Clinical trial NCT03818672
Conditions: Severe Hepatic Impairment
Sponsor: Bausch Health Americas, Inc.
Start date: 2019-01-29; Completion date: 2020-02-02
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to characterize the steady state plasma

Detailed description:
The primary objective of this study is to characterize the steady state plasma PK of rifaximin (550 mg BID) in subjects with severe hepatic impairment (MELD 19 to 25 and MELD \>25), as well as healthy subjects with normal hepatic function.

Arms: arm 1: Rifaximin 550 mg BID
Interventions: intervention 1: Rifaximin
Intervention descriptions: intervention 1: Rifaximin 550 MG BID

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol  
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1
Title Page
Clinical Study Protocol
Protocol RFPK4045
A PHASE 4, OPEN LABEL STUDY TO EVALUATE THE STEADY-
STATE PHARMACOKINETICS OF RIFAXIMIN 550 MG TABLETS IN 
HEALTHY SUBJECTS AND SUBJECTS WITH SEVERE HEPATIC 
IMPAIRMENT
Developmental phase of study:
Phase IV
Study design
Open Label, Repeat Dose, Parallel Design
Date:
21 Nov 2017
08 Oct 2018 (Amendment 1)
Sponsor representative
Sponsor 
Salix Pharmaceuticals, Inc., a division of 
Valeant Pharmaceuticals North America LLC 
(VPNA)
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807
Statement of Confidentiality
The information in the following document is confidential. The information contained herein will not be disclosed to others 
without written authorization from Salix Pharmaceuticals, Inc. (Salix) or Valeant Pharmaceutical International Inc. (VPII) 
and its affiliates. Salix. is a wholly-owned subsidiary of VPII as of April 1, 2015, and VPNA is the affiliate in USA. 
Santarus Inc. is a wholly-owned subsidiary of Salix. 
This clinical investigation will be conducted in accordance with the Declaration of Helsinki on Ethical Principles for 
Medical Research Involving Human Subjects, and with Good Clinical Practice (GCP), as required by the US Code of 
Federal Regulations applicable to clinical studies (21 CFR Parts 11, 50, 54, 56 and 312, 42 USC 282(j), International 
Conference on Harmonisation, Harmonised Tripartite Guideline E6(R2): GCP and E2A: Safety Data Management, and 
applicable local regulations. 
Any brand names/product names are trademarks of their respective owners. 
NCT03818672




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Personnel Responsible for Conducting the Study
Protocol RFPK4045
A Phase 4, Open-Label Study to Evaluate the Steady-State Pharmacokinetics of 
Rifaximin 550mg Tablets in Healthy Subjects and Subjects with Severe Hepatic 
Impairment
Valeant Pharmaceuticals North 
America, LLC 
400 Somerset Corporate Boulevard
Bridgewater, NJ 08807
Contract Research Organization
MedTrials, Inc. 
2626 Cole Avenue, Suite 400
Dallas, TX  75204
 


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Principal Investigator Protocol Agreement Page 
I agree: 
x To assume responsibility for the proper conduct of this clinical study at this site and to 
conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by the sponsor. 
x That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirements to obtain 
written and dated approval from the Institutional or Central Review Board (IRB) or 
Independent Ethics Committee (IEC) for the study protocol, written informed consent, 
consent-form updates, subject-recruitment procedures (eg, advertisements), and any 
other written information to be provided to the subjects, before initiating this clinical 
study. 
x Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspects of the clinical study. 
x To permit direct monitoring and auditing by the sponsor or sponsor’s representatives 
and inspection by the appropriate regulatory authority(ies). 
x That I am thoroughly familiar with the appropriate use of the investigational 
products(s), as described in this protocol, and any other information provided by the 
sponsor or designee, including, but not limited to, the current investigator Brochure or 
equivalent document and approved product label (if applicable). 
x To provide sufficient time, and adequate numbers of qualified staff and facilities for 
the foreseen duration of the clinical study to conduct the study properly, ethically, and 
safely. 
x To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and 
functions. 
 
Principal Investigator (print name): __________________ 
 
Affiliation:______________________________________ 
 
 
 
 
 
Principal Investigator (signature) 
 
Date 
 


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2 Synopsis 
Name of Sponsor/Company: Salix Pharmaceuticals, Inc., a division of VPNA, LLC 
Name of Investigational Product: Rifaximin, 550 mg tablets 
Name of Active Ingredient: Rifaximin  
Title of Study: A Phase 4, Open-Label Study to Evaluate the Steady-State 
Pharmacokinetics of Rifaximin 550mg Tablets in Healthy Subjects and Subjects with 
Severe Hepatic Impairment 
Number of clinical centers: 1 to 3 clinical centers in the US 
Objectives:  
Primary: To characterize the steady-state plasma pharmacokinetics (PK) of rifaximin 
(550 mg BID) in subjects with severe hepatic impairment (Model for End Stage Liver 
Disease [MELD] 19 to 25 and MELD >25), as well as healthy subjects with normal 
hepatic function. 
Exploratory: To assess the effect of rifaximin administration on the intestinal 
microbiome in subjects with severe hepatic impairment (MELD 19 to 25 and MELD 
>25). 
Methodology:  
This is a Phase 4, open-label, repeat-dose, parallel-design study in 12 subjects with 
severe hepatic impairment (MELD 19 to 25 and MELD >25) and 6 healthy subjects 
with normal hepatic function.  At least 6 of the hepatically impaired subjects will have 
MELD score >25.  Efforts will be made to match subjects across groups in terms of 
age, weight, and sex.  Eligible subjects will complete a Screening Period of up to 21 
days prior to dosing (Day 1), a 7-day Treatment Period, and Follow-Up by phone 
3 (+1) days later.  Subjects will be admitted to the Clinical Research Unit (CRU) on the 
day prior to initiation of dosing (Day -1; CRU admission).  A plasma sample for PK 
analysis will be collected on Day 1 prior to the first dose.  Subjects will receive 550 mg 
rifaximin BID approximately 12 hours apart for 6 days beginning on Day 1 (Baseline).  
On Day 7 (End of Treatment; EOT), the final dose of study drug will be administered 
in the morning following an overnight fast of 10 hours. Plasma samples for PK analysis 
will be collected pre-dose (within 1 hour of the dose) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 
6, 8, 10, 12, 16, 20, and 24 hours post-dose.  Additionally, a trough blood sample will 
be collected on Days 2-6, prior to administration of the first daily dose of rifaximin.   
Subjects will reside in the CRU for 9 days and will be discharged following the final 
PK sample collection if safety parameters are acceptable to the Investigator. Each 
subject will be contacted for a follow-up phone call on 3 (+1) Days following end of 
treatment.  
Number of patients planned: N = 18, 12 subjects with liver impairment and 6 
matched healthy volunteer subjects.  At least 6 of the hepatic impaired subjects will 
have a MELD score of >25. 


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Diagnosis and main criteria for inclusion:  
Hepatically impaired subjects will be ≥18 years of age, have a diagnosis of liver 
cirrhosis and a MELD score of ≥19 at Screening.  Note: At least 6 of the hepatically 
impaired subjects will have a MELD score of >25.  
Key exclusion criteria: 
Subject has known allergy to rifaximin, rifampin, or other rifamycins, excipients and/or 
vehicles used in the formulation, or any other clinically significant allergies. 
Subject has participated in an investigational drug or device study within 30 days prior 
to Day 1 (Baseline). 
Subject has any concurrent illness (other than liver cirrhosis), disability or 
circumstance that may affect the interpretation of clinical data, could cause 
noncompliance with treatment or visits or otherwise contraindicates participation in 
this study in the opinion of the investigator. 
Investigational product, dosage and mode of administration: Rifaximin 550 mg 
tablets taken orally two times a day (BID). 
Duration of treatment: The duration of treatment is for 7 days. 
Criteria for evaluation:  
Efficacy: 
x No efficacy analyses are planned. 
Safety:   
x Incidence of treatment-emergent adverse events (AEs) and serious adverse 
events (SAEs).  
x Changes from baseline in clinical laboratory parameters. 
x Changes from baseline in vital signs. 
Pharmacokinetics: 
x Pharmacokinetic parameters to be estimated for rifaximin and 25-desacetyl 
rifaximin, if measurable, will include: maximum observed plasma 
concentration (Cmax), time of the maximum concentration (Tmax), and area under 
the plasma concentration versus time curve (AUC) during the 12-hour dose 
interval tau (τ), AUC0-24, AUClast. 
Exploratory: 
x Gastrointestinal microbiota from stool samples and antibiotic resistance from 
bacteria cultured from stool samples will be analyzed before and after treatment 
with Rifaximin 550 mg BID for one week. 
Statistical Methods: The Intent-to-Treat (ITT) population will be used for safety 
analyses.  The ITT population will include all subjects who ingested at least one dose 
of study drug.  Safety evaluations will be based on the incidence of AEs, changes in 
vital signs, and clinical laboratory results.  Exposure to study medication and reasons 
for discontinuation of study treatment will be tabulated.  The PK population will 


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include subjects from whom sufficient data are obtained for calculation of rifaximin 
plasma PK parameters.   
The effect of severe hepatic impairment will be compared to the matched control group 
of healthy subjects.  An analysis of variance will be performed, and data for Cmax, 
AUC0-τ, and CL/F will be natural log transformed prior to analysis.  The 90% 
confidence intervals (CIs) of the hepatic impairment group mean relative to the 
matched control group mean will be obtained.  The effect of hepatic impairment will be 
assessed by examining the 90% CIs for the mean ratio of the hepatic impairment group 
relative to the matched healthy group. 
A continuous analysis using linear regression will be performed to evaluate the 
relationship between estimated creatinine clearance and rifaximin CL/F. 
Gastrointestinal microbiota data will be summarized descriptively by total counts (per 
gram of stool sample); by species of aerobic and anaerobic bacteria; and by bacterial 
resistance to antibiotics (including rifaximin and rifampin). 
Sample size calculations: 
A formal sample size estimate was not calculated.  The number of subjects planned for 
this study is considered sufficient to compare the pharmacokinetics of rifaximin in 
patients with severe hepatic impairment to healthy subjects.    
 
