 348 patients, including 265 exposed for 6 months and 202 
exposed for more than a year (mean exposure was 364 days).  The safety of XIFAXAN 550 mg taken two times a day for 
reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-
controlled clinical trial (n=140) and in a long term follow-up study (n=280).  The population studied had a mean age of 56 
(range: 21 to 82) years; approximately 20% of the patients were ≥65 years old, 61% were male, 86% were White, and 4% 
were Black.  Ninety-one percent of patients in the trial were taking lactulose concomitantly. The most common adverse 
reactions that occurred at an incidence ≥5% and at a higher incidence in XIFAXAN-treated subjects than in the placebo 
group in the 6-month trial are provided in Table 1. 
Table 1: Most Common Adverse Reactions1 in HE Trial 
Number (%) of Patients 
MedDRA Preferred Term 
XIFAXAN Tablets 
Placebo 
550 mg TWICE  DAILY 
n=159 
4 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n=140 
Peripheral edema 
21 (15%) 
13 (8%) 
Nausea 
20 (14%) 
21 (13%) 
Dizziness 
18 (13%) 
13 (8%) 
Fatigue 
17 (12%) 
18 (11%) 
Ascites 
16 (11%) 
15 (9%) 
Muscle spasms 
13 (9%) 
11 (7%) 
Pruritus 
13 (9%) 
10 (6%) 
Abdominal pain 
12 (9%) 
13 (8%) 
Anemia 
11 (8%) 
6 (4%) 
Depression 
10 (7%) 
8 (5%) 
Nasopharyngitis 
10 (7%) 
10 (6%) 
Abdominal pain upper 
9 (6%) 
8 (5%) 
Arthralgia 
9 (6%) 
4 (3%) 
Dyspnea 
9 (6%) 
7 (4%) 
Pyrexia 
9 (6%) 
5 (3%) 
Rash 
7 (5%) 
6 (4%) 
1. reported in >5% of Patients Receiving XIFAXAN and at a higher incidence than placebo 
Irritable Bowel Syndrome with Diarrhea 
The safety of XIFAXAN for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients 
were randomized to XIFAXAN 550 mg three times a day for 14 days.  Across the 3 studies, 96% of patients received at 
least 14 days of treatment with XIFAXAN.  In Trials 1 and 2, 624 patients received only one 14-day treatment.  Trial 3 
evaluated the safety of XIFAXAN in 328 patients who received 1 open-label treatment and 2 double-blind repeat 
treatments of 14 days each over a period of up to 46 weeks.  The combined population studied had a mean age of 47 
(range: 18 to 88) years of whom approximately 11% of the patients were >65 years old, 72% were female, 88% were 
White, 9% were Black and 12% were Hispanic. 
The adverse reaction that occurred at a frequency >2% in XIFAXAN-treated patients at a higher rate than placebo in 
Trials 1 and 2 for IBS-D was: 
• 
nausea (3% XIFAXAN, 2% placebo) 
The adverse reactions that occurred at a frequency >2% in XIFAXAN-treated patients (n=328) at a higher rate than 
placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were: 
• 
ALT increased (XIFAXAN 2%, placebo 1%) 
• 
nausea (XIFAXAN 2%, placebo 1%) 
Less Common Adverse Reactions 
The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of 
TD and IBS-D and in less than 5% of patients in clinical trials of HE: 
Hepatobiliary disorders: Clostridium colitis 
Investigations: Increased blood creatine phosphokinase 
Musculoskeletal and connective tissue disorders: myalgia 
5 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 Postmarketing Experience 
The following adverse reactions have been identified during post-approval use of XIFAXAN.  Because these reactions are 
reported voluntarily from a population of unknown size, estimates of frequency cannot be made.  These reactions have 
been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. 
Infections and Infestations 
Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)]. 
General 
Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and 
difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported.  These events occurred as early as 
within 15 minutes of drug administration. 
7 DRUG INTERACTIONS 
7.1 Effects of XIFAXAN on Other Drugs 
Substrates of Cytochrome P450 enzymes 
Rifaximin is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 in 
clinical use based on in vitro studies [see Clinical Pharmacology (12.3)]. 
An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in 
patients with normal liver function, XIFAXAN at the recommended dosing regimen is not expected to induce CYP3A4.  
It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates 
in patients with reduced liver function who have elevated rifaximin concentrations. 
7.2 Effects of Other Drugs on XIFAXAN 
In vitro studies suggested that rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1 and OATP1B3.  
Concomitant cyclosporine, an inhibitor of P-glycoprotein and OATPs significantly increased the systemic exposure to 
rifaximin.  
Cyclosporine  
Co-administration of cyclosporine, with XIFAXAN resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and 
AUC∞ in healthy subjects.  The clinical significance of this increase in systemic exposure is unknown [see Warnings and 
Precautions (5.4), Clinical Pharmacology (12.3)]. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary 
There are no available data on XIFAXAN use in pregnant women to inform any drug associated risks.  Teratogenic 
effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits 
during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human 
doses of 600 mg to 1650 mg per day.  In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations 
were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body 
weight gain [see Data]. In the U.S. general population, the estimated background risk of major birth defects and 
6 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the 
potential risk to a fetus. 
Data 
Animal Data 
Rifaximin was teratogenic in rats at doses of 150 to 300 mg/kg (approximately 2.5 to 5 times the recommended dose for 
TD [600 mg per day], and approximately 1.3 to 2.6 times the recommended dose for HE [1100 mg per day], and 
approximately 0.9 to 1.8 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). 
Rifaximin was teratogenic in rabbits at doses of 62.5 to 1000 mg/kg (approximately 2 to 33 times the recommended dose 
for TD [600 mg per day], and approximately 1.1 to 18 times the recommended dose for HE [1100 mg per day], and 
approximately 0.7 to 12 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). These 
effects include cleft palate, agnathia, jaw shortening, hemorrhage, eye partially open, small eyes, brachygnathia, 
incomplete ossification, and increased thoracolumbar vertebrae. 
A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development 
at oral doses of rifaximin up to 300 mg/kg per day (approximately 5 times the recommended dose for TD [600 mg per 
day], and approximately 2.6 times the recommended dose for HE [1100 mg per day], and approximately 1.8 times the 
recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). 
8.2 Lactation 
Risk Summary 
There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, 
or the effects of rifaximin on milk production.  The development and health benefits of breastfeeding should be 
considered along with the mother’s clinical need for XIFAXAN and any potential adverse effects on the breastfed infant 
from XIFAXAN or from the underlying maternal condition. 
8.4 Pediatric Use 
The safety and effectiveness of XIFAXAN has not been established in pediatric patients less than 12 years of age with TD 
or in patients less than 18 years of age for HE and IBS-D.   
8.5 Geriatric Use 
Of the total number of patients in the clinical study of XIFAXAN for HE, 19% of patients were 65 and over, while 2% 
were 75 and over. In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over.  No 
overall differences in safety or effectiveness were observed between these subjects and younger subjects for either 
indication. Clinical studies with XIFAXAN for TD did not include sufficient numbers of patients aged 65 and over to 
determine whether they respond differently than younger subjects.  Other reported clinical experience has not identified 
differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot 
be ruled out. 
8.6 Renal Impairment 
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. 
8.7 Hepatic Impairment 
Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the 
systemic exposure (i.e., AUCτ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-
7 


 
 
 
 
 
 