 
 


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3 Table of Contents  
1 
Title Page ............................................................................................................................ 1 
2 
Synopsis .............................................................................................................................. 5 
3 
Table of Contents ................................................................................................................ 8 
3.1 
List of Figures................................................................................................................11 
3.2 
List of Abbreviations and Definitions of Terms ........................................................... 12 
4 
Introduction....................................................................................................................... 14 
4.1 
Disease Background ..................................................................................................... 14 
4.2 
Rifaximin Background ................................................................................................. 14 
4.2.1 
Clinical Experience with Rifaximin ......................................................................... 15 
4.3 
Rationale for the Study ................................................................................................. 16 
5 
Study Objectives and Purpose .......................................................................................... 17 
5.1 
Primary Objective ......................................................................................................... 17 
5.2 
Exploratory Objectives ................................................................................................. 17 
5.3 
Pharmacokinetic Endpoints .......................................................................................... 17 
5.4 
Safety Endpoints ........................................................................................................... 18 
5.5 
Exploratory Endpoints .................................................................................................. 18 
6 
Investigational Plan .......................................................................................................... 18 
6.1 
Overview of Study Design ........................................................................................... 18 
7 
Selection and Withdrawal of Subjects .............................................................................. 19 
7.1 
Inclusion/Exclusion for Subjects with Severe Hepatic Impairment ............................. 19 
7.1.1 
Hepatic Impairment Subject Inclusion Criteria ........................................................ 19 
7.1.2 
Hepatic Impairment Subject Exclusion Criteria ....................................................... 20 
7.2 
Inclusion/Exclusion for Healthy Subjects .................................................................... 22 
7.2.1 
Healthy Subjects Inclusion Criteria .......................................................................... 22 
7.2.2 
Healthy Subjects Exclusion Criteria ......................................................................... 23 
7.3 
Screen Failures ............................................................................................................. 25 
7.4 
Premature Subject Discontinuation from Study Treatment or Study ........................... 25 
8 
Treatment Plan .................................................................................................................. 26 
8.1 
Methods of Assigning Subjects to Treatment Groups .................................................. 26 
8.2 
Randomization and Blinding ........................................................................................ 26 


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8.3 
Concomitant Medications and Therapies ..................................................................... 26 
8.3.1 
Prohibited Therapy ................................................................................................... 27 
8.4 
Treatment Compliance ................................................................................................. 28 
8.5 
Protocol Deviations and Violations .............................................................................. 28 
9 
Study Drug Materials and Management ........................................................................... 28 
9.1 
Formulation and Supply ............................................................................................... 28 
9.1.1 
Packaging and Labeling ........................................................................................... 29 
9.1.2 
Storage, Handling, and Disposal of Study Drug ...................................................... 29 
9.1.3 
Dosing (including Dosing Schedule) ........................................................................ 29 
9.1.4 
Rationale for Dose Selection .................................................................................... 29 
9.2 
Study Drug Accountability ........................................................................................... 29 
10 Study Procedures and Evaluations.................................................................................... 30 
10.1 Schedule of Evaluations and Procedures ...................................................................... 30 
10.1.1 
Screening (Day –21 to Day -2) ................................................................................. 30 
10.1.2 
CRU Check-in: Day-1 .............................................................................................. 32 
10.1.3 
Day 1 (Baseline; pre-dose) ....................................................................................... 32 
10.1.4 
Day 1 (Dosing and Post-dose) .................................................................................. 33 
10.1.5 
Day 2 – Day 6 ........................................................................................................... 33 
10.1.6 
Day 7 (End of Treatment [EOT] or Early Termination) ........................................... 34 
10.1.7 
Day 8 ........................................................................................................................ 35 
10.1.8 
3 days (+ 1) after EOT: Follow-Up Phone Call ........................................................ 35 
10.2 Assessment of Pharmacokinetics ................................................................................. 35 
10.3 Stool Testing/Microbiome Assessment ........................................................................ 36 
10.4 Assessment of Safety .................................................................................................... 37 
10.4.1 
Adverse Events ......................................................................................................... 37 
10.4.2 
Physical Examination ............................................................................................... 37 
10.4.3 
Vital Signs ................................................................................................................ 37 
10.4.4 
Clinical Laboratory Tests .......................................................................................... 38 
10.4.5 
Electrocardiogram .................................................................................................... 39 
10.4.6 
Pregnancy Testing ..................................................................................................... 39 
10.5 Other Assessments ........................................................................................................ 39 
10.5.1 
Medical History ........................................................................................................ 39 
10.5.2 
Model for End Stage Liver Disease .......................................................................... 39 
10.5.3 
Child-Pugh Classification System ............................................................................ 39 
10.5.4 
Concomitant Medications ......................................................................................... 40 


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11 Safety Reporting ............................................................................................................... 41 
11.1 Operating Definitions for Assessing Safety ................................................................. 41 
11.1.1 
Adverse Event .......................................................................................................... 41 
11.1.2 
Serious Adverse Event .............................................................................................. 42 
11.1.3 
Assessment of Severity ............................................................................................. 43 
11.1.4 
Assessment of Causality ........................................................................................... 44 
11.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs
 ...................................................................................................................................... 44 
11.3 Method and Frequency for Detecting AEs and SAEs .................................................. 44 
11.3.1 
Time period for Detecting and Reporting of AEs and SAEs .................................... 45 
11.3.2 
Post-Study SAEs ...................................................................................................... 45 
11.4 Documenting AEs and SAEs ........................................................................................ 45 
11.5 Follow-Up of AEs and SAEs ........................................................................................ 46 
11.6 Prompt Reporting of SAEs to Sponsor ......................................................................... 46 
11.7 Pregnancy Reporting .................................................................................................... 47 
11.8 Transmission of SAE Reports and Pregnancy Notification Forms .............................. 47 
11.9 Regulatory Reporting Requirements for SAEs ............................................................ 47 
12 Statistics ............................................................................................................................ 47 
12.1 Randomization .............................................................................................................. 47 
12.2 Determination of Sample Size ...................................................................................... 48 
12.3 Analysis Populations .................................................................................................... 48 
12.4 Subject Disposition ....................................................................................................... 48 
12.5 Demographic and Baseline Characteristics .................................................................. 48 
12.6 Analysis Methods ......................................................................................................... 48 
12.6.1 
Pharmacokinetic Analyses ........................................................................................ 48 
12.6.2 
Microbiome Analyses ............................................................................................... 50 
12.6.3 
Safety Analyses ........................................................................................................ 50 
12.6.3.1 
Extent of Exposure and Treatment Compliance ................................................... 50 
12.6.3.2 
Adverse Events ..................................................................................................... 50 
12.6.3.3 
Clinical Laboratory Assessments .......................................................................... 51 
12.6.3.4 
Vital Signs ............................................................................................................. 51 
12.6.3.5 
Concomitant Medications ..................................................................................... 51 
12.7 Statistical and Analytical Issues ................................................................................... 51 
12.7.1 
Adjustment for Covariates ........................................................................................ 51 


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12.7.2 
Handling of Dropouts or Missing Data .................................................................... 51 
12.7.3 
Interim Analysis and Data Monitoring ..................................................................... 51 
13 Quality Control and Quality Assurance ............................................................................ 52 
13.1 Investigator Information and Training .......................................................................... 52 
13.2 Study Monitoring.......................................................................................................... 52 
13.3 Audits and Inspections ................................................................................................. 52 
13.4 Data Quality Assurance ................................................................................................ 53 
14 Ethics and Administrative Issues ...................................................................................... 53 
14.1 Institutional Review Board (IRB) Approval................................................................. 53 
14.2 Subject Information and Informed Consent ................................................................. 54 
14.3 Study and Site Closure or Discontinuation .................................................................. 55 
14.3.1 
Study Discontinuation .............................................................................................. 55 
14.3.2 
Study Site Discontinuation ....................................................................................... 56 
14.4 Data Handling and Record Keeping ............................................................................. 56 
14.4.1 
Case Report Forms and Database Processing .......................................................... 56 
14.4.2 
Source Documents .................................................................................................... 57 
14.4.3 
Subject Tracking ....................................................................................................... 57 
14.4.4 
Study Files ................................................................................................................ 57 
14.4.5 
Data Management ..................................................................................................... 57 
14.5 Confidentiality .............................................................................................................. 57 
14.6 Record Retention .......................................................................................................... 58 
14.7 Financing and Insurance ............................................................................................... 58 
14.7.1 
Finance ..................................................................................................................... 58 
14.7.2 
Insurance and Indemnification ................................................................................. 58 
14.8 Publication Policy ......................................................................................................... 59 
15 References......................................................................................................................... 59 
16 Appendices ....................................................................................................................... 61 
16.1 Overall Time and Events Schedule............................................................................... 61 
16.2 CYTOCHROME P450 ENZYME INDUCER/INHIBITOR COMPOUNDS* ............. 62 
 
3.1 List of Figures 
Figure 1: 
Study Design Schema ..................................................................................... 19 


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3.2  List of Abbreviations and Definitions of Terms 
Abbreviation or 
specialist term 
Definition or Explanation 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
BID 
two times a day 
CI 
confidence interval 
CLD 
Chronic Liver Disease 
CRF  
Case Report Form 
CRU 
Clinical Research Unit 
DNA 
Deoxyribonucleic Acid 
ECG 
electrocardiogram 
EDC 
Electronic Data Capture 
FDA  
Food and Drug Administration 
GCP 
Good Clinical Practices 
Hb 
hemoglobin 
Hct 
hematocrit 
HE 
Hepatic encephalopathy 
HIPAA 
Health Insurance Portability and Accountability Act (of 1996) 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 


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Abbreviation or 
specialist term 
Definition or Explanation 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-stage Liver Disease 
MIC 
Minimum inhibitory concentration 
PK 
pharmacokinetics 
PPACA  
Physician Payment Sunshine Provision of the Patient Protection and Affordable 
Care Act 
PP 
per protocol 
RNA 
Ribonucleic Acid 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SBP 
Spontaneous bacterial peritonitis 
SD 
standard deviation 
SOP 
standard operating procedures 
US 
United States 
USPI 
US Prescribing Information 
WHO 
World Health Organization 
 
 
 


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4 Introduction 
4.1 Disease Background 
The magnitude of the health care burden caused by liver disease in the United States (U.S.) is 
significant from both a societal and health economic perspective.  Approximately 2.6 million 
people have liver disease in the U.S.  Cirrhosis is a major cause of much of chronic liver 
disease (CLD) in the U.S., and is the 12th leading cause of death (Pleis, 2007).  Hepatic 
encephalopathy (HE) is a complication of CLD that strongly impacts survival (Stewart, 2009; 
Bustamante, 1999), results in frequent hospitalizations, (Leevy, 2007; Poordad, 2007; Bajaj, 
2010) increases dependence on care providers (Miyazaki, 2010) and greatly contributes to 
the clinical and socio-economic burden of CLD.  Rifaximin, a minimally absorbed, gut-
selective antibiotic, has been shown to significantly reduce the risk of overt HE recurrence 
and HE-related hospitalizations, in a double blind, placebo-controlled, 6-month study 
enrolling patients with a recent history of recurrent, overt HE, and a Model for End Stage 
Liver Disease (MELD) score of ≤25 (Bass, 2010), with a safety profile similar to placebo.  
One of the limitations of this study was that only few patients (<9%) with more severe liver 
disease (MELD ≥19) were enrolled and adequate pharmacokinetic (PK) and safety data for 
treatment with rifaximin in this more severe population are not currently available.  
Therefore, the current study will be conducted to provide rifaximin PK data for patients with 
MELD scores ≥19. 
FDA requires that the sponsor completes post-marketing requirement (PMR) 1615-3 entitled, 
“A pharmacokinetic trial in patients with severe hepatic impairment (MELD 19 – 25 and 
MELD > 25). The present trial protocol is designed to meet the PMR objective and is subject 
to FDA review and approval, under IND 059133.  
4.2 Rifaximin Background 
Details regarding the safety and efficacy of rifaximin are found in the US prescribing 
information (XIFAXAN® US Package Insert 2016).  Rifaximin is a nonaminoglycoside, 
semisynthetic antibiotic of the rifamycin class.  It is a non-systemic, poorly-absorbed, broad-
spectrum, oral antibiotic specific for enteric pathogens of the GI tract (Salix, 2014; Gerard, 
2005; Gillis, 1995; Hoover, 1993).  Rifaximin has important advantages in treatment of HE 
relative to previously used antibiotics.  For example, rifaximin has minimal systemic 
exposure regardless of food intake or presence of GI disease.  The lack of systemic exposure 
makes rifaximin safe and well tolerated.  Rifaximin’s antibacterial activity is due to its 
binding to the beta-subunit of the bacterial deoxyribonucleic acid (DNA)-dependent 


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ribonucleic acid (RNA) polymerase, resulting in inhibition of bacterial RNA synthesis.  It is 
active against numerous Gram-positive and Gram-negative bacteria, both aerobic and 
anaerobic.  In vitro data indicate rifaximin is active against species of Staphylococcus, 
Streptococcus, Enterococcus, and members of the Enterobacteriaceae family.  Bacterial 
reduction or an increase in antimicrobial resistance in the colonic flora does not occur to a 
clinically significant extent. 
4.2.1 
Clinical Experience with Rifaximin 
Rifaximin has been investigated in numerous clinical trials of subjects with HE at daily doses 
ranging from 400 to 1200 mg at a treatment duration of 3 to 30 days, or at 1200 mg/day for 
14 days/month for 3 to 6 months.  Studies conducted have demonstrated short- and long-term 
efficacy following treatment regimens of ≤21 days (i.e., acute treatment) or longer treatment 
durations of 3 months and 6 months.  Results of these studies demonstrated efficacy and a 
favorable safety profile for rifaximin in patients with HE.  A randomized double-blind 
placebo controlled multi-center trial of 299 subjects with cirrhosis (Study RFHE3001) (Bass, 
2010) was conducted to support registration.  This 6-month study enrolled subjects in 
remission from recurrent HE, (history of ≥2 HE episodes with severity of Conn 2 or greater) 
and demonstrated that rifaximin significantly reduced the risk of an episode of HE as 
compared with placebo, (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 
0.28 to 0.64; P <0.001).  Furthermore, significantly fewer subjects in the rifaximin group had 
a hospitalization involving HE, as compared with placebo group; hazard ratio of 0.50 (95% 
CI, 0.29 to 0.87; P = 0.01).  Rifaximin maintained remission from hepatic encephalopathy 
more effectively than placebo.  Rifaximin 550 mg two times a day (BID) was approved by 
the US Food and Drug Administration (FDA) in March 2010 for the reduction in risk of 
recurrent overt HE.  
At the time of the NDA submission, 348 patients with HE were exposed to rifaximin, 
including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure 
was 364 days).  The safety of rifaximin 550 mg taken two times a day for reducing the risk of 
overt HE 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 were peripheral edema, nausea, dizziness, fatigue, 


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ascites, muscle spasms, pruritus, abdominal pain, anemia, depression, nasopharyngitis, 
abdominal pain upper, arthralgia, dyspnea, pyrexia, and rash. 
In a study to characterize the pharmacokinetics of rifaximin in healthy subjects, 
administration of a single 550 mg oral dose to fasted and fed subjects resulted in mean AUC 
values of 11.1 ng.h/mL and 22.5 ng.h/mL, respectively.  Multiple-dose twice daily (BID) or 3 
times daily (TID) regimens in healthy subjects resulted in mean AUC values of 12.3 ng.h/mL 
(AUCtau, steady-state), and 9.3 ng.h/mL (AUCtau, steady-state), respectively (RFPK1007).  
Subjects with non-C IBS had mean AUCtau values following a single dose and multiple TID 
doses of 9.69 ng.h/mL and 16.0 ng.h/mL, respectively, reflecting an accumulation ratio (Rc; 
multiple-dose AUCtau/single-dose AUCtau) of 1.77 (RFPK1010).  In subjects with hepatic 
impairment, systemic exposure is higher than that observed in healthy subjects.  Following 
repeat dosing of a 550 mg BID regimen in hepatic impaired subjects in RFHE3002PK, mean 
steady-state AUCtau values of 118 ng.h/mL, 161 ng.h/mL, and 246 ng.h/mL were observed 
in Child-Pugh A, Child Pugh B, and Child-Pugh C subjects, respectively.  In a study to 
determine the effect of P-glycoprotein inhibition on the pharmacokinetics of rifaximin, an in 
vitro substrate of P-glycoprotein, healthy subjects received a single oral dose of rifaximin 
550 mg with or without a single oral 600 mg dose of cyclosporine, a potent P-glycoprotein 
inhibitor (RFDI1045).  Systemic rifaximin exposure (as measured by plasma Cmax and 
AUC0-∞) was increased following co-administration of rifaximin with cyclosporine in this 
study; mean Cmax was 40.0 ng/mL and mean AUC0-∞ was 314 ng.hr/mL following single 
doses of rifaximin plus cyclosporine compared with mean Cmax of 0.48 ng/mL and mean 
AUC0-∞ of 2.53 ng.hr/mL following single-dose rifaximin alone.  While the effect of the 
combination of hepatic impairment and P-glycoprotein on rifaximin pharmacokinetics has 
not been examined, a nonclinical toxicology study in dogs (BQG0004) provides greater than 
30-fold and greater than 24-fold safety exposure margins over the mean exposures for the P-
glycoprotein and hepatic impairment effects, respectively. 
4.3 Rationale for the Study 
A pharmacokinetic investigation of hepatically impaired subjects (RFHE3002PK) was 
conducted as a sub-study to Phase 3 open-label study RFHE3002 using a 550 mg BID 
rifaximin dosing regimen.  Systemic exposure to rifaximin was significantly higher in 
patients with hepatic impairment compared to healthy subjects.  Patients with hepatic 
impairment had mean apparent oral clearance reduced by 88% and the half-life was increased 
by 2-fold compared to healthy subjects. The mean Cmax and AUCtau were 6-fold and 11-fold 
higher, respectively, than in healthy subjects. When the PK parameters were analyzed by 


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liver function, the mean Cmax and AUCtau in patients in moderate (Child-Pugh B) hepatic 
impairment were 28% and 36% higher than in patients with mild (Child-Pugh A) hepatic 
impairment. The mean Cmax and AUCtau in patients increased as Model for End Stage Liver 
Diseases (MELD) score increased as well. Mean steady-state AUCtau values of 118 ng.h/mL, 
161 ng.h/mL, and 246 ng.h/mL were observed in Child-Pugh A, Child Pugh B, and Child-
Pugh C subjects, respectively.   
The clinical trials submitted as part of the approved new drug application (NDA) for 
rifaximin did not include patients with the most severe hepatic impairment (Model for End-
Stage Liver Disease [MELD] score >25) and only limited numbers of patients with Child-
Pugh C subjects. Therefore, as part of Phase 4 post marketing requirements requested by 
FDA, this study is being conducted to characterize the pharmacokinetics of rifaximin in 
patients with severe hepatic impairment.   
5 Study Objectives and Purpose 
5.1 Primary Objective 
The primary objective of this study is to characterize the steady state plasma PK of rifaximin 
(550 mg BID) in subjects with severe hepatic impairment (MELD 19 to 25 and MELD >25), 
as well as healthy subjects with normal hepatic function. 
5.2 Exploratory Objectives 
The exploratory objective of this study is to assess the effect of rifaximin administration on 
the intestinal microbiome in subjects with severe hepatic impairment (MELD 19 to 25 and 
MELD >25). 
5.3 Pharmacokinetic Endpoints 
Non-compartmental analysis of the plasma PK data for rifaximin and 25-desacetyl rifaximin, 
if measurable, will be performed using Phoenix WinNonlin version 6.3 or higher (Pharsight 
Corporation).  
Pharmacokinetic parameters to be estimated for rifaximin and 25-desacetyl rifaximin, if 
measurable, will include:  
x Maximum observed plasma concentration (Cmax).  
x Time of the maximum concentration (Tmax). 


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x Area under the plasma concentration versus time curve (AUC) during the 12-hour 
dose interval tau (τ). 
x AUC0-24. 
x AUClast. 
Other parameters, including apparent oral clearance (CL/F), volume of distribution (V/F), 
and half-life (t½) will be estimated as permitted by the data. 
5.4 Safety Endpoints 
The safety endpoints will be the following: 
x Incidence of treatment-emergent adverse events (AEs) and serious adverse events 
(SAEs).  
x Changes from baseline in clinical laboratory parameters. 
x Changes from baseline in vital signs. 
5.5 Exploratory Endpoints 
Gastrointestinal microbiota from stool samples and antibiotic resistance from bacteria 
cultured from stool samples will be analyzed before and after treatment with Rifaximin 550 
mg BID for one week. 
6 Investigational Plan 
6.1 Overview of Study Design 
This is a Phase 4, open-label, repeat-dose, parallel-design study in 12 subjects with severe 
hepatic impairment (MELD 19 to 25 and MELD >25) and 6 healthy subjects with normal 
hepatic function.  At least 6 hepatically impaired subjects will have MELD score >25.  
Efforts will be made to match subjects across groups in terms of age, weight, and sex.  
Eligible subjects will complete a Screening Period of up to 21 days prior to dosing (Day 1), a 
7-day Treatment Period, and Follow-Up by phone 3 (+1) days later.  Subjects will be 
admitted to the Clinical Research Unit (CRU) on the day prior to the initiation of dosing 
(Day -1; CRU admission).  A plasma sample for PK analysis will be collected on Day 1 prior 
the first dose. Subjects will receive 550 mg rifaximin BID approximately 12 hour apart for 6 
days beginning on Day 1 (Baseline).  On Day 7 (End of Treatment; EOT), the final dose of 
study drug will be administered in the morning following an overnight fast of 10 hours and 
plasma samples for PK analysis will be collected pre-dose (within 1 hour of the dose) and at 
0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours post-dose.  Additionally, a 
trough blood sample will be collected on Days 2-6, prior to administration of the first daily 


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dose of rifaximin.  Subjects will reside in the CRU for 9 days and will be discharged 
following the final PK sample collection if safety parameters are acceptable to the 
Investigator.  Each subject will be contacted for a follow-up phone call 3 + 1 days following 
end of treatment.  The study schematic is presented in Figure 1.  
Each dose will be administered with a total of 240 mL of water.  During the first 4 hours after 
dose administration, subjects should not lie flat; they should be allowed to sit or stand.  
Subjects will receive standardized meals while in the CRU.   
Subjects will discontinue non-study rifaximin on Day -1 and will only use rifaximin provided 
as study drug by the sponsor during the Treatment Period.  Subjects may resume their 
prescription rifaximin use following CRU discharge.   
Stool samples for microbiome analysis will be collected in the Screening Period and on 
Day 7 or 8. 
Figure 1: 
Study Design Schema 
 