 
Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively, 
compared to that in healthy volunteers.  No dosage adjustment is recommended because rifaximin is presumably acting 
locally.  Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic 
impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. 
10 OVERDOSAGE 
No specific information is available on the treatment of overdosage with XIFAXAN.  In clinical studies at doses higher 
than the recommended dose (greater than 600 mg per day for TD, greater than 1100 mg per day for HE or greater than 
1650 mg per day for IBS-D), adverse reactions were similar in subjects who received doses higher than the recommended 
dose and placebo. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive 
measures as required. 
11 DESCRIPTION 
XIFAXAN tablets contain rifaximin, a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin 
SV. Rifaximin is a structural analog of rifampin.  The chemical name for rifaximin is 
(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-
octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidazole-1,15(2H)-dione,25-
acetate. The empirical formula is C43H51N3O11 and its molecular weight is 785.9.  The chemical structure is represented 
below: 
XIFAXAN tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin.   
Inactive ingredients:  
Each 200 mg tablet contains colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose,  
microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide.  
Each 550 mg tablet contains colloidal silicon dioxide, glycerol palmitostearate, microcrystalline cellulose, polyethylene  
glycol/macrogol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide.  
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Rifaximin is an antibacterial drug [see Clinical Pharmacology (12.4)]. 
8 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
12.3 Pharmacokinetics 
Absorption 
In healthy subjects, the mean time to reach peak rifaximin plasma concentrations was about an hour and the mean Cmax 
ranged 2.4 to 4 ng/mL after a single dose and multiple doses of XIFAXAN 550 mg. 
Travelers’ Diarrhea 
Systemic absorption of XIFAXAN (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on 
Days 1 and 3 of a three-day course of treatment.  Rifaximin plasma concentrations and exposures were low and variable. 
There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses).  Peak plasma 
rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL 
on Day 3. Similarly, AUC0-last estimates were 6.95 ± 5.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day 3. 
XIFAXAN is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral 
administration [see Warnings and Precautions (5.1)]. 
Hepatic Encephalopathy 
Mean rifaximin exposure (AUCτ) in patients with a history of HE was approximately 12-fold higher than that observed in 
healthy subjects.  Among patients with a history of HE, the mean AUC in patients with Child-Pugh Class C hepatic 
impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment [see Warnings and 
Precautions (5.4) and Use in Specific Populations (8.7)]. 
Irritable Bowel Syndrome with Diarrhea 
In patients with irritable bowel syndrome with diarrhea (IBS-D) treated with XIFAXAN 550 mg three times a day for 14 
days, the median Tmax was 1 hour and mean Cmax and AUC were generally comparable with those in healthy subjects.  
After multiple doses, AUCtau was 1.65-fold higher than that on Day 1 in IBS-D patients (Table 2). 
Table 2. Mean (± SD) Pharmacokinetic Parameters of Rifaximin Following XIFAXAN 550 mg Three 
Times a Day in IBS-D Patients and Healthy Subjects 
Healthy Subjects 
IBS-D Patients 
Single-Dose 
(Day 1) 
n=12 
Multiple-Dose 
(Day 14) 
n=14 
Single-Dose 
(Day 1) 
n=24 
Multiple-Dose 
(Day 14) 
n=24 
Cmax (ng/mL) 
4.04 (1.51) 
2.39 (1.28) 
3.49 (1.36) 
4.22 (2.66) 
Tmax (h)1 
0.75 (0.5-2.1) 
1.00 (0.5-2.0) 
0.78 (0-2) 
1.00 (0.5-2) 
AUCtau (ng•h/mL) 
10.4 (3.47) 
9.30 (2.7) 
9.69 (4.16) 
16.0 (9.59) 
Half-life (h) 
1.83 (1.38) 
5.63 (5.27) 
3.14 (1.71) 
6.08 (1.68) 
1. Median (range) 
Food Effect in Healthy Subjects 
A high-fat meal consumed 30 minutes prior to XIFAXAN dosing in healthy subjects delayed the mean time to peak 
plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold but did 
not significantly affect Cmax. 
Distribution 
Rifaximin is moderately bound to human plasma proteins.  In vivo, the mean protein binding ratio was 67.5% in healthy 
subjects and 62% in patients with hepatic impairment when XIFAXAN was administered. 
9 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elimination  
The mean half-life of rifaximin in healthy subjects at steady-state was 5.6 hours and was 6 hours in IBS-D patients.   
Metabolism: 
In an in vitro study rifaximin was metabolized mainly by CYP3A4.  Rifaximin accounted for 18% of radioactivity in 
plasma suggesting that the absorbed rifaximin undergoes extensive metabolism. 
Excretion: 
In a mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total 
recovery, 96.62% of the administered radioactivity was recovered in feces mostly as the unchanged drug and 0.32% was 
recovered in urine mostly as metabolites with 0.03% as the unchanged drug. 
Biliary excretion of rifaximin was suggested by a separate study in which rifaximin was detected in the bile after 
cholecystectomy in patients with intact gastrointestinal mucosa. 
Specific Populations 
Hepatic Impairment 
The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy 
subjects. 
The pharmacokinetics of rifaximin in patients with a history of HE was evaluated after administration of XIFAXAN 550 
mg twice a day. The pharmacokinetic parameters were associated with a high variability and mean rifaximin exposure 
(AUCτ) in patients with a history of HE was higher compared to those in healthy subjects.  The mean AUCτ  in patients 
with hepatic impairment of Child-Pugh Class A, B, and C was 10-, 14-, and 21-fold higher, respectively, compared to that 
in healthy subjects (Table 3). 
Table 3. Mean (± SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with a 
History of Hepatic Encephalopathy by Child-Pugh Class1 
Healthy 
Subjects 
(n=14) 
Child-Pugh Class 
A (n=18) 
B (n=15) 
C (n=6) 
AUCtau 
(ng•h/mL) 
12.3 ± 4.8 
118 ± 67.8 
169 ± 55.7 
257 ± 100.2 
Cmax 
(ng/mL) 
3.4 ± 1.6 
19.5 ± 11.4 
25.4 ± 11.9 
39.7 ± 13.4 
Tmax 
2 
(h) 
0.8 (0.5, 4.0) 
1 (0.9, 10) 
1 (1.0, 4.2) 
1 (0, 2) 
1. Cross-study comparison with pharmacokinetic parameters in healthy subjects 
2. Median (range) 
Renal Impairment 
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. 
Drug Interaction Studies 
Effect of other drugs on rifaximin 
10 