7 Selection and Withdrawal of Subjects 
7.1 Inclusion/Exclusion for Subjects with Severe Hepatic Impairment 
7.1.1 
Hepatic Impairment Subject Inclusion Criteria 
A subject will be eligible for inclusion in this study if all of the following criteria are met: 
1. Subject provides written informed consent as documented on the Institutional Review 
Board (IRB) approved informed consent document.    
2. Subject is ≥18 years of age at Screening.  
3. Male or non-pregnant, non-breast feeding female. 
Day -1
Day 1
Day 2 to Day 6
Day 7
Day 8
Day -21 to Day -2
Screening Visit
Check-in
BID Rifaximin 550mg
Check-out
PK Sampling Times
Day 7: Pre-Dose, 0.25, 0.5, 
0.75, 1, 1.5, 2, 4, 6, 8, 10, 
12, & 16 hrs post-dose
Single stool 
sample during 
Screening
3 (+1) days from Day 7
Follow-up
Phone call
Single stool 
sample Days 7 or 
8 after last dose
PK Sampling Times
Pre-dose trough 
Days 2 - 6 
Baseline
PK Sample at 20 
& 24 hours post-
dose
Pre-Dose PK Sample
Note: Only the AM dose is given on Day 7


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4. Females of childbearing (reproductive) potential must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test at Screening and Day 
1, and agree to use an acceptable method of contraception throughout their 
participation in the study.  Examples of acceptable methods of contraception include 
double barrier methods (condom with spermicide jelly or diaphragm with 
spermicide), hormonal methods (oral contraceptives, patches or medroxyprogesterone 
acetate), or an intrauterine device with a documented failure rate of less than 1% per 
year.  Abstinence may be considered an acceptable method of contraception at the 
discretion of the investigator. 
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral 
tubal ligation) or who are postmenopausal (total cessation of menses for >1 year) will 
not be considered “females of childbearing potential.” 
5. Subject has a diagnosis of liver cirrhosis. 
6. Subject has a MELD score of ≥19 at Screening.  Note: At least 6 subjects will have a 
MELD score of >25. 
7. Subject is capable of understanding the requirements of the study, is willing to comply 
with all the study procedures, and is willing to attend all study visits. 
7.1.2 
Hepatic Impairment Subject Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria are 
met: 
1. Subject has known allergy to rifaximin, rifampin, or other rifamycins, or to excipients 
and/or vehicles used in the formulation or other clinically significant allergies. 
2. Subject has participated in an investigational drug or device study within the 30 days 
prior to Day 1 (Baseline). 
3. Subject is an employee of the site that is directly involved in the management, 
administration, or support of this study or is an immediate family member of the same. 
4. Subject has any concurrent illness (other than liver cirrhosis), disability or circumstance 
that may affect the interpretation of clinical data, could cause noncompliance with 
treatment or visits or otherwise contraindicates participation in this study in the opinion 
of the investigator. 
5. Subject is pregnant or at risk of pregnancy, or is lactating. 


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6. Subject has a history of tuberculosis infection or has received treatment for a 
tuberculosis infection.  To rule out tuberculosis infection, any one of the following 
criteria must apply: a) negative tuberculin skin test or negative tuberculosis blood test 
or b) if a subject has had a previous positive test, they must have a current negative 
chest X-ray (within 6 months of enrollment), or a current negative blood tuberculosis 
test.   
7. Subject is positive for human immunodeficiency virus (HIV), hepatitis B and/or 
hepatitis C on Screening assessments. 
8. Subject has been diagnosed with chronic respiratory insufficiency that in the opinion 
of the investigator would prevent completion of the study, interfere with analysis of 
study results, or negatively impact the subject’s participation in the study.   
9. Subject has renal insufficiency requiring routine dialysis. 
10. Subject has an active spontaneous bacterial peritonitis infection or subject requires 
daily prophylactic antibiotic therapy.   
11. Subject shows presence of intestinal obstruction or has inflammatory bowel disease. 
12. Subject has an active malignancy within the last 5 years (exceptions basal cell 
carcinomas of the skin, or if female, in situ cervical carcinoma that has been surgically 
excised). 
13. Subject has current GI bleeding or has had a GI hemorrhage of sufficient severity to 
require hospitalization and a transfusion of ≥ 2 units of blood within 3 months prior to 
Screening.  
14. Subject is anemic, as defined by hemoglobin of ≤8 g/dL.   
15. Subject has significant hypovolemia, or any electrolyte abnormality that can affect 
mental function (e.g., serum sodium <125 mmol/L, serum calcium >10 mg/dL). 
16. Subject has severe hypokalemia as defined by a serum potassium level <2.5 mmol/L. 
17. Subject’s current, required medications are prohibited concurrent medications per 
protocol.  Subjects will discontinue non-study rifaximin on Day -1 and will only use 
rifaximin provided as study drug by the sponsor during the Treatment Period through 
CRU discharge.   
18. Subject is positive for Clostridium difficile toxin via stool examination at Screening. 
NOTE:  Results of stool tests must be confirmed as negative for Toxins A and B prior 


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to Day -1.  A stool sample must be collected during the Screening Period.  Testing will 
be performed by enzyme immunoassay (EIA). 
19. Subject has an acute illness within 1 week of CRU admission. 
20. Subject has donated plasma within 7 days of drug administration. 
21. Subject has donated 1 or more pints of blood (or equivalent blood loss) within 30 days 
prior to drug administration.  
22. The subject has known or suspected illicit drug use within the past year, or positive 
findings on urine drug screen (except for allowed prescription medications), or has used 
any tobacco or nicotine products during the 6 months prior to screening and does not 
agree to refrain from using tobacco or nicotine products during the study. 
23. The subject has received any type of vaccination within 7 days of drug administration. 
24. Subject reports consumption of more than 2 alcoholic drinks daily, more than 14 
alcoholic drinks within 14 days before the screening evaluation (an alcoholic drink is 
defined as 1.5 oz liquor, one 12 oz can of beer, or 5 oz of wine), or consumption of any 
alcohol within 24 hours of first drug administration. 
25. The subject has consumed grapefruit juice, grapefruits, or Seville oranges within 24 
hours of first drug administration and does not agree to refrain from consuming these 
foods during the study. 
7.2 Inclusion/Exclusion for Healthy Subjects  
7.2.1 
Healthy Subjects Inclusion Criteria 
A healthy volunteer subject will be eligible for inclusion in this study if all of the following 
criteria are met: 
1. Subject provides written informed consent as documented on the Institutional Review 
Board (IRB) approved informed consent document.    
2. Subject is ≥18 years of age at Screening.  
3. Male or non-pregnant, non-breast feeding female. 
4. Females of childbearing (reproductive) potential must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test at Screening and Day 
1, and agree to use an acceptable method of contraception throughout their participation 
in the study.  Examples of acceptable methods of contraception include double barrier 


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methods (condom with spermicide jelly or diaphragm with spermicide), hormonal 
methods (oral contraceptives, patches or medroxyprogesterone acetate), or an 
intrauterine device with a documented failure rate of less than 1% per year.  Abstinence 
may be considered an acceptable method of contraception at the discretion of the 
investigator. 
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral 
tubal ligation) or who are postmenopausal (total cessation of menses for >1 year) will 
not be considered “females of childbearing potential.” 
5. Subject has normal (or abnormal and clinically insignificant) laboratory values at 
screening. 
6. Subject is medically normal with no significant abnormal findings at the Baseline 
physical examination. 
7. Subject is capable of understanding the requirements of the study, is willing to comply 
with all the study procedures, and is willing to attend all study visits. 
8. Subject has not consumed and agrees to abstain from taking any dietary supplements 
or non-prescription drugs (except as authorized by the Investigator and Medical 
Monitor) for 3 days prior to CRU admission through Follow-Up.  
9. Subject has not consumed and agrees to abstain from taking any prescription drugs 
(except as authorized by the Investigator and Medical Monitor) during the 14 days prior 
to CRU admission through Follow-Up. 
7.2.2 
Healthy Subjects Exclusion Criteria 
A healthy volunteer will not be eligible for inclusion in this study if any of the following 
criteria are met: 
1. Subject has known allergy to rifaximin, rifampin, or other rifamycins, or to excipients 
and/or vehicles used in the formulation or other clinically significant allergies. 
2. Subject has participated in an investigational drug or device study within the 30 days 
prior to Baseline (Day 1). 
3. Subject is an employee of the site that is directly involved in the management, 
administration, or support of this study or is an immediate family member of the same. 
4. Subject has any concurrent illness, disability or circumstance that may affect the 
interpretation of clinical data, could cause noncompliance with treatment or visits or 
otherwise contraindicates participation in this study in the opinion of the investigator. 


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5. Subject is pregnant or at risk of pregnancy, or is lactating. 
6. Subject has a history of tuberculosis infection or has received treatment for a 
tuberculosis infection.  To rule out tuberculosis infection, any one of the following 
criteria must apply: a) negative tuberculin skin test or negative tuberculosis blood test 
or b) if a subject has had a previous positive test, they must have a current negative 
chest X-ray (within 6 months of enrollment), or a current negative blood tuberculosis 
test.   
7. Subject is positive for human immunodeficiency virus (HIV), hepatitis B and/or 
hepatitis C on Screening assessments. 
8. Subject has an acute illness within 1 week of CRU admission. 
9. Subject has donated plasma within 7 days of drug administration. 
10. Subject has donated 1 or more pints of blood (or equivalent blood loss) within 30 days 
prior to drug administration.  
11. Subject is positive for Clostridium difficile toxin via stool examination at Screening. 
NOTE:  Results of stool tests must be confirmed as negative for Toxins A and B prior 
to Day -1.  A stool sample must be collected during the Screening Period.  Testing will 
be performed by enzyme immunoassay (EIA). 
12. Subject has any of the following laboratory abnormalities: 
a. Serum creatinine ≥ 1.5 × the upper limit of normal; 
b. Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, or 
total bilirubin ≥ 2 × the upper limit of normal; 
c. Hemoglobin < 10.0 g/dL; 
d. Absolute neutrophil count, or lymphocyte count ≤ 500 cells/μL. 
13. Subject has known or suspected illicit drug use within the past year, or positive findings 
on urine drug screen, or has used any tobacco or nicotine products during the 6 months 
prior to screening and does not agree to refrain from using tobacco or nicotine products 
during the study. 
14. Subject has received any type of vaccination within 7 days of drug administration. 
15. Subject reports consumption of more than 2 alcoholic drinks daily, more than 14 
alcoholic drinks within 14 days before the screening evaluation (an alcoholic drink is 


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defined as 1.5 oz liquor, one 12 oz can of beer, or 5 oz of wine), or consumption of any 
alcohol within 24 hours of first drug administration. 
16. Subject has consumed grapefruit juice, grapefruits, or Seville oranges within 24 hours 
of first drug administration and does not agree to refrain from consuming these foods 
during the study. 
17. Subject has consumed foods and substances that are known to inhibit and/or induce 
cytochrome P450 (CYP) or P-glycoprotein within 24 hours of first drug administration 
and does not agree to refrain from consuming these foods during the study, and/or has 
received treatment with any drugs known to be P-glycoprotein or CYP enzyme 
inducers or inhibitors within 30 days prior to first drug administration (see Appendix 2 
or http://medicine.iupui.edu/flockhart/table.htm for a complete listing of excluded 
potential CYP inducers/inhibitors). 
18. Subject has a history of Gilbert's disease or cholecystectomy. 
7.3 Screen Failures 
Screening evaluations will be used to determine eligibility of each subject for enrollment.  
Subjects who fail to meet eligibility criteria during the Screening period will be considered 
screen failures.  
7.4 Premature Subject Discontinuation from Study Treatment or Study 
Subjects will be encouraged to complete the study; however, they may voluntarily withdraw 
at any time.  Subjects withdrawn from the study may be replaced. 
In the event that a subject prematurely withdraws consent from further participation in the 
study for any reason other than an AE/SAE, the subject will be encouraged to complete the 
End of Treatment (Day 7) and all applicable assessments (except that plasma for PK will not 
be collected from subjects who early terminate the study) in order to obtain full data capture 
for that subject.  
If a subject prematurely withdraws from the study at any time due to an AE or SAE, 
applicable End of Treatment (Day 7) assessments will be completed, and the subject will be 
followed for at least 14 days, or until resolution or stabilization of the condition resulting in 
withdrawal has been confirmed. 
For all cases of premature withdrawal from the study, the investigator must provide the 
reason for discontinuation on the appropriate CRF page. 


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A decision by the investigator to discontinue a subject from study treatment and/or study 
participation should be discussed with the Sponsor. 
8 Treatment Plan 
8.1 Methods of Assigning Subjects to Treatment Groups 
Not applicable 
8.2 Randomization and Blinding 
This is an open-label, single arm study.  Study drug will not be blinded. 
8.3 Concomitant Medications and Therapies 
Subjects are not to take any medications (prescription or over the counter), alternative 
therapy(ies), or herbal supplement(s) during this study (14 days prior to dosing through end-
of study), unless the investigator, after discussion with the medical monitor (if feasible), 
determines use of medication is required; contraceptives are allowed during this study as 
defined in inclusion criterion.  All medications, alternative therapy(ies), and/or herbal 
supplement(s) used during Screening and any ongoing or new medications / therapies taken 
while the subject is participating in the study will be recorded in the source documents (drug 
name, start and stop dates, and indication) and on the appropriate page of the electronic case 
report form (CRF). 
For hepatically impaired subjects, stable doses of the following medications will be allowed 
during the study: 
x Stable dose of antidepressants 
x Stable opioid regimen. Stable regimen includes dose, pattern of use (e.g., as needed 
[PRN] or chronic dosing) combinations of opioids, and route of administration (e.g., 
oral or transdermal administration; parenteral administration is prohibited) for at least 
4 weeks prior to Visit 2 (Baseline). The dose and regimen of opioid(s) should remain 
unchanged (i.e., < 20% change in dose and no change in opioid[s]) throughout the 
trial).  
x Subjects who require concomitant antibiotic therapy with a once per week dosing 
regimen (e.g., ciprofloxacin 500-750 mg dose/week) for spontaneous bacterial 


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peritonitis (SBP) may participate in the study if they started their therapy at least 1 
month prior to Visit 1 (Screening).  
x Neurontin (gabapentin) and Lyrica (pregabalin) if a stable dose has been taken for at 
least 2 months prior to Visit 1 (Screening) and the dosage is expected to remain 
unchanged throughout the trial.  
x Laxatives or stool softeners will be allowed to treat constipation at the discretion of 
the investigator but should be used sparingly to avoid diarrhea.  
8.3.1 
Prohibited Therapy 
Use of the following medications is prohibited within the inclusion/exclusion specified pre-
study timeframes and throughout the study unless otherwise noted: 
x Milk thistle within 30 days of Day 1 (Baseline). 
x Investigational drugs within 30 days of Day 1 (Baseline). 
x Daily prophylactic antibiotics within 30 days of Day 1 (Baseline). 
The following concomitant medications are prohibited after Screening and throughout the 
study: 
x Non-study rifaximin (200 mg or 550 mg tablets) is prohibited beginning Day 1 and 
throughout the Treatment Period.  Subjects may resume their prescription rifaximin 
use following CRU discharge. 
x Psychoactive, neuroactive agents (except as allowed per protocol) and psychotropic 
drugs. 
x Warfarin-type anticoagulants. 
x Rifampin or other rifamycin derivatives (except study drug). 
x Alternative, herbal or complementary therapies for liver cirrhosis other than those 
required to manage fluid and electrolyte homeostasis. 
Consumption of certain foods and substances that are known to inhibit and/or induce CYP 
are not permitted during this study as specified in exclusion criteria.   (See Appendix 16.2 or 
http://medicine.iupui.edu/clinpharm/ddis/main-table for a complete listing of excluded 
potential CYP inducers/inhibitors). 


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All over the counter and prescription medications are prohibited for healthy subjects.  If any 
medication is required during the study for healthy subjects, the subject may be discontinued 
from the study at the discretion of the Investigator or the Sponsor. 
8.4 Treatment Compliance 
All doses of study drug will be administered in the CRU under study staff supervision to 
monitor and document treatment compliance.   
8.5 Protocol Deviations and Violations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. Deviations usually have an impact on individual patients or a small group of 
patients and do not involve inclusion/exclusion or primary endpoint criteria.  
A protocol violation occurs when there is non-adherence to the protocol that results in a 
significant, additional risk to the patient, when the patient or investigator has failed to adhere 
to significant protocol requirements (inclusion/exclusion criteria) and the patient was 
enrolled without prior sponsor approval, or when there is non-adherence to FDA regulations 
and/or ICH GCP guideline. 
The investigator or designee must document and explain in the patients’ source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol 
amendment(s) should be submitted to the IRB/IEC for review and approval, to the sponsor 
for agreement, and to the regulatory authorities, if required. 
9 Study Drug Materials and Management 
All study medication will be dispensed by the pharmacy or an appropriately qualified 
member of the study staff assigned by the investigator to this task. 
9.1 Formulation and Supply 
Rifaximin will be supplied as pink-colored, coated, oval, biconvex tablets each containing 
550 mg rifaximin.  Inactive ingredients include: colloidal silicon dioxide, disodium edetate, 


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glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron 
oxide, sodium starch glycolate, talc, and titanium dioxide. 
9.1.1 
Packaging and Labeling 
The rifaximin 550 mg tablets will be supplied in appropriate containers and labeled for 
clinical trial material according to applicable FDA and ICH guidelines.    
9.1.2 
Storage, Handling, and Disposal of Study Drug  
The investigator has overall responsibility for ensuring that study medication is stored in a 
secure, limited-access location under the specified appropriate storage conditions until it is 
assigned and handed over to the study subject.  The locked area will be maintained under 
controlled temperature conditions at 20-25°C (68-77°F); excursions are permitted to 15 to 
30°C (59 to 86° F).  Limited responsibility may be delegated to the pharmacy or member of 
the study team, but this delegation must be documented.  Study medication will be 
distributed by the pharmacy or assigned member of the study team.  Temperature monitoring 
is required at the storage location to ensure that the investigational product is maintained 
within the required temperature range.  The investigator is responsible for ensuring that the 
temperature is monitored throughout the total duration of the trial and that records are 
maintained.  No study medication stock or returned inventory may be removed from the 
investigational site without prior consent by the Sponsor except as required to be dispensed 
to subjects participating in the study.  All returned and unused study medication shall be 
returned or destroyed as instructed by the Sponsor. 
9.1.3 
Dosing (including Dosing Schedule) 
Each subject will receive twice daily doses of rifaximin (approximately 12 hours apart) for 6 
days followed by the morning dose only on Day 7. 
9.1.4 
Rationale for Dose Selection 
The dose regimen for rifaximin used in this study (550 mg BID) is approved by the FDA for 
the reduction of risk in overt HE in patients with liver cirrhosis. 
9.2 Study Drug Accountability 
Only authorized site personnel may dispense study drug.  Investigational drug orders, records 
of study drug receipt, dispensing, and running inventory will be examined and reconciled 
throughout the study.  Only subjects enrolled in the study may receive study drug in 
accordance with all applicable regulatory requirements. 


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Study drug reconciliation will be conducted periodically during monitoring visits to ensure 
appropriate receipt, storage, dispensing and documentation of returned study drug.  Upon 
completion of the study, this material will be subjected to final inspection and reconciliation. 
The following information will be collected regarding study drug and recorded in the 
subject’s source document: 
x Subject dosing compliance (%) for study drug. 
10 Study Procedures and Evaluations 
A schedule of assessments to be performed during the study is provided in Overall Time and 
Events Schedule, at Section 16.1.  
The subject should rest in the seated position for approximately 5 minutes prior to collection 
of any assessments. 
10.1 Schedule of Evaluations and Procedures 
10.1.1 Screening (Day –21 to Day -2) 
After signing the informed consent, patients will undergo the screening procedures to 
confirm eligibility to participate in the study. 
During Screening, the following procedures/assessments will be performed: 
x Obtain written informed consent prior to performing any study evaluations. 
x Assign subject identification number. 
x Record medical history and demographic information (date of birth, sex, ethnicity, and 
race), including verification of tuberculosis history.  Note: Efforts will be made to 
match subjects across groups for age, weight and sex. 
x Review subject eligibility. 
x Assessment of MELD score and Child-Pugh classification (A, B, or C). 
x Perform physical examination. 
x Measure height and weight.  Height and weight will be used to calculate body mass 
index (BMI). 