 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An in vitro study suggests that rifaximin is a substrate of CYP3A4. 
In vitro rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1, and OATP1B3.  Rifaximin is not a substrate of 
OATP2B1. 
Cyclosporine 
In vitro in the presence of P-glycoprotein inhibitor, verapamil, the efflux ratio of rifaximin was reduced greater than 50%.  
In a clinical drug interaction study, mean Cmax for rifaximin was increased 83-fold, from 0.48 to 40.0 ng/mL; mean AUC∞ 
was increased 124-fold, from 2.54 to 314 ng●h/mL following co-administration of a single dose of XIFAXAN 550 mg 
with a single 600 mg dose of cyclosporine, an inhibitor of P-glycoprotein [see Drug Interactions (7.2)]. 
Cyclosporine is also an inhibitor of OATP, breast cancer resistance protein (BCRP) and a weak inhibitor of CYP3A4.  
The relative contribution of inhibition of each transporter by cyclosporine to the increase in rifaximin exposure is 
unknown. 
Effect of rifaximin on other drugs 
In in vitro drug interaction studies the IC50 values for rifaximin was >50 micromolar (~60 mcg) for CYP isoforms 1A2, 
2A6, 2B6, 2C9, 2C19, 2D6, and 2E1.  In vitro IC50 value of rifaximin for CYP3A4 was 25 micromolar.  Based on in vitro 
studies, clinically significant drug interaction via inhibition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 by 
rifaximin is not expected. 
The inhibitory effect of rifaximin on P-glycoprotein transport was observed in an in vitro study.  The effect of rifaximin 
on P-gp transporter was not evaluated in vivo. 
In in vitro studies, rifaximin at 3 micromolar inhibited the uptake of estradiol glucuronide via OATP1B1 by 64% and via 
OATP1B3 by 70% while the uptake of estrone sulfate via OATP1A2 was inhibited by 40%.  The inhibitory potential of 
rifaximin on these transporters at the clinically relevant concentrations is unknown. 
Midazolam 
In an in vitro study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 micromolar.  No significant 
induction of CYP3A4 enzyme using midazolam as a substrate was observed when rifaximin was administered three times 
a day for 7 days at 200 mg and 550 mg doses in two clinical drug interaction studies in healthy subjects. 
The effect of XIFAXAN 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a 
single dose of either 2 mg intravenous midazolam or 6 mg oral midazolam was evaluated in healthy subjects. No 
significant difference was observed in the systemic exposure or elimination of intravenous or oral midazolam or its major 
metabolite, 1’-hydroxymidazolam, between midazolam alone or together with XIFAXAN.  Therefore, XIFAXAN was not 
shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times a day dosing regimen. 
When single dose of 2 mg midazolam was orally administered after administration of XIFAXAN 550 mg three times a 
day for 7 days and 14 days to healthy subjects, the mean AUC of midazolam was 3.8% and 8.8% lower, respectively, than 
when midazolam was administered alone.  The mean Cmax of midazolam was lower by 4 to 5% when XIFAXAN was 
administered for 7-14 days prior to midazolam administration.  This degree of interaction is not considered clinically 
meaningful. 
Oral Contraceptives Containing Ethinyl Estradiol and Norgestimate 
The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if 
XIFAXAN 200 mg orally administered three times a day for 3 days (the dosing regimen for travelers’ diarrhea) altered the 
11 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.5 mg norgestimate.  
Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by 
XIFAXAN. 
An open-label oral contraceptive study was conducted in 39 healthy female subjects to determine if XIFAXAN 550 mg 
orally administered three times a day for 7 days altered the pharmacokinetics of a single dose of an oral contraceptive 
containing 0.025 mg of ethinyl estradiol (EE) and 0.25 mg norgestimate (NGM).  Mean Cmax of EE and NGM was lower 
by 25% and 13%, after the 7-day XIFAXAN regimen than when the oral contraceptive was given alone. The mean AUC 
values of NGM active metabolites were lower by 7% to approximately 11%, while AUC of EE was not altered in 
presence of rifaximin. The clinical relevance of the Cmax and AUC reductions in the presence of rifaximin is not known. 
12.4 Microbiology 
Mechanism of Action 
Rifaximin is a semi-synthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent 
RNA polymerase blocking one of the steps in transcription.  This results in inhibition of bacterial protein synthesis and 
consequently inhibits the growth of bacteria.  
Drug Resistance and Cross-Resistance 
Resistance to rifaximin is caused primarily by mutations in the rpoB gene. This changes the binding site on DNA 
dependent RNA polymerase and decreases rifaximin binding affinity, thereby reducing efficacy. Cross-resistance between 
rifaximin and other classes of antimicrobials has not been observed.   
Antibacterial Activity 
Rifaximin has been shown to be active against the following pathogens both in vitro and in clinical studies of infectious 
diarrhea as described in the Indications and Usage (1.1) section: 
Escherichia coli (enterotoxigenic and enteroaggregative strains). 
Susceptibility Tests 
In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI).1,2,3 
However, the correlation between susceptibility testing and clinical outcome has not been determined. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by 
oral gavage for two years at 150 to 250 mg/kg per day (doses equivalent to 2.4 to 4 times the recommended dose of 200 
mg three times daily for TD, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for HE, 
based on relative body surface area comparisons).  There was no increase in tumors in Tg.rasH2 mice dosed orally with 
rifaximin for 26 weeks at 150 to 2000 mg/kg per day (doses equivalent to 1.2 to 16 times the recommended daily dose for 
TD and equivalent to 0.7 to 9 times the recommended daily dose for HE, based on relative body surface area 
comparisons). 
Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow 
micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay.  There was no 
effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 
12 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
5 times the clinical dose of 600 mg per day for TD, and approximately 2.6 times the clinical dose of 1100 mg per day for 
HE, adjusted for body surface area).  
14 CLINICAL STUDIES 
14.1 Travelers’ Diarrhea 
The efficacy of XIFAXAN given as 200 mg orally taken three times a day for 3 days was evaluated in 2 randomized, 
multi-center, double-blind, placebo-controlled studies in adult subjects with travelers’ diarrhea.  One study was conducted 
at clinical sites in Mexico, Guatemala, and Kenya (Study 1).  The other study was conducted in Mexico, Guatemala, Peru, 
and India (Study 2).  Stool specimens were collected before treatment and 1 to 3 days following the end of treatment to 
identify enteric pathogens.  The predominant pathogen in both studies was Escherichia coli. 
The clinical efficacy of XIFAXAN was assessed by the time to return to normal, formed stools and resolution of 
symptoms.  The primary efficacy endpoint was time to last unformed stool (TLUS) which was defined as the time to the 
last unformed stool passed, after which clinical cure was declared.  Table 4 displays the median TLUS and the number of 
patients who achieved clinical cure for the intent to treat (ITT) population of Study 1.  The duration of diarrhea was 
significantly shorter in patients treated with XIFAXAN than in the placebo group. More patients treated with XIFAXAN 
were classified as clinical cures than were those in the placebo group. 
Table 4. Clinical Response in Study 1 (ITT population)  
XIFAXAN 
(n=125) 
Placebo 
(n=129) 
Estimate 
(97.5% CI) 
Median TLUS 
(hours) 
32.5 
58.6 
21 
(1.26, 2.50) 
Clinical cure, 
n (%) 
99 (79) 
78 (60) 
192 
(5.3, 32.1) 
1. Hazard Ratio (p-value <0.001) 
2. Difference in rates (p-value <0.01) 
Microbiological eradication (defined as the absence of a baseline pathogen in culture of stool after 72 hours of therapy) 
rates for Study 1 are presented in Table 5 for patients with any pathogen at baseline and for the subset of patients with 
Escherichia coli at baseline. Escherichia coli was the only pathogen with sufficient numbers to allow comparisons 
between treatment groups. 
Even though XIFAXAN had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in 
duration of diarrhea and a higher clinical cure rate than placebo.  Therefore, patients should be managed based on clinical 
response to therapy rather than microbiologic response. 
Table 5. Microbiologic Eradication Rates in Study 1 Subjects with a Baseline Pathogen 
XIFAXAN 
Placebo 
Overall 
48/70 (69) 
41/61 (67) 
E. coli 
38/53 (72) 
40/54 (74) 
The results of Study 2 supported the results presented for Study 1. In addition, this study provided evidence that subjects 
treated with XIFAXAN with fever and/or blood in the stool at baseline had prolonged TLUS.  These subjects had lower 
clinical cure rates than those without fever or blood in the stool at baseline.  Many of the patients with fever and/or blood 
in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily Campylobacter jejuni, isolated in the 
baseline stool. 
13 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Also in this study, the majority of the subjects treated with XIFAXAN who had Campylobacter jejuni isolated as a sole 
pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17).  In addition 
to not being different from placebo, the microbiologic eradication rates for subjects with Campylobacter jejuni isolated at 
baseline were much lower than the eradication rates seen for Escherichia coli. 
In an unrelated open-label, pharmacokinetic study of oral XIFAXAN 200 mg taken every 8 hours for 3 days, 15 adult 
subjects were challenged with Shigella flexneri 2a, of whom 13 developed diarrhea or dysentery and were treated with 
XIFAXAN. Although this open-label challenge trial was not adequate to assess the effectiveness of XIFAXAN in the 
treatment of shigellosis, the following observations were noted: eight subjects received rescue treatment with 
ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours (2), or because they developed 
severe dysentery (5), or because of recurrence of Shigella flexneri in the stool (1); five of the 13 subjects received 
ciprofloxacin although they did not have evidence of severe disease or relapse. 
14.2 Hepatic Encephalopathy 
The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, 
double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada and Russia who were defined as being in 
remission (Conn score of 0 or 1) from hepatic encephalopathy (HE).  Eligible subjects had ≥2 episodes of HE associated 
with chronic liver disease in the previous 6 months.    
A total of 299 subjects were randomized to receive either XIFAXAN (n=140) or placebo (n=159) in this study.  Patients 
had a mean age of 56 years (range, 21-82 years), 81% <65 years of age, 61% were male and 86% White.  At baseline, 
67% of patients had a Conn score of 0 and 68% had an asterixis grade of 0.  Patients had MELD scores of either <10 
(27%) or 11 to 18 (64%) at baseline. No patients were enrolled with a MELD score of >25.  Nine percent of the patients 
were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. 
Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode.  Other 
reasons for early study discontinuation included: adverse reactions (XIFAXAN 6%; placebo 4%), patient request to 
withdraw (XIFAXAN 4%; placebo 6%) and other (XIFAXAN 7%; placebo 5%).    
The primary endpoint was the time to first breakthrough overt HE episode.  A breakthrough overt HE episode was defined 
as a marked deterioration in neurological function and an increase of Conn score to Grade ≥2. In patients with a baseline 
Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1.  
Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 
subjects (46%) in the placebo group during the 6-month treatment period.  Comparison of Kaplan-Meier estimates of 
event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month 
treatment period.  Presented below in Figure 1 is the Kaplan-Meier event-free curve for all subjects (n=299) in the study. 
14 


 
 
 
 
 
 
 
 graph
Figure 1 Kaplan-Meier Event-Free Curves1 in HE Study (Time to First Breakthrough-HE Episode up to 6 
Months of Treatment, Day 170) (ITT Population)  
Note: Open diamonds and open triangles represent censored subjects. 
1Event-free refers to non-occurrence of breakthrough HE. 
When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of 
XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, 
duration of current remission and diabetes. The differences in treatment effect could not be assessed in the following 
subpopulations due to small sample size: non-White (n=42), baseline MELD >19 (n=26), Child-Pugh Class C (n=31), and 
those without concomitant lactulose use (n=26).  
HE-related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were 
reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%) in the XIFAXAN and placebo groups respectively. 
Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE-
related hospitalizations by 50% during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free 
curves is shown in Figure 2. 
15 


 
 
 
 
 
 
 graph
Figure 2 Kaplan-Meier Event-Free Curves1 in Pivotal HE Study (Time to First HE-Related  
Hospitalization in HE Study up to 6 Months of Treatment, Day 170) (ITT Population)   
Note: Open diamonds and open triangles represent censored subjects. 
1Event-free refers to non-occurrence HE-related hospitalization. 
14.3 Irritable Bowel Syndrome with Diarrhea 
The efficacy of XIFAXAN for the treatment of IBS-D was established in 3 randomized, multi-center, double-blind, 
placebo-controlled trials in adult patients.  
Trials 1 and 2 – Design 
The first two trials, Trials 1 and 2 were of identical design.  In these trials, a total of 1258 patients meeting Rome II 
criteria for IBS* were randomized to receive XIFAXAN 550 mg three times a day (n=624) or placebo (n=634) for 14 
days and then followed for a 10-week treatment-free period.  The Rome II criteria further categorizes IBS patients into 3 
subtypes: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or alternating IBS (bowel habits 
alternating between diarrhea and constipation). Patients with both IBS-D and alternating IBS were included in Trials 1 
and 2. XIFAXAN is recommended for use in patients with IBS-D. 
*Rome II Criteria: At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort 
or pain that has two out of three features: 1. Relieved with defecation; and/or 2. Onset associated with a change in 
frequency of stool; and/or 3. Onset associated with a change in form (appearance) of stool. 
Symptoms that Cumulatively Support the Diagnosis of Irritable Bowel Syndrome: 
– Abnormal stool frequency (for research purposes “abnormal” may be defined as greater than 3 bowel movements per 
day and less than 3 bowel movements per week); Abnormal stool form (lumpy/hard or loose/watery stool); Abnormal 
stool passage (straining, urgency, or feeling of incomplete evacuation); Passage of mucus; Bloating or feeling of 
abdominal distension. 
16 


 
 
 
 
 
 
 
 
 
 