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x Perform vital signs (oral temperature, seated blood pressure and pulse).  Subjects 
should be allowed to rest in the seated position for approximately 5 minutes prior to 
collection of blood pressure and pulse. 
x Obtain 12-lead ECG.  Assessments for clinically significant findings may be repeated 
if necessary.   
x Collect samples for laboratory tests: 
o Blood samples for hematology, chemistry, coagulation, and testing for 
tuberculosis, HIV, hepatitis B surface antigen, and hepatitis C virus. 
o Blood sample for serum pregnancy testing for females of childbearing 
potential.  A negative pregnancy test must be confirmed prior to check-in on 
Day -1.   
o Urine for a urine pregnancy test for females of child-bearing potential.  A 
negative pregnancy test must be confirmed to continue participation in the 
study.   
o Urine samples for urinalysis and urine drug/nicotine/alcohol screen. 
NOTE: Blood sample collection for the clinically significant laboratory results 
may be repeated, if necessary.  Results from all laboratory tests must be 
received and reviewed prior to CRU check-in on Day -1.   
x Record any AEs and SAEs since the time of informed consent.   
x Record concomitant medications. 
x Stool collection and processing for: 
o Presence of enteric infections (this stool sample analysis must be available 
prior to check-in on Day -1). 
o Microbiota characterization. 
NOTE:  If the subject cannot produce a stool sample at Screening, dispense a stool sample kit 
and instruct subjects on collection of the stool sample to be returned to the site at least 7 
days prior to Day -1.  The results for the stool sample are needed before check-in to the 
CRU.   


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10.1.2 CRU Check-in: Day-1 
The following are to be completed upon checking into the facility on Day -1 (subjects should 
check-in the day prior to dosing and will be confined until the completion of the blood 
sample collection for PK on Day 8): 
x Check-in to CRU. 
x Review subject eligibility. 
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.   
x Perform vital sign assessments (oral temperature, seated blood pressure and pulse).  
Subjects should be allowed to rest in the seated position for approximately 5 minutes 
prior to collection of blood pressure and pulse. 
x Assess for AEs and SAEs. 
x Assess for changes in concomitant medications. 
Note: subjects will have to fast overnight (water provided ad libitum) for approximately 10 
hours prior to the AM dosing on Day 1. 
10.1.3 Day 1 (Baseline; pre-dose) 
The following procedures will be performed on Day 1 pre-dose: 
x Review subject eligibility. 
x Assessment of MELD score and Child-Pugh classification (A, B, or C). 
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.   
x Perform pre-dose vital sign assessments (oral temperature, seated blood pressure and 
pulse).  Subjects should be allowed to rest in the seated position for approximately 5 
minutes prior to collection of blood pressure and pulse.   
x Collect samples for laboratory tests: 
o Blood samples for hematology, chemistry, and coagulation. 
o Blood sample for serum cystatin C. 
o Urine samples for urinalysis and urine drug/nicotine/alcohol screen. 


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o For females of childbearing potential, blood for a serum pregnancy test and 
urine for a urine pregnancy test.  A negative urine pregnancy test must be 
confirmed prior to dosing.  
x Assess for changes in concomitant medications. 
x Assess for pre-dose AEs and SAEs. 
x Collect a pre-dose PK blood sample (3 mL in a sodium heparin tube) within 1 hour 
prior to administration of first daily dose of rifaximin 550 mg. 
10.1.4 Day 1 (Dosing and Post-dose) 
x Administer 550 mg tablet of rifaximin with a total of 240 mL of water.  Actual time of 
dose should be recorded in source documents and eCRF.  The fast should continue for 
at least 1 hour after dosing.  Water is permitted ad libitum.  The subject should remain 
upright for 4 hours after the dose administration.   
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.   
x Administer the 2nd daily dose of rifaximin 550 mg approximately 12 hours after the 
first dose.  Actual time of the dose should be recorded in source documents and eCRF. 
x Perform vital sign assessment 6 hours post-dose (oral temperature, seated blood 
pressure and pulse).  Subjects should be allowed to rest in the seated position for 
approximately 5 minutes prior to collection of blood pressure and pulse. 
x Assess for AEs and SAEs.   
x Asses for changes in concomitant medications 
10.1.5 Day 2 – Day 6 
The following procedures will be performed on Days 2 through 6: 
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.   
x Collect a blood sample for PK every morning prior to administration of the first daily 
dose of rifaximin 550 mg.  Administer rifaximin 550 mg BID.  Each dose of rifaximin 
should be given with a total of 240 mL of water.  The two doses should be given 
approximately 12 hours apart, and the actual time of dosing should be recorded in 
source documents and eCRF.   


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x Assess for AEs and SAEs.   
x Asses for changes in concomitant medications. 
Note: subjects will have to fast overnight (water provided ad libitum) for approximately 10 
hours prior to the AM dosing on Day 7. 
10.1.6 Day 7 (End of Treatment [EOT] or Early Termination) 
The following procedures will be performed on Day 7: 
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.   
x Perform pre-dose vital sign assessments (oral temperature, seated blood pressure and 
pulse).  Subjects should be allowed to rest in the seated position for approximately 5 
minutes prior to collection of blood pressure and pulse.  
x Collect samples for laboratory tests: 
o Blood samples for hematology, chemistry, coagulation and serum pregnancy 
test (for females of child-bearing potential). 
o Urine samples for urinalysis. 
x Collect a pre-dose PK blood sample (3 mL in a sodium heparin tube) within 1 hour 
prior to administration of first daily dose of rifaximin 550 mg.   
x Administer morning 550 mg tablet of rifaximin with a total of 240 mL of water.  
Actual time of dose should be recorded in source documents and eCRF.  The fast 
should continue for at least 1 hour after dosing.  Water is permitted ad libitum.  The 
subject should remain upright for 4 hours after the dose administration.   
x Collect PK blood samples (3 mL in sodium heparin tube) at 0.25, 0.5, 0.75, 1, 1.5, 2, 
4, 6, 8, 10, 12, and 16 hours with a window of ± 5 minutes from the 0.25 hour time 
point to the 4 hour time point, and ± 15 minutes from the 6 hour time point to the 16 
hour time point.     
x On Day 7, subjects will be asked to provide a stool sample for microbiota 
characterization prior to leaving the CRU on Day 8.  Subjects can provide a stool 
sample at any time on Day 7 or 8. 
x Assess for AEs and SAEs.   
x Asses for changes in concomitant medications. 


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x Assessment of MELD score and Child-Pugh classification (A, B, or C). 
10.1.7 Day 8 
x Perform symptom-driven physical exam (general appearance, skin, thorax/lungs, 
cardiovascular, abdomen, extremities), if necessary.  
x Assess for AEs and SAEs. 
x Asses for changes in concomitant medications. 
x Collect a PK blood samples (3 mL in sodium heparin tube) at 20 and 24 hours (± 15 
minutes) post Day 7 dose.  
x Discharge from the CRU after the 24 hour PK blood sample collection.   
NOTE: Subjects must provide a stool sample on Day 7 or 8 prior to discharge from the CRU. 
10.1.8 3 days (+ 1) after EOT: Follow-Up Phone Call 
The follow-up phone call will occur 2 (+1) days following discharge from the clinic on Day 
8.  For early termination, follow-up phone call will occur 3 + 1 days after the last study drug 
dose. 
x Record AEs and SAEs.   
x Record concomitant medication. 
10.2 Assessment of Pharmacokinetics 
Pharmacokinetic endpoints are presented in Section 5.3.  Pharmacokinetic analyses to be 
performed are described in Section 12.6.1. 
Blood Samples 
Blood samples (3 mL) will be drawn into 3 mL sodium heparin tubes at the following times 
(actual blood collection times will be recorded in the source documents and eCRF):  
 
x Day 1: pre-dose (within 1 hour before dosing). 
x Day 2-6: trough sample collected prior to administration of the first daily dose of 
rifaximin (AM dose). 
x Day 7/8: pre-dose (within 1 hour before dosing), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 
12, 16, 20, and 24 hours. 


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Windows for blood samples are ± 5 minutes from the 0.25 hour time point to the 4 hour time 
point, and ± 15 minutes from the 6 hour time point to the 24 hour time point. 
Collecting, Processing, and Shipping PK Samples 
Blood samples will be drawn and processed for plasma as described in the Laboratory 
Manual.  The yield of plasma will be subdivided into 2 samples (~0.5 mL).  One set (Set 1) 
of these samples will be shipped to MicroConstants, Inc. (San Diego, California, USA) for 
analysis upon processing of the final PK sample for each subject.  The second set of samples 
(Set 2) will be shipped to MicroConstants, Inc., as directed by the Sponsor. 
Bioanalytical Methods 
Bioanalysis of all plasma samples will be performed by MicroConstants, Inc. (San Diego, 
California, USA).  Plasma concentrations of rifaximin and 25-desacetyl rifaximin will be 
determined using a validated reversed-phase high performance liquid chromatographic 
method with tandem quadrupole mass spectrometric detection using a validated analytical 
procedure.  The lower limit of quantification, deviation of calibration standards from the 
theoretical value, and precision will be established using standard methods.  Performance of 
the assay during the analysis of unknown samples will be monitored and reported. 
10.3 Stool Testing/Microbiome Assessment 
Fresh stool samples will be collected if possible.  If the subject cannot produce a sample during 
the visit, the subject will be issued a collection kit and asked to collect a specimen at home, 
refrigerate it immediately, and bring it to the clinic as soon as possible.  Stool samples will be 
separated into 2 mL aliquots in polypropylene cryovials, stored at ≤ -20° C at the clinical site, 
and shipped on dry ice to the central laboratory. 
x Screening: 
o Testing will be performed prior to Day -1 (Check-in) to identify the presence 
of enteric infections.  A negative test must be confirmed for all subjects to 
enroll, including negative C. difficile Toxin A & B.  Stool samples will also be 
collected for microbiota testing. 
x Treatment: 
o Stool samples will be collected for microbiota testing on Day 7/8.  
Microbiota Characterization (Susceptibility Testing):  This study will characterize the 
susceptibility of the stool microbiota (specifically Gram-negative rods and C. difficile) to 
rifaximin, rifampin, and other selected antibiotics of clinical interest.  For Gram-negative 
cultures, colonies will be grown on MacConkey agar and minimum inhibitory concentrations 


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(MICs) will be determined by the microbroth dilution method (per CLSI document M-7 A8).  
For C. difficile anaerobic chamber cultures, tested antibiotics will include rifaximin, 
vancomycin, metronidazole, and fidaxomicin.  The assessment of bacteria (aerobic and 
anaerobic) will be characterized by the number of colony forming units/gram of stool for 
both anaerobic and aerobic bacteria. 
Microbiota Characterization (Composition, Diversity, DNA Sequencing):  This study 
will characterize intestinal microbiota in terms of composition and diversity, as well as 
sequencing for specific organisms of interest.  Bacterial DNA will be isolated from fecal 
samples, and the hyper-variable regions of the 16S rRNA gene will be amplified using two-
step PCR with Illumina HiSeq2000 sequencing technology.  
Long-term storage for future exploratory analysis.  Subjects must be advised of and 
provide consent to this stool collection for storage. 
10.4 Assessment of Safety 
10.4.1 Adverse Events 
Safety data collection for this study begins at the time of the subject’s signing of the 
informed consent document according to the operating definitions defined in Section 11.1 of 
the protocol.  The investigator is responsible for the detection and documentation of events 
that meet the definition of an AE or SAE as provided in this protocol.  Assessments of 
occurrences of AEs or SAEs should be conducted during each study visit or as reported by 
the subject outside of scheduled visits.  In order to fulfill safety reporting obligations, the 
investigator should include in his or her assessment any AEs resulting from study 
participation regardless of relation to study drug (e.g., complications resulting from the 
taking of a blood sample) 
10.4.2 Physical Examination 
A physical examination will be performed at Screening. 
A symptom-driven physical exam will be performed at any time during the study as deemed 
necessary by the investigator. 
10.4.3 Vital Signs 
Vital signs will include seated blood pressure (mmHg), pulse (beats per minute), and oral 
temperature (°C) and will be obtained after the subject has been seated for at least 5 minutes.  
Blood pressure will be measured on the same arm throughout the study.  Blood pressure, 


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pulse, and oral temperature will be obtained at Screening, after CRU Check-in on Day -1, 
prior to dosing on Day 1, 6 hours post-dose on Day 1, and at Day 7/Early Termination.  
Height and weight will be measured at Screening to calculate BMI. 
10.4.4 Clinical Laboratory Tests 
Clinical laboratory evaluations are to be performed by licensed clinical laboratory.  Blood 
samples for clinical laboratory tests are to be drawn at Screening, Day 1, and Day 7/ET, prior 
to dosing. 
Additional laboratory testing may occur as needed for safety assessments during the study.   
The clinical laboratory parameters to be evaluated are as follows: 
x Hematology: hemoglobin, hematocrit, red blood cell count, red cell mass 
measurements, white blood cell count with differential, and platelet count (Screening, 
Day 1 pre-dose and Day 7/ET) 
x QuantiFERON®-TB Gold test (Screening) 
x Serum cystatin C (Day 1 pre-dose) 
x Blood Chemistry: Alanine aminotransferase, aspartate aminotransferase, gamma-
glutamyl transferase, alkaline phosphatase, total bilirubin, blood urea nitrogen, 
creatinine, calculated creatinine clearance, uric acid, electrolytes (Na+, K+, HCO3- and 
Cl-), lactate dehydrogenase, calcium, albumin, glucose, cholesterol (total and HDL), 
and triglycerides (Screening, Day 1 pre-dose and Day 7/ET) 
x Coagulation: Prothrombin time and international normalized ratio. (Screening, Day 1 
pre-dose and Day 7/ET) 
x Urinalysis: Routine urine analysis (including, but not limited to, white blood cell 
count, red blood cell count, and protein) as indicated by dipstick.  If there are any 
positive findings microscopic examination should be performed to quantify the results 
(Screening and Day 7/ET) 
x HIV and hepatitis B & C: Testing will be performed for HIV, hepatitis B surface 
antigen, and hepatitis C virus (Screening) 


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x Urine alcohol/drug/nicotine screen: Urine will be collected for a drug screening test 
from all subjects.  At a minimum, the sample will be tested for the presence of 
cocaine, tetrahydrocannabinol, barbiturates, amphetamines, benzodiazepines, opiates, 
and cotinine (Screening and Day 1 pre-dose) 
10.4.5 Electrocardiogram 
At Screening, a 12-lead ECG will be recorded on all subjects (hepatically impaired and 
healthy subjects) in the supine position after 5 minutes of rest to assess for cardiac 
abnormalities. 
10.4.6 Pregnancy Testing 
A urine pregnancy test will be performed for all females of child-bearing potential at 
Screening and Day -1.  A serum pregnancy test will be performed at Screening, Day -1 and 
Day 7/Early Termination. 
10.5 Other Assessments 
10.5.1 Medical History 
Each subject’s complete medical history is to be recorded in source documents and the 
appropriate eCRF pages during Visit 1 (Screening). Medical history must include the current 
MELD score, the current Child-Pugh score, etiology and the date of first diagnosis of chronic 
liver impairment (cirrhosis). 
10.5.2 Model for End Stage Liver Disease 
MELD is a scoring system used in assessing the severity of CLD.  
x The OPTN MELD calculator will be used for MELD calculations in this study; 
https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ (or 
most current link available for the OPTN MELD calculator)    
10.5.3 Child-Pugh Classification System 
The Child-Pugh classification system for the severity of liver disease is listed below.  The 
classification system determines severity of liver disease according to the degree of ascites 
(via clinical assessment), the serum concentrations of bilirubin and albumin, International 
Normalized Ratio, and the degree of encephalopathy. 


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Parameter 
Score Assigned 
1 
2 
3 
Ascites 
Absent 
Mild 
Moderate to Severe 
Bilirubin, mg/dL 
< 2 
2-3 
> 3 
Albumin, g/dL 
> 3.5 
2.8-3.5 
< 2.8 
International 
Normalized Ratio 
< 1.7 
1.71 - 2.20 
> 2.20 
Encephalopathy* 
None 
Grade 1-2 
Grade 3-4 
 
Encephalopathy is classified as Grade 0-4 using the Conn scoring system below:   
x Grade 0 = No personality or behavioral abnormality detected. 
x Grade 1 = Trivial lack of awareness, euphoria or anxiety; shortened attention span, 
impairment of addition or subtraction. 
x Grade 2 = Lethargy; disorientation for time; obvious personality change; 
inappropriate behavior. 
x Grade 3 = Somnolence to semi-stupor, responsive to stimuli; confused; gross 
disorientation; bizarre behavior. 
x Grade 4 = Coma; unable to test mental state. 
Grade 
Score 
A: well-compensated disease 
5 to 6 
B: significant functional compromise 
7 to 9 
C: decompensated disease 
10 to 15 
 
A total score of 5 to 6 is considered grade A (well-compensated disease); 7 to 9 is grade B 
(significant functional compromise); and 10 to 15 is grade C (decompensated disease). 
10.5.4 Concomitant Medications 
All concomitant medications will be collected and recorded on the source documents and 
eCRF from Screening through end of study. 


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11 Safety Reporting 
The Sponsor maintains a robust pharmacovigilance system comprised of a governance 
framework and standard operating procedures supporting a systematic process for review, 
evaluation, and management of accumulating safety data from clinical trials and other 
sources to: 
x Identify a potential new safety signal; 
x Ensure that an investigational product’s risks are adequately assessed and 
communicated to investigators, IRBs/IECs, and regulatory bodies during clinical 
development. 
Findings and/or safety data obtained during this study will provide information for the 
overall review of safety that is conducted by the Sponsor on a routine basis.  The Sponsor 
will report expeditiously any findings from clinical trials (ongoing or completed), 
epidemiological studies, pooled analysis of multiple studies, and findings from animal or in 
vitro testing that suggest a significant risk in humans exposed to the study product.  
Safety data collection for this study begins at the time of the subject’s signing of the 
informed consent document according to the operating definitions defined in this section of 
the protocol.  The investigator is responsible for the detection and documentation of events 
that meet the definition of an unanticipated problem (refer to protocol Section 10.1), AE or 
SAE. 
11.1 Operating Definitions for Assessing Safety 
11.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a study product and which does not necessarily have a causal relationship with 
the treatment. 
An AE can therefore be any unfavorable and unintended sign (that could include a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a study product, without any judgment about causality (i.e., whether or not considered 
related to the study product). 


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Additionally, an event that is associated with study participation (regardless of administration 
of or relationship to study drug) should be treated as a reportable adverse event for this 
protocol (e.g., complications resulting from the taking of a blood sample or performance of a 
protocol required procedure).  
An AE does include the following: 
x Exacerbation or worsening of a pre-existing illness. 
NOTE: If the pre-existing illness is the disease under study, then “exacerbation” refers to an 
unexpected worsening from the condition at baseline. 
x Increase in frequency or intensity of a pre-existing episodic event or condition. 
x Condition detected or diagnosed after study product administration even though it may 
have been present prior to the start of the study. 
x Symptom associated with disease not previously reported by the subject.  
An AE does not include the following: 
x Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
as event terms; the condition that led to the procedure is the AE if it meets the 
definition of an AE. 
x Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for cosmetic elective surgery; and social and/or convenience 
admissions). 
x Overdose of either study product or concurrent medication without any signs or 
symptoms.  
x Symptoms associated with disease, which are consistent with the subject’s usual 
clinical course; unless the subject experiences worsening of their symptom(s) or the 
symptom(s) meet the criteria for an SAE. 
11.1.2 Serious Adverse Event 
A SAE is any AE, occurring at any dose, which results in any of the following outcomes 
(“Occurring at any dose” does not imply that the subject received study product.): 
x Results in death. 
x Is life threatening. 
NOTE: Life-threatening means that the subject was, in the view of the investigator or 
Sponsor, at immediate risk of death at the time of the event.  This definition does not refer 
to an event which hypothetically might have caused death if it were more severe.  
x Requires inpatient hospitalization or prolongation of existing hospitalization. 


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NOTE: Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered to be an AE.  “In-patient” hospitalization means the subject has 
been formally admitted to a hospital for medical reasons.  This may or may not be 
overnight.  It does not include presentation at a casualty or emergency room. 
x A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle) that may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
x A congenital anomaly or birth defect in the offspring of a subject who received study 
product. 
x Important medical events that do not result in death, are not life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   
NOTE: Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
11.1.3 Assessment of Severity 
The severity assigned to an AE should be determined by the maximum severity of the AE. 
The categories described below should be used to estimate the severity of AEs: 
x Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
x Moderate: Mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/therapy required 
x Severe: Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required; hospitalization or prolongation of current 
hospitalization possible; may be incapacitating or life threatening 


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11.1.4 Assessment of Causality 
The investigator should assess the relationship of the AE, if any, to the study drug using the 
following definitions: 
Related: Event or laboratory test abnormality with reasonable time relationship to drug 
intake.  Cannot be attributed to disease or other drugs.  Response to withdrawal is clinically 
reasonable and re-challenge is not required. 
Probable: Event or laboratory test abnormality with reasonable time relationship to drug 
intake. Unlikely to be attributed to disease or other drugs. Response to withdrawal is 
clinically reasonable and re-challenge is not required. 
Possible: Event or laboratory test abnormality with reasonable time relationship to drug 
intake. Could also be explained by disease or other drugs. Information on drug withdrawal 
may be lacking or unclear. 
Unlikely: Event or laboratory test abnormality with a time to drug intake that makes a 
relationship improbable (but not impossible). Disease or other drugs provide plausible 
explanations.   
Not Related: Event or laboratory test abnormality with a time to drug intake that makes a 
relationship implausible. Disease or other drugs provide plausible explanations. 
11.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., abnormal findings during examinations or ECG monitoring) that are 
judged by the investigator as clinically significant must be recorded as AEs or SAEs if they 
meet the definition of an AE or SAE.  The investigator should exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment (including ECG monitoring) is clinically significant. 
11.3 Method and Frequency for Detecting AEs and SAEs 
At each visit, after the subject has had an opportunity to spontaneously mention any 
problems, the investigator should inquire about AEs by asking the following standard 
questions: 
1. "Have you had any (other) medical problems since your last visit/assessment?" 