 
Trial 3 - Design 
Trial 3 evaluated repeat treatment in adults with IBS-D meeting Rome III criteria** for up to 46 weeks. A total of 2579 
were enrolled to receive open-label XIFAXAN for 14 days. Of 2438 evaluable patients, 1074 (44%) responded to initial 
treatment and were evaluated over 22 weeks for continued response or recurrence of IBS-symptoms. A total of 636 
patients had symptom recurrence and were randomized into the double-blind phase of the study. These patients were 
scheduled to receive XIFAXAN 550 mg three times a day (n=328) or placebo (n=308) for two additional 14-day repeat 
treatments courses separated by 10 weeks.  See Figure 3. 
Figure 3 Trial 3 Study Design  
The IBS-D population from the three studies had mean age of 47 (range: 18 to 88) years of which approximately 11% of 
patients were ≥65 years old, 72% were female and 88% were White. 
**Rome III Criteria: Recurrent abdominal pain or discomfort (uncomfortable sensation not described as pain) at least 3 
days/month in last 3 months associated with two or more of the following: 1. Improvement with defecation; 2. Onset 
associated with a change in frequency of stool; 3. Onset associated with a change in form (appearance) of stool. 
Trials 1 and 2 - Results 
Trials 1 and 2 included 1258 IBS-D patients (309 XIFAXAN, 314 placebo); (315 XIFAXAN, 320 placebo). The primary 
endpoint for both trials was the proportion of patients who achieved adequate relief of IBS signs and symptoms for at least 
2 of 4 weeks during the month following 14 days of treatment.  Adequate relief was defined as a response of “yes” to the 
following weekly Subject Global Assessment (SGA) question: “In regards to your IBS symptoms, compared to the way 
you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? 
[Yes/No].” 
17 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adequate relief of IBS symptoms was experienced by more patients receiving XIFAXAN than those receiving placebo 
during the month following 2 weeks of treatment (SGA-IBS Weekly Results: 41% vs. 31%, p=0.0125; 41% vs. 32%, 
p=0.0263 (See Table 6). 
Table 6. Adequate Relief of IBS Symptoms During the Month Following Two Weeks of Treatment 
Trial 1 
Trial 2 
XIFAXAN 
Placebo 
Treatment 
XIFAXAN 
Placebo 
Treatment 
n=309 
n=314 
Difference 
n=315 
n=320 
Difference 
Endpoint 
n (%) 
n (%) 
(95% CI1) 
n (%) 
n (%) 
(95% CI1) 
Adequate 
Relief of IBS 
Symptoms2 
126 (41) 
98 (31) 
10% 
(2.1%, 17.1%) 
128 (41) 
103 (32) 
8% 
(1.0%, 15.9%) 
1. Confidence Interval 
2. The p-value for the primary endpoint for Trial 1 and for Trial 2 was <0.05. 
The trials examined a composite endpoint which defined responders by IBS-related abdominal pain and stool consistency 
measures. Patients were monthly responders if they met both of the following criteria:  
• 
experienced a ≥30% decrease from baseline in abdominal pain for ≥2 weeks during the month following 2 weeks 
of treatment 
• 
had a weekly mean stool consistency score <4 (loose stool) for ≥2 weeks during the month following 2 weeks of 
treatment   
More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in Trials 1 and 2. 
(see Table 7). 
Table 7. Efficacy Responder Rates in Trial 1 and 2 During the Month Following Two Weeks of 
Treatment 
Trial 1 
Trial 2 
XIFAXAN 
Placebo 
Treatment 
XIFAXAN 
Placebo 
Treatment 
n=309 
n=314 
Difference 
n=315 
n=320 
Difference 
Endpoint 
n (%) 
n (%) 
(95% CI1) 
n (%) 
n (%) 
(95% CI1) 
Abdominal 
Pain and Stool 
Consistency 
Responders2 
144 (47) 
121 (39) 
8% 
(0.3%, 15.9%) 
147 (47) 
116 (36) 
11%
 (2.7%, 18.0%) 
Abdominal 
Pain 
Responders 
159 (51) 
132 (42) 
9%
 (1.8%, 17.5%) 
165 (52) 
138 (43) 
9% 
(1.5%, 17.0%) 
Stool 
Consistency 
Responders 
244 (79) 
212 (68) 
11% 
(4.4%, 18.2%) 
233 (74) 
206 (64) 
10%
 (2.3%, 16.7%) 
1. Confidence Interval 
2. The p-value for the composite endpoint for Trial 1 and 2 was <0.05 and <0.01, respectively. 
Trial 3 - Results 
In TARGET 3, 2579 patients were scheduled to receive an initial 14-day course of open-label XIFAXAN followed by 4 
weeks of treatment-free follow-up.  At the end of the follow-up period, patients were assessed for response to treatment.  
Patients were considered a responder if they achieved both of the following: 
18 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
•   ≥3 0 % i m pr o ve me nt fr o m b aseli ne i n t he wee kl y a vera ge a b d o mi nal pai n sc ore base d o n t he dail y q uesti o n: “I n 
re g ar ds t o y o ur s pecific I B S sy m pt o ms of a b d o mi n al p ai n, o n a sc ale of 0- 1 0, w h at w as y o ur w orst I B S-rel ate d 
a b d o mi n al p ai n over t he l ast 2 4 h o urs ? ‘ Zer o’ me a ns y o u h ave n o p ai n at all; ‘ Te n’ me a ns t he w orst p ossi ble 
p ai n y o u c a n i m a gi ne ”. 
•   at least a 5 0 % re d ucti o n i n t he n u m ber of da ys i n a wee k w it h a dail y st o ol c o nsiste nc y of Brist ol St o ol Scale t y pe 
6 or 7 c o m pare d wit h baseli ne w here 6 =fl uff y pieces wit h  ra g ge d e d ges, a m us h y st o ol; 7 = water y st o ol, n o s oli d 
pieces; e ntirel y li q ui d. 
Res p o n ders were t he n f oll o we d f or rec urre nce of t heir I B S-relate d s y m pt o ms of a b d o mi nal pai n or  m us h y/ water y st o ol 
c o nsiste nc y f or u p t o 2 0 treat me nt-free wee ks. 
W he n patie nts e x perie nce d rec urre nce of  t heir s y m pt o ms of a b d o mi nal pai n or  m us h y/ water y st o ol c o nsiste nc y f or 3 
wee ks of a r olli n g 4- wee k peri o d, t he y were ra n d o mi ze d i nt o t he d o u ble- bli n d, place b o-c o ntr olle d re peat treat me nt p hase. 
Of 1 0 7 4 patie nts w h o res p o n de d t o o pe n- la bel XI F A X A N, 3 8 2 e x perie nce d a peri o d of s y m pt o m i nacti vit y or decrease 
t hat di d n ot re q uire re peat treat me nt b y t he ti me t he y disco nti n ue d, i ncl u di n g patie nts w h o c o m plete d t he 2 2 wee ks after 
i nitial treat me nt wit h XI F A X A N. See Fi g ure 3. 
O verall, 1 2 5 7 of 2 5 7 9 patie nts ( 4 9 %) were n o nres p o n ders i n t he o pe n-la bel p h ase a n d per t he st u d y pr ot oc ol were 
wit h dra w n fr o m t he st u d y.  Ot her reas o ns f or disc o nti n uati o n i ncl u de: patie nt re q uest ( 5 %), patie nt l ost t o f oll o w- u p ( 4 %), 
a d verse reacti o n ( 3 %), a n d ot her ( 0. 8 %). 
T here were 1 0 7 4 ( 4 4 %) of 2 4 3 8 e val ua bl e patie nts w h o res p o n de d t o i nitial treat me nt wit h i m pr o ve me nt i n a b d o mi nal 
pai n a n d  st o ol c o nsiste nc y. T he res p o nse rate f or eac h I B S s y m pt o m d uri n g t he o pe n-la bel p hase of Trial 3 is si milar t o 
t he rates see n i n Trials 1 a n d 2 (see Ta ble 7).  A t otal of 6 3 6 patie nts s u bse q ue ntl y ha d si g n a n d s y m pt o m rec urre nce a n d 
were ra n d o mize d t o t he re peat treat me nt p hase.  T he me di a n ti me t o rec urre nce f or patie nts w h o e x perie nce d i nitial 
res p o nse d uri n g t he o pe n-la bel p hase wit h XI FA X A N was 1 0 wee ks (ra n ge 6 t o 2 4 wee ks).   
T he XI F A X A N a n d place b o treat me nt gr o u ps ha d si milar base li n e I B S s y m pt o m sc ores at t he ti me of rec urre nce a n d 
ra n d o mizati o n t o t he d o u ble- bli n d p hase, b ut s y m pt o m sc ores were less se vere t ha n at st u d y e ntr y i nt o t he o pe n-la bel 
p hase. 
Patie nts were dee me d t o ha ve rec urre nt si g ns a n d s y m pt o ms b y t he f oll o wi n g criteria: a ret ur n of a b d o mi nal pai n or lac k 
of st o ol c o nsiste nc y f or at least 3 wee ks d uri n g a 4- wee k f oll o w- u p peri o d. T he pri mar y e n d p oi nt i n t he d o u ble- bli n d, 
place b o-c o ntr olle d p orti o n of t he trial was t he pr o p orti o n of patie nts w h o were res p o n ders t o re peat treat me nt i n b ot h I B S-
relate d a b d o mi nal pai n a n d  st o ol c o nsiste nc y as defi ne d a b o ve d uri n g t he 4 wee ks f oll o wi n g t he first re peat treat me nt wit h 
XI F A X A N. T he pri mar y a nal ysis was perf or me d usi n g t he w o rst case a nal ysis met h o d w here patie nts wit h < 4 da ys of 
diar y e ntries i n a gi ve n wee k are c o nsi dere d as n o n-res p o n ders f or t hat wee k. 
M ore patie nts recei vi n g XI F A X A N were m o nt hl y res p o n ders f or a b d o mi nal pai n a n d st o ol c o nsiste nc y i n t he pri mar y 
a nal ysis i n Trial 3 (see Ta ble 8). 
1 9 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 8. Efficacy Responder Rates in Trial 3 in a Given Week for at Least 2 Weeks During Weeks 3 to 6 
of the Double-Blind, First Repeat Treatment Phase 
Placebo 
(n=308) 
n (%) 
XIFAXAN
 (n=328) 
n (%) 
Treatment 
Difference 
(95% CI1) 
Combined Responder2: 
Abdominal Pain and Stool 
Consistency Responders3 
97 (31) 
125 (38) 
7% 
(0.9%, 16.9%) 
Abdominal Pain Responders 
(>30% reduction in 
abdominal pain) 
130 (42) 
166 (51) 
9% 
(1.6%, 17.0%) 
Stool Consistency 
Responders (>50% reduction 
from baseline in days/week 
with loose or watery stools) 
154 (50) 
170 (52) 
2% 
(-4.7%, 11.0%) 
1. Confidence Intervals were derived based on CMH test adjusting for center and patients’ time to recurrence during  
maintenance phase.  
2. Primary endpoint 
3. Subjects were IBS-related abdominal pain and stool consistency responders if they were both weekly IBS-related abdominal 
pain responders and weekly stool consistency responders in a given week for at least 2 weeks during Weeks 3 to 6 in the 
double-blind first repeat treatment phase. Weekly responder in IBS-related abdominal pain was defined as a 30% or greater 
improvement from baseline in the weekly average abdominal pain score. Weekly responder in stool consistency was defined 
as a 50% or greater reduction in the number of days in a week with stool consistency of type 6 or 7 compared with baseline. 
The p-value for this composite endpoint was <0.05. 
Thirty six of 308 (11.7%) of placebo patients and 56 of 328 (17.1%) of XIFAXAN-treated patients responded to the first 
repeat treatment and did not have recurrence of signs and symptoms through the treatment-free follow-up period (10 
weeks after first repeat treatment).  The response rate difference was 5.4% with 95% confidence interval (1.2% to 11.6%). 
15 REFERENCES 
• 
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 
Ninth Edition. CLSI document M07-A9. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 
• 
Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. 
CLSI document M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. 
• 
Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement. CLSI 
document M100-S2. Wayne, PA: Clinical and Laboratory Standards Institute, 2014. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
The 200 mg tablet is a pink-colored, round, biconvex tablet with “Sx” debossed on one side.  It is available in the 
following presentation: 
• 
NDC 65649-301-03, bottles of 30 tablets 
The 550 mg tablet is a pink-colored, oval, biconvex tablet with “rfx” debossed on one side.  It is available in the following 
presentations: 
• 
NDC 65649-303-02, bottles of 60 tablets    
• 
NDC 65649-303-03, carton of 60 tablets, Unit Dose  
• 
NDC 65649-303-04, carton of 42 tablets, Unit Dose  
20 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Storage 
Store XIFAXAN Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP 
Controlled Room Temperature]. 
17 PATIENT COUNSELING INFORMATION 
Persistent Diarrhea 
For those patients being treated for travelers’ diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours 
or worsens. Advise the patient to seek medical care for fever and/or blood in the stool [see Warnings and Precautions 
(5.1)]. 
Clostridium difficile-Associated Diarrhea 
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including 
XIFAXAN, and may range in severity from mild diarrhea to fatal colitis.  Treatment with antibiotics alters the normal 
flora of the colon which may lead to C. difficile. Patients can develop watery and bloody stools (with or without stomach 
cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.  If diarrhea occurs 
after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible 
[see Warnings and Precautions (5.4)]. 
Administration with Food 
Inform patients that XIFAXAN may be taken with or without food. 
Antibacterial Resistance 
Counsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections.  They do 
not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat a bacterial infection, patients 
should be told that although it is common to feel better early in the course of therapy, the medication should be taken 
exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the 
immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by 
XIFAXAN or other antibacterial drugs in the future. 
Severe Hepatic Impairment 
Inform patients with severe hepatic impairment (Child-Pugh Class C) that there is an increase in systemic exposure to  
XIFAXAN [see Warnings and Precautions (5.4)].  
Manufactured for:  
Salix Pharmaceuticals, Inc.  
Raleigh, NC 27615  
By:  
Patheon  
Whitby, Ontario L1N 5Z5, Canada  
XIFAXAN® is a trademark of Alfa Wassermann S.p.A., used under license by Salix Pharmaceuticals, Inc.  
21 


 
 
 
 
  
 
 
 
  
 
 
 
 
Copyright © Salix Pharmaceuticals, Inc.  
Rifaximin for Travelers’ Diarrhea, Hepatic encephalopathy and IBS are protected by US Patent Nos. 7,045,620;  
7,612,199; 7,902,206; 7,906,542; 8,158,781; 8,158,644; 8,193,196; 8,518,949; 8,741,904; 8,835,452; and 8,853,231.  
Rifaximin for Travelers’ Diarrhea is also protected by US Patent No. 7,928,115. Rifaximin for Hepatic encephalopathy is  
also protected by US Patent No. 8,642,573; 8,829,017; 8,946,252; and 8,969,398. Rifaximin for IBS is also protected by  
US Patent Nos. 6,861,053; 7,452,857; 7,718,608; and 8,309,569.  
Web site: www.Salix.com  
All rights reserved.  
9457401  
Rev. 05/2015  
22 


Protocol No. 1526 RIF_2 
Sandoz GmbH 
CONFIDENTIAL 
rifaximin 200 mg 
 
 
 
Version 2.0, October 29, 2015 
Page 90 of 90 
 
Appendix II Commonly Used Medications, with Antimuscarinic Effects 
Commonly Used Medications With Antimuscarinic Effects♦ 
Antibiotics 
Antihistamines 
Cardiovascular 
CNS 
GI 
Immunosuppressants 
Respiratory 
Ampicillin 
Diphenhydramine 
Captopril 
Alprazolam 
Atropine 
Azathioprine 
Ipratropium 
Piperacillin 
Hydroxyzine 
Digoxin 
Chlordiazepoxide 
Cimetidine 
Cyclosporine 
Theophylline 
Cefalothin 
 
Diltiazem 
Diazepam 
Ranitidine 
Dexamethasone 
Tiotropium 
Cefoxitin 
 
Furosemide 
Flurazepam 
 
Hydrocortisone 
 
Clindamycin 
 
Hydrochlorothiazide 
Oxazepam 
 
Prednisolone 
 
Gentamicin 
 
Hydralazine 
Codeine 
 
 
 
Tobramycin 
 
Methyldopa 
Oxycodone 
 
 
 
Vancomycin 
 
Nifedipine 
Tricyclic 
Antidepressants 
 
 
 
 
 
Triamterene 
Phenelzine 
 
 
 
 
 
Warfarin 
Phenobarbital 
 
 
 
 
 
 
Chlorpromazine 
 
 
 
 
 
 
Olanzapine 
 
 
 
 
 
 
Clozapine 
 
 
 
CNS=central nervous system; GI= gastrointestinal 
♦ Adapted from Tune et al (1992) & Tune (2001)   
Source: Antimuscarinics  
Department of Pharmacology. Tulane University SOM 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
Protocol Title: 
Protocol Number: 
Protocol Version, Date 
  
A randomized, double-blind, parallel group, placebo-
controlled, multi-center, therapeutic equivalence study to 
compare Rifaximin 200 mg tablets (Sandoz GmbH) to 
Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and 
placebo in patients with travelers’ diarrhea 
1526 RIF_2 / NCT02920242
Version 2.0, 29 Oct 2015 
 
Document Version, Date 
FINAL 1.0, 26 May 2017 
Prepared by: 
 
On behalf of: 
Sandoz GmbH 
Confidentiality statement: 

The information provided in this document is strictly confidential.

The recipients of the SAP must not disclose the confidential information
contained within this document or any related information to other
persons without the permission of the sponsor.

In addition, the recipients of the SAP must keep this confidential
document in a controlled environment which prevents unauthorized
access to the document.






 
Statistical Analysis Plan (SAP) 
 
 
SIGNATURE PAGE 


Statistical Analysis Plan (SAP) 
 
 
REVISION HISTORY 
Version/Date 
Version name 
Section 
Changes implemented 
1.0/26May2017 
1.0 
N/A 
Original version 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 4 of 29
 
TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................... 2 
REVISION HISTORY .................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
1 INTRODUCTION ..................................................................................................................... 8 
2 STUDY OBJECTIVES ............................................................................................................ 9 
2.1 Primary objectives ............................................................................................................ 9 
2.2 Secondary objective .......................................................................................................... 9 
3 STUDY DESIGN ................................................................................................................... 10 
3.1 General study design ...................................................................................................... 10 
3.2 Randomization, blinding and unblinding ....................................................................... 12 
3.2.1 Procedure for Breaking the Randomization Code .............................................. 12 
3.3 Study treatments and assessments .................................................................................. 12 
4 STUDY ENDPOINTS ........................................................................................................... 15 
4.1 Primary efficacy endpoints ............................................................................................. 15 
4.2 Secondary efficacy endpoints ......................................................................................... 15 
4.3 Safety endpoints ............................................................................................................. 15 
5 SAMPLE SIZE AND POWER ............................................................................................. 16 
6 ANALYSIS POPULATIONS ................................................................................................ 17 
6.1 Safety Population ............................................................................................................ 17 
7 STATISTICAL CONSIDERATIONS AND ANALYSIS ..................................................... 18 
7.1 Derived Variables ........................................................................................................... 18 
7.2 Definitions ...................................................................................................................... 18 
7.2.1 Definitions relative to safety criteria/AEs .......................................................... 18 
7.3 Handling of missing data and outliers ............................................................................ 19 
7.3.1 Missing data analysis methods ........................................................................... 19 
8 STATISTICAL METHODS ................................................................................................... 20 
8.1 General statistical conventions ....................................................................................... 20 
8.2 Patient disposition........................................................................................................... 21 
8.3 Protocol deviations ......................................................................................................... 21 
8.4 Demographics and baseline characteristics .................................................................... 21 
8.4.1 Demographics ..................................................................................................... 21 
8.4.2 Medical history ................................................................................................... 22 
8.4.3 Prior and concomitant medications .................................................................... 22 
8.5 Extent of exposure .......................................................................................................... 22 
8.5.1 Treatment duration ............................................................................................. 22 
8.5.2 Treatment compliance ........................................................................................ 22 
8.6 Safety analyses ............................................................................................................... 23 
8.6.1 Adverse events .................................................................................................... 23 
8.6.2 Clinical laboratory evaluations ........................................................................... 24 
8.6.3 Vital signs ........................................................................................................... 24 
8.6.4 Physical examinations ........................................................................................ 25 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 5 of 29
 
8.7 Interim analysis............................................................................................................... 25 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ........................... 26 
10 REFERENCES ...................................................................................................................... 27 
11 APPENDICES ....................................................................................................................... 28 
 
 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 6 of 29
 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
GI 
Gastrointestinal 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization  
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat  
PP 
Per-Protocol 
PT 
Preferred Term  
RLD 
reference listed drug  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TD 
Travelers’ Diarrhea 
TEAE 
Treatment-Emergent Adverse Events 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 7 of 29
 
TOC 
Test of cure  
USA 
United States of America  
WHO 
World Health Organization 
 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 8 of 29
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of 
the safety data derivations and data displays for study protocol 1526 RIF_2, Version 2.0, 
titled “A randomized, double-blind, parallel group, placebo-controlled, multi-center, 
therapeutic equivalence study to compare Rifaximin 200 mg tablets (Sandoz GmbH) to 
Xifaxan® 200 mg tablets (Salix Pharmaceuticals, Inc.) and placebo in patients with 
travelers’ diarrhea” dated 29 Oct 2015 for Final analysis. The SAP was prepared by 
 
Biostatistics and Programming Department, specifically drafted by 
 
 
 
 
 
reviewed 
by 
 
 
 
 
 
 
and 
 
 
 
 Final analyses will be executed 
by 
. 
 
. The last patient last visit was on April 23rd, 
2017. The final analysis, which will include only safety analysis due to low number of 
randomized patients, will be scheduled after the last patient has completed the 30 day 
safety follow up, and the resulting clinical database has been cleaned, quality-checked 
and locked.  
The table of contents and templates for the TFLs will be produced in a separate 
document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report 
(CSR). 
The preparation of this SAP has been based on International Conference on 
Harmonisation (ICH) guidelines1,2. 
All data analyses and generation of TFLs will be performed using SAS 9.3® or higher. 
 
 


Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: 1526 RIF_2 
Version: FINAL 1.0, Date 26 May 2017
Page 9 of 29
 
2 
STUDY OBJECTIVES 
2.1 Primary objectives 
The primary objective of this study is to demonstrate the therapeutic equivalence of 
Rifaximin 200 mg tablets to Xifaxan 200 mg tablets in patients with travelers’ diarrhea 
(TD). In addition, the efficacy of Rifaximin and Xifaxan will be compared to Placebo to 
assess the assay sensitivity of the study. 
2.2 Secondary objective 
The secondary objective of this study is to compare the safety and tolerability of Rifaximin 
200 mg tablets to Xifaxan 200 mg tablets and to Placebo in patients with TD. 
 
 


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3 
STUDY DESIGN 
3.1 General study design 
This study is a randomized, double-blind, parallel group, placebo-controlled, multi-center 
therapeutic equivalence study to compare Rifaximin 200 mg tablets to Xifaxan 200 mg 
tablets and placebo in patients with TD. 
The reference listed drug (RLD) in this study is the rifaximin 200 mg tablet marketed in 
United States of America (USA) by Salix Pharmaceuticals, Inc. under the trade name 
Xifaxan®. The investigational product produced by Sandoz GmbH also contains 200 mg 
of rifaximin.  
Patients will undergo screening procedures at the study site and eligible patients will be 
randomized to one of the study treatments. Treatments administered (randomized in 2:2:1 
ratio) are: 
• 
Rifaximin 200 mg tablets 
• 
Xifaxan 200 mg tablets 
• 
Placebo tablets 
The first dose will be self-administered immediately following randomization, thus initiating 
Study Day 1. Subsequent doses will be taken approximately once every 8 hours for 72 
hours for a total of 9 doses. Study Day 1 will begin with the first administration of study 
drug and Study Day 2 will begin 24 hours after the first treatment. Study Day 3 will begin 
48 hours after the first treatment. Depending on the timing of the first administration of 
study drug on Visit 1, a Study Day may extend across 2 calendar days. Thus, the final 
dose(s) of study drug taken on Study Day 3 may actually be taken on the 4th calendar day 
of the study. 
Patients will be contacted by telephone on Study Day 3 to determine if their condition has 
improved. Patients will return to the study site on Study Day 5 (± 1 day) for the test of cure 
(TOC)/End of Study (EOS) visit. Patients will participate in the study for a maximum of 7 
calendar days. 
Patients will maintain an electronic Patient Diary daily for recording the date, time and 
form of all stools passed; the time and date of study drug administration; the presence or 
absence and severity of signs and symptoms of enteric infection; body temperature; and 
presence or absence of blood in the stool. 
The use of any concomitant medications and the occurrence of any AEs will be 
recorded on a paper Supplemental Form. 
A schematic presentation of study design is as shown in Figure 1. 
 


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Figure 1: Study Flow Chart 
 
 
 


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3.2 Randomization, blinding and unblinding 
At each study center, patients who are eligible to enter the double-blind treatment period 
will be randomized to generic Rifaximin 200 mg, Xifaxan 200 mg or matching Placebo 
according to a 2:2:1 randomization ratio through an Interactive Web Response System 
(IWRS).  
The staff at the study center, the Sponsor and its representatives, and all patients will be 
blinded to the identity of the investigational product. 
3.2.1 Procedure for Breaking the Randomization Code 
The treatment code may be broken for an individual patient in the case of an emergency 
and when the knowledge of the investigational product is essential for the clinical 
management of the safety of this patient. The Investigator must make every effort to 
contact the Medical Monitor before breaking the treatment code. The Investigator will be 
able to access the IWRS database to receive the treatment code, 24 hours a day and 7 
days a week. A record will be kept at each study center of all broken treatment codes, of 
the person who broke the treatment code, date, time and of the reasons for breaking the 
treatment code.  In the case of a code break, the Investigator must inform the Sponsor or 
its representative immediately, without revealing to the Sponsor or its representative 
personnel the result of the code break.  
The Sponsor will have a designated Safety Manager at the Central Case Processing Site 
that has access to the randomization codes via the IWRS who may unblind a case if it is 
deemed medically appropriate. 
3.3 Study treatments and assessments 
The duration of participation for a patient is a maximum of 7 calendar days, including a 
maximum of 4 calendar days of treatment with study drug (depending on the number of 
doses taken on Calendar Day 1). 
A detailed description of study procedures and assessments to be conducted during the 
study is provided in the protocol and summarized in the Schedule of Study 
Schedule/Flowchart in Table 1 below. 
 


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Table 1: Schedule of Study Assessments 
 
AE=Adverse Event; EOS=End of Study; ICF=Informed Consent Form; TD=travelers’ diarrhea; TOC=test of cure  
* Screening/Randomization (Study Day 0) and Study Day 1 are the same day. Study days are 24 hour periods. Study Day 1 will begin with the administration of the 
first dose of study drug, Study Day 2 will begin 24 hours after the administration of the first dose of study drug, and so on. Depending on the timing of the first dose of 
study drug, one Study Day may extend over two calendar days. Depending on the timing of the first dose, and given the window of ± 1 day for the TOC/EOS Visit, the 
TOC/EOS Visit can take place anywhere from Calendar Day 4 to Calendar Day 7.  
1 Informed consent must be obtained before the patient undergoes any study-specific procedures. The Investigator must confirm that the patient is able to read and 
understand the language of the ICF, Patient Information, the electronic Patient Diary, and the Supplemental Form.  
2 Weight and height will be measured at Screening; weight will be measured at the TOC/EOS visit. Body mass index (BMI) will be calculated at Screening and 
TOC/EOS.  
3 Vital signs (respiratory rate, heart rate, blood pressure, and body temperature) will be performed at Screening and the TOC/EOS Visit. They will be obtained in the 
sitting position after the patient has rested for 5 minutes. The date and time of the assessment should be recorded.  
4 To include hematology, clinical chemistry and urinalysis.  
5 A stool sample will be obtained for fecal leukocyte testing and culture prior to randomization to study drug and on TOC/EOS. Stool culture for pathogenic organisms 
including: Enterotoxigenic Escherichia coli (ETEC); Enteroaggregative E.coli (EAEC); Shigella spp; Salmonella spp; Campylobacter jejuni; Plesiomonas spp; 
Aeromonas spp; Rotavirus; Giardia lamblia; Entamoeba histolytica, Cryptosporidium spp. 
6 For female patients of childbearing potential (not post-menopausal or have not undergone surgical sterilization), the results of the urine pregnancy test must be 
negative to confirm eligibility prior to randomization.  
7 The first dose of study drug is considered to be on Day 1, and is to be taken as soon as possible following completion of the Screening/Randomization procedures. 
The remaining 8 doses are to be taken at even intervals for 3 doses per day – a total of 9 doses of study drug are to be taken.  
8 At Screening/Randomization, the patient will be given an electronic Patient Diary in which to record his/her symptoms; time of study drug administration; and date, 
time and form of all stools passed. The Patient Diary will be reviewed by the Investigator during the call on Study Day 3 at the TOC/EOS Visit.  
9 Site will contact patient on Study Day 3 to check on their clinical status (i.e., if their condition has improved) and review completion of Diary and Supplemental Form. 
Information on AEs and concomitant medication will also be collected.  


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10 Patients will be given a paper Supplemental Form for documentation of the administration of any concomitant medications or the occurrence of any AEs. The 
Form will be reviewed by the Investigator during the call on Study Day 3 and at the TOC/EOS Visit.  
11 A follow-up phone call is to be performed should the patient have any ongoing AE at the TOC/EOS Visit. Any ongoing related AEs will be followed until resolution 
or until assessed by the Investigator to be permanent.  
 


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4 
STUDY ENDPOINTS 
4.1 Primary efficacy endpoints 
The primary endpoint of this study is clinical cure at the TOC/EOS Visit (Study Day 5 ± 1 
day). Clinical cure is defined as either: 
• 
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 
4.2 Secondary efficacy endpoints 
Following are the secondary endpoints in this study: 
• 
Time to Last Unformed Stool (TLUS) defined as the interval beginning with the first 
dose of study drug and ending with the last unformed stool passed  
• 
Proportion of patients with clinical failure defined as failure to achieve formed stool 
within ≤ 3 days (72 hours) of the start of treatment with the study drug or clinical 
deterioration or worsening of symptoms by Study Day 5 (± 1 day)  
• 
Proportion of patients with improvement of diarrheal syndrome, defined as 
reduction of ≥ 50% in the number of unformed stools (soft or watery) passed 
during the intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours, and 96-
120 hours after the first dose of study drug, compared to the number of unformed 
stools passed during the 24 hours immediately preceding first dose of study drug  
• 
The number of unformed stools (soft or watery) passed during the intervals 0-24 
hours, 24-48 hours, 48-72 hours, 72-96 hours, and 96-120 hours after the first 
dose of study drug  
• 
The presence or absence and severity of signs and symptoms of enteric infection 
(abdominal pain/cramps, excessive gas/flatulence, nausea, vomiting, fecal 
urgency, tenesmus) – the proportion of patients with signs and symptoms of 
enteric infection during the intervals 0-24 hours, 24-48 hours, 48-72 hours, 72-96 
hours, and 96-120 hours after the first dose of study drug  
• 
Microbiological cure defined as a post-treatment culture that was negative for the 
pre-treatment etiologic pathogen. 
4.3 Safety endpoints 
The safety endpoints in this study are: 
1. Incidence of reported adverse events (AEs) 
2. Changes in vital signs and clinical laboratory parameters 
 
 


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5 
SAMPLE SIZE AND POWER 
According to the FDA Draft Guidance on rifaximin3 sample sizes should be chosen 
such that the power is sufficient to establish therapeutic equivalence between generic 
and RLD rifaximin (Xifaxan) and sufficient to show that both are active compared to 
placebo (study sensitivity). Therapeutic equivalence is to be shown for the PP (per 
protocol) population whereas study sensitivity is to be shown for the modified Intent to 
Treat (mITT) population.  
A sample size of 135 in the generic Rifaximin and 135 in the  Xifaxan treatment groups 
achieve approximately 
 power to detect therapeutic equivalence when the 
margin of equivalence, given in terms of the difference, extends from -0.20 to 0.20. The 
calculations assume that: 
• 
two one-sided Z tests (pooled) at the 0.05 significance level are used 
(corresponding to a 90% CI for the difference of success proportions); 
• 
 
• 
 
 
Concerning the assessment of study sensitivity, a sample size of 170 in the generic 
Rifaximin group and Xifaxan® group and 85 in the Placebo group achieve approximately 
 power to detect a difference between the group proportions of 
, 
assuming that: 
• 
 
 
• 
two-sided Z tests (pooled) at the 0.05 level will be used. 
Patients will be randomized 2:2:1 to generic Rifaximin (n=180), Xifaxan (n=180), and 
Placebo (n=90). A total of 450 patients will be randomized. As it can be anticipated that no 
more than 5% of patients will be excluded from the mITT population, and no more than 
20% of patients from the mITT population will be excluded from the PP population this 
sample size will have sufficient power to show therapeutic equivalence and study 
sensitivity. 
 
 


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6 
ANALYSIS POPULATIONS 
6.1 Safety Population 
The Safety population includes all randomized patients who received at least 1 dose of the 
study product. In this population, treatment will be assigned based upon the treatment 
patients actually receive regardless of the treatment to which they were randomized. The 
safety population will be used for safety analyses. 
 
 
 


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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 Derived Variables 
The below table provide the list of derived variables for duration derivations, drug 
compliance, baseline derivations and other important derivations applicable for this study. 
Variables 
Formula 
Derivation of Duration 
Study day 
Study days will be based on the day and time of first 
administration of study drug which is Day 1. Subsequent 
study days will be calculated as 24 hours interval from 
the first dose. 
Duration 
of 
Study 
Drug 
(hours) 
The date/time of last dose – date/time of first dose  
rounded to hours  
Drug Compliance 
Compliance  
(Number of tablets taken)/ (Number of scheduled 
tablets) x 100 
 
For a patient that drops out early, the number of 
scheduled tablets should be the number the patient 
should have taken till the time subject dropped out. 
Baseline Derivations 
Baseline 
Baseline is defined as the last non-missing assessment 
prior to start of the first study drug administration. 
Change from baseline 
Post baseline value – Baseline 
Percent change from baseline [(Post baseline value – Baseline)/Baseline]*100  
7.2 Definitions 
7.2.1 Definitions relative to safety criteria/AEs 
7.2.1.1 Adverse Event (AE) 
An adverse event/experience (AE) is any untoward medical occurrence in a patient or 
clinical investigation patient administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 


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of a medicinal product, whether or not considered related to the medicinal product.  
7.2.1.2 Serious Adverse Event (SAE) 
A SAE is any AE that: 
• 
results in death 
• 
is life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
is a congenial anomaly/birth defect  
• 
requires inpatient hospitalization or prolongation of existing inpatient hospitalization 
• 
is medically significant: medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as 
important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed above. These should also usually be 
considered serious.  
Whether AE is serious and the seriousness criteria met will be collected on eCRF. 
7.2.1.3 Pre-treatment AEs, Treatment-emergent AEs 
• 
An AE is defined as pre-treatment if its onset date/time is before the date/time of 
the first intake of study mediation 
• 
An AE is defined as treatment-emergent if its onset date/time is on or after the 
date/time of the first intake of study mediation or if a pre-existing condition 
becomes worse after the date/time of first intake of study drug. 
7.2.1.4 Treatment-related AEs 
Relationship of AE with study drug is recorded on eCRF page with options “Suspected”, 
“Not Suspected”, and “Not Applicable”. Any AE with “Suspected” relationship to the study 
drug will be considered as treatment-related.  
7.3 Handling of missing data and outliers 
Missing safety data will not be imputed and will be presented as observed. 
7.3.1 Missing data analysis methods 
Not Applicable. 
 


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8 
STATISTICAL METHODS 
8.1 General statistical conventions 
All data analyses will be performed using the SAS® software package version 9.3 or 
higher. 
In general, continuous variables will be summarized using the following standard 
descriptive summary statistics: number of observations, arithmetic mean, standard 
deviation, minimum, lower quartile, median, upper quartile, maximum. Categorical data 
will be described using count and frequency. Percentages will be rounded to one decimal 
place. Shift tables will be provided, where appropriate.  
All analyses and summaries will be presented by treatment group, unless otherwise 
specified. 
The following international dictionaries (in latest available version) will be used for medical 
coding:  
• 
Diagnoses: Medical Dictionary for Regulatory Activities (MedDRA) v18.1 
• 
Medications: World Health Organization (WHO) Drug Dictionary including 
Anatomical Therapeutic Chemical (ATC) classification Sept 2014 
• 
AEs: MedDRA v18.1 
All patient data, including those derived, will be presented in individual patient data 
listings. Unless otherwise stated, unscheduled visit results will be included in date/time 
chronological order, within patient listings only. All listings will be sorted by investigational 
site, patient number, date/time and visit. The actual treatment group as well as patient’s 
sex and age will be stated on each listing. Unless otherwise stated, data listings will 
include all patients in Safety population. 
 
 


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8.2 Patient disposition 
Patient disposition information will be summarized by treatment group and overall. The 
number of patients screened, the number and percent of patients who are screen failure, 
randomized, who took a dose of study drug, who were randomized and not treated, who 
complete the study and who withdraw early from the study will be presented. Screen 
failure percentage is calculated from number of screened patients and other percentages 
are calculated among number of randomized patients. Patients from Safety Population will 
be summarized using descriptive statistics displaying number and percentage. Percentage 
will be done using the number of randomized as denominator. 
The primary reason for early withdrawal will also be summarized by treatment group in 
Safety Population. 
Patient disposition will be listed for all patients screened. 
Treatment Misallocations: 
If a subject was: 
• 
Randomized but not treated, they are by definition excluded from the safety 
analyses as not receive at least of one dose of study drug. 
• 
Randomized but took incorrect treatment, then they will be reported under the 
treatment they actually received for all safety analyses. 
8.3 Protocol deviations 
A listing will include the inclusion/exclusion criteria violated at Screening/Randomization 
as well as other protocol deviations identified based on data recorded on the eCRF and/or 
protocol deviation Logs from 
 Medical for all randomized patients. 
Major protocol deviations defined as below will be listed separately: 
• 
Lack of compliance defined as having administered <75% or >125% of the 
scheduled doses for the specified duration of the study 
• 
Completion of the TOC/EOS Visit outside the specified visit window (Study Day 5 
±1 day) (if patient did not discontinue the study due to lack of treatment effect or 
worsening of the underlying condition requiring alternate or supplemental therapy). 
8.4 Demographics and baseline characteristics 
8.4.1 Demographics 
Age, height, weight, BMI, the number of formed stools in the past 24 hours at baseline, the 
number of unformed stools in the past 24 hours at baseline, and the duration (days) in the 
host country will be summarized descriptively. Sex, Race, Ethnicity, country of residence, 
signs and symptoms of enteric infection (abdominal pain or cramps, nausea, vomiting, 


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fecal urgency, gas/flatulence, and tenesmus), and pathogen status (inflammatory/invasive 
pathogens, diarrheagenic E Coli group without evidence of inflammatory/invasive 
pathogens, other pathogens without evidence of inflammatory/invasive pathogens) at 
baseline will be summarized. Safety population will be used for reporting. 
8.4.2 Medical history 
Listing for medical history will be presented by system organ class (SOC) and preferred 
term (PT) Medical Dictionary for Regulatory Affairs® (MedDRA) Version 19.0 or higher. 
8.4.3 Prior and concomitant medications 
Prior medications are defined as those medications with a start date prior to the first dose 
of study drug. Concomitant medications are defined as those medications with a start date 
on or after the first dose of study drug. Prior medications were recorded in medical history 
at the Screening/Randomization visit. The administration of any concomitant medication or 
herbal/dietary supplements during the study will be recorded by patients on the 
Supplemental Form provided at the Screening/Randomization Visit. The form will be 
reviewed by the Investigator during the call on Study Day 3 and at the TOC/EOS Visit. 
Prior and concomitant medications will be recorded on the eCRF by the investigator. Prior 
and concomitant medications used in this study will be coded by using the latest available 
version of the World Health Organization (WHO) Drug Dictionary including Anatomical 
Therapeutic Chemical (ATC) classification.  
Listing for prior and concomitant medications will be presented. 
8.5 Extent of exposure  
8.5.1 Treatment duration 
At TOC/EOS Visit, the date/time of first dose and last dose, in addition to the actual total 
number of tablets taken will be recorded in the eCRF. Duration of study drug (in hours) will 
be the date/time of last dose – date/time of first dose rounded to hours. 
Study drug exposure will be summarised by treatment group on the Safety Population 
using descriptive statistics. 
The actual total number of tablets taken will be summarized by treatment group using 
descriptive statistics. 
8.5.2 Treatment compliance 
Treatment compliance in this study will be monitored by tablet count as described in 
section 7.1.  


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Summary of treatment compliance will be presented by treatment group by the number of 
subjects (n), mean, standard deviation, median, min, and max. They will also be 
summarized in categories “< 75%”, “75-125%” and  “> 125%” using frequency tables. 
Treatment compliance will be summarized and listed based on the Safety Population. 
8.6 Safety analyses 
All definitions relative to safety endpoints are detailed in Section 7.2.1 
Safety analyses will be conducted on the Safety Population (treated patients) and will be 
performed for all safety variables specified below.  
All safety data will be summarized by treatment group and overall.  
The safety analyses of changes from baseline to a specific time point in safety variables 
(e.g., laboratory parameters, vital signs, and physical examination) will only include 
patients from the Safety Population who have data available for both the baseline and the 
time point under consideration unless otherwise specified. 
No statistical test will be performed. 
8.6.1 Adverse events 
All Adverse events (AEs) will be classified by System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 
19.0 or higher. 
Incidences of Treatment-Emergent Adverse Events (TEAEs) will be tabulated by SOC and 
PT. Incidences of TEAEs will also be presented by maximum severity (intensity), 
seriousness and relatedness to study drug. Subjects who discontinued due to AEs will be 
summarized by SOC and PT in a separate table. Patients are counted only once in each 
SOC, and only once in each PT category. The table will be sorted in alphabetical order by 
SOC and in decreasing frequency of PT based on total reports within each SOC.  
In summary, the following tables will be developed for summarizing AEs.  
• 
Overall summary of TEAEs, it includes number and percentage of subjects with 
any TEAEs, subjects with any treatment-emergent SAE, subjects with any severe 
TEAEs, subjects with any treatment-related TEAEs, subjects with TEAEs leading 
to study discontinuation, subjects with death. 
• 
Summary of TEAEs by SOC and PT 
• 
Summary of treatment-emergent SAEs by SOC and PT 
• 
Summary of TEAEs by SOC and PT and maximum severity 
• 
Summary of TEAEs by SOC and PT (treatment-related) 
• 
Summary of treatment-emergent SAEs by SOC and PT (treatment-related) 


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• 
Summary of TEAEs by SOC and PT and maximum severity (treatment-related) 
• 
Discontinuations due to TEAEs by SOC and PT 
• 
Death due to TEAEs by SOC and PT 
In addition, an overall summary for the categories above will be prepared by treatment 
group and overall. 
Individual patient data listings will be provided for those with non-treatment emergent AEs, 
TEAEs, treatment-emergent SAEs, treatment-related TEAEs, deaths, and discontinuation 
due to AEs. 
Regarding the summaries by severity and causality the following rule will be applied: if a 
patient experiences more than one AE within the same SOC or with the same preferred 
term, the AE with the highest severity or closest relationship to study treatment will be 
used for the analysis.  
8.6.2 Clinical laboratory evaluations 
Laboratory data will be subjected to both a quantitative analysis (descriptive summary 
statistics) and qualitative analysis where frequencies of normal, abnormal low, and 
abnormal high values will be computed. 
Hematology, 
blood 
chemistry 
and 
urine 
samples 
will 
be 
collected 
at 
Screening/Randomization Visit and TOC/EOS Visit. Urine pregnancy test will be done on 
all females of child bearing potential (not post-menopausal or not surgically sterile) prior to 
randomization at Screening/Randomization Visit and at TOC/EOS Visit. If a subject has 
repeated laboratory values for a given time point, the value from the last evaluation will be 
used. For the purposes of summarization in both the tables and listings, all laboratory 
values will be presented in SI units. If a lab value is reported using a nonnumeric qualifier 
e.g., less than (<) a certain value, or greater than (>) a certain value, the given numeric 
value will be used in the summary statistics, ignoring the nonnumeric qualifier. 
Please refer to protocol section 12.4 for detailed list of parameters collected in blood 
samples for analyses. Summary statistics of measurements, change from baseline values, 
percent change from baseline values for hematology, chemistry, and urinary parameters 
will be presented at Screening/Randomization Visit and TOC/EOS Visit by treatment 
group. Shift tables displaying changes with respect to the normal range between baseline 
and TOC/EOS Visit will be provided. A listing of all subjects with abnormal values at any 
time point will be given. 
8.6.3 Vital signs 
Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be 
measured at Screening/Randomization Visit, TOC/EOS Visit and unscheduled visit. Vital 


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sign measurements at baseline and TOC/EOS Visit, and change at TOC/EOS Visit from 
baseline will be summarized by visit and treatment group. 
A patient data listing of all clinically significant abnormal vital signs, including findings from 
unscheduled visits, will be provided. 
8.6.4 Physical examinations 
Physical examinations will be performed at Screening/Randomization Visit, TOC/EOS 
Visit and unscheduled visit. Shifts (normal, abnormal, not done) from baseline to 
TOC/EOS Visit will be summarized using patient counts and percentages.  
A patient data listing of all physical examination abnormal findings, including findings from 
unscheduled visits, will be provided. 
8.7 Interim analysis 
Not applicable 
 


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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
 This SAP v1.0 
excludes efficacy analyses from the final analyses due to low number of randomized 
patients.  
 


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10 
REFERENCES 
1) ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- 
adopted December 1995). 
2) ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted 
March 1998). 
3) Draft Guidance on Rifaximin, recommended February 2012.  
 


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11 
APPENDICES 
Appendix A – Interim Analysis 
Not Applicable 
 


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Appendix B - Visit Window 
Not Applicable