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2. "Have you taken any new medicines, other than those given to you in this study, since 
your last visit/assessment?" 
11.3.1 Time period for Detecting and Reporting of AEs and SAEs 
From the time of informed consent through study completion/withdrawal, including the 
follow-up period. 
11.3.2 Post-Study SAEs 
Investigators are not obligated to actively seek SAE information in former study participants, 
but investigators are encouraged to notify the Sponsor of any SAEs of which they become 
aware occurring at any time after a subject has discontinued or completed the study that they 
judge may be reasonably related to study treatment or study participation. 
11.4 Documenting AEs and SAEs 
All AEs that occur after the subject has signed the informed consent document and during the 
course of the study, regardless of causality or seriousness, will be assessed and recorded in 
the subject’s medical records and in the eCRF. In addition, SAEs must be documented on the 
paper SAE Report Form.  
A separate paper SAE Report Form should be used for each SAE.  However, if at the time of 
initial reporting, multiple SAEs are present that are temporally and/or clinically related, they 
may be reported on the same SAE Report Form. 
The investigator should attempt to establish a diagnosis for the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and SAE and not the individual signs/symptoms. 
For clinically significant abnormal laboratory findings or other abnormal assessments 
meeting the definition of an AE or SAE, a diagnosis, if known (or clinical signs and 
symptoms if diagnosis is unknown), should be recorded by the investigator.  If a diagnosis is 
unknown and clinical signs and symptoms are not present, then the abnormal finding should 
be recorded. When documenting as an SAE on the SAE Report Form, relevant laboratory 
data should either be recorded in the ‘Details of Relevant Assessments’ section of the SAE 
Report Form (including the reference range and units) or copies of the laboratory report (with 
reference ranges and units) should be sent with the SAE Report Form. 
The SAE Report Form should be completed as thoroughly as possible and signed by the 
investigator or his/her designee before transmittal to the CRO.  It is very important that the 


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investigator provide his/her assessment of causality to study product at the time of initial 
SAE reporting. 
11.5 Follow-Up of AEs and SAEs 
All AEs, regardless of seriousness, must be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or the subject is lost to follow-up.  The 
investigator is responsible to ensure that follow-up includes any supplemental investigations 
as may be indicated to elucidate as completely as practical the nature and/or causality of the 
AE.  This may include additional laboratory tests or investigations, histopathological 
examinations, relevant hospital records (i.e., discharge summary), or consultation with other 
health care professionals. 
The Sponsor may request that the investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations.  If a subject dies during participation in the 
study or during a recognized follow-up period, the Sponsor should be provided with a copy 
of any postmortem findings, including histopathology. 
For SAEs, new or updated information should be recorded on the originally completed paper 
SAE Report Form and all changes signed and dated by the investigator or designee.  By 
signing the SAE Report Form, the investigator or designee attests to the accuracy and 
completeness of the data and that he/she has reviewed and approved the report being 
submitted.  The investigational sites IRB must be notified about SAEs in accordance with the 
requirements of the governing IRB. 
11.6 Prompt Reporting of SAEs to Sponsor 
SAEs must be reported promptly to the CRO once the investigator determines that the event 
meets the protocol definition of a SAE. 
Prompt reporting of a SAE requires the following: 
x Completion and transmission of the SAE Report Form to the CRO via fax or email 
within 24 hours of the investigator’s knowledge of the event.  In parallel, a 
corresponding AE with the SAE details should be entered into the AE eCRF within 48 
hours of submitting the paper SAE Report Form.  
Prompt reporting of additional information for previously reported SAEs should follow the 
same reporting timeframe as initial reports. In addition, the corresponding AE in the AE 
eCRF (as applicable) should be updated to ensure all data points documented in the AE eCRF 
are aligned with the matching data points on the paper SAE Report Form. 


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11.7 Pregnancy Reporting
Pregnancies detected in subjects assigned to study treatment should be reported within 24 
hours of investigator’s awareness to CRO via fax or email, using the Sponsor’s Pregnancy 
Notification Form.  If a female subject becomes pregnant following assignment to study 
treatment, the study product will be immediately discontinued and the subject will be 
followed until the outcome of the pregnancy is known. 
The CRO should be notified via fax or email of any updates on the status of the pregnancy as 
soon as the information becomes available by update and/or amendment of the initial 
pregnancy notification form. 
Although pregnancy occurring in a clinical study is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy, for medical reasons, will be 
recorded as an AE or SAE and followed as such.
11.8 Transmission of SAE Reports and Pregnancy Notification Forms
Completed SAE Report Forms and completed pregnancy notification forms will be 
transmitted to the CRO via the fax number provided below: 
11.9 Regulatory Reporting Requirements for SAEs
The investigator, or responsible person per local requirements, must comply with the 
applicable local regulatory requirements related to the reporting of SAEs and IND safety 
reports to regulatory authorities and their IRB.
12 Statistics
A detailed statistical analysis plan (SAP) will be prepared for this study.  The plan will 
contain a discussion of the statistical methods, a description of the computational algorithms 
and data handling conventions, and specifications for the data summaries and listings.  It will 
be finalized before database lock. 
12.1 Randomization
This is an open-label, non-randomized study. 


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12.2 Determination of Sample Size 
Six subjects per group is the minimum recommendation from FDA guidance 
“Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, 
and Impact on Dosing and Labeling.”  A total of 12 subjects with severe liver impairment 
will be enrolled to meet the combined objectives of effects of liver impairment on the PK of 
rifaximin. 
12.3 Analysis Populations 
The Intent-to-Treat (ITT) population will be used for safety analyses.  The ITT population 
will include all subjects who ingested at least one dose of study drug.     
The PK population will include subjects from whom sufficient data are obtained for 
calculation of rifaximin plasma PK parameters.   
12.4 Subject Disposition 
Subject disposition will be summarized using descriptive statistics. 
12.5 Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive 
statistics. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Medical history data will be listed in subject data listings. 
12.6 Analysis Methods 
Pharmacokinetic and safety endpoints are shown in Section 5.3 and Section 5.4. 
12.6.1 Pharmacokinetic Analyses 
All subjects who receive study medication and have sufficient samples collected for valid 
estimation of PK parameters during any dosing period will be considered evaluable for the 
PK analyses.  Descriptive PK parameters for rifaximin and 25-desacetyl rifaximin will be 
determined using Phoenix WinNonlin version 6.3 (Pharsight Corporation) or higher.   
At a minimum, the following PK Parameters will be calculated, data permitting: 


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Cmax,ss 
Maximum observed concentration at steady-state, observed by inspection of 
individual study participant plasma concentration time plots. 
Tmax,ss 
Time of maximum observed concentration at steady-state, obtained directly 
from the observed concentration time data 
λz 
Terminal phase elimination rate constant, estimated by linear regression of 
logarithmically transformed concentration versus time data.  Calculation of λz 
requires a minimum of 3 data points after (and not including) Cmax.  The 
adjusted R2 for the linear regression must be at least 0.80. 
t½ 
Terminal phase half-life, estimated using the equation [ln(2)/λz] 
AUCτ 
At steady state, the area under the plasma concentration time curve from time 0 
to the end of the dosing interval (12 hours).  
CL/F 
(Rifaximin 
only) 
Apparent plasma clearance divided by bioavailability, calculated as Dose/AUCτ 
at steady state. 
 
Rifaximin and 25-desacetyl rifaximin plasma concentrations will be summarized by hepatic 
function group for each collection time point and collection period with statistics of the 
number of subjects evaluated (N), arithmetic mean, geometric mean, standard deviation, 
coefficient of variation, median, minimum, and maximum.  
An analysis of variance (ANOVA) will be performed and PK parameters of Cmax and AUCτ 
for rifaximin and 25-desacetyl rifaximin will be natural log transformed prior to analysis.  
The 90% confidence intervals (CIs) of the hepatic impairment group mean relative to the 
matched control group mean will be obtained.  The effect of hepatic impairment will be 
assessed by examining the 90% CIs for the mean ratio of the hepatic impairment group 
relative to the matched healthy group. 
A continuous analysis using linear regression will be performed to evaluate the relationship 
between estimated creatinine clearance and rifaximin CL/F. 


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12.6.2 Microbiome Analyses 
Gastrointestinal microbiota data will be summarized descriptively by total counts (per gram 
of stool sample); by species of aerobic and anaerobic bacteria; and by bacterial resistance to 
antibiotics (including rifaximin and rifampin). 
12.6.3 Safety Analyses 
Safety analyses will be descriptive and evaluations will be based on the incidence, intensity 
and types of treatment-emergent AEs, and changes in clinical laboratory results and vital 
signs.  Concomitant medication will be summarized descriptively.  Physical examination 
findings will be listed.  Adverse events will be coded using the MedDRA coding dictionary.  
Concomitant medications will be coded using the World Health Organization Drug 
dictionary. 
12.6.3.1 Extent of Exposure and Treatment Compliance 
Exposure to study drug and treatment compliance will be summarized descriptively. 
12.6.3.2 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Affairs 
(MedDRA) coding dictionary.  Treatment-emergent AEs will be defined as any event with a 
start date occurring on or after treatment on Day 1. 
The incidence of treatment-emergent AEs will be summarized by body system and MedDRA 
preferred term, overall and by treatment group.  If a subject reports the same AE more than 
once, then that subject will only be counted once for the summary of that AE, using the most 
severe intensity. 
Treatment-emergent AEs will be summarized as follows: 
x All treatment-emergent AEs. 
x All treatment-emergent AEs by intensity. 
x All treatment-emergent AEs by relationship to study drug. 
x All treatment-emergent SAEs. 
x All treatment-emergent AEs that led to premature discontinuation of study drug. 


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12.6.3.3 Clinical Laboratory Assessments 
Hematology, blood chemistry, and urinalysis parameters will be summarized at baseline and 
at each time point, as well as changes from baseline to end of study.  Laboratory values and 
changes from baseline in laboratory values will be summarized descriptively. 
A summary of shifts from baseline to final evaluation will be given for each parameter.  The 
normal range for each parameter will be used to create categories of low, normal, or high.  
Any result higher than upper limit of normal or lower than lower limit of normal will be 
categorized as high or low respectively, and any result within the lower and upper limits of 
normal will be categorized as normal.  The number and percentage of subjects in each shift 
category from baseline to final evaluation will be shown for each parameter. 
All potentially clinically significant values for clinical laboratory tests will be assessed by the 
investigator.  Out of range laboratory values that may be potentially clinically significant will 
be flagged for review. 
12.6.3.4 Vital Signs 
Vital sign measurements will be summarized at baseline and at each time point.  In addition, 
changes from baseline to last visit in vital sign measurements will be summarized.  For each 
summary, the N, mean, median, SD, minimum, and maximum values will be presented. 
12.6.3.5 Concomitant Medications 
Concomitant medications taken from Screening and during the study will be categorized by 
the World Health Organization (WHO) classification for therapeutic class and drug name and 
summarized by number and percentage of subjects. 
12.7 Statistical and Analytical Issues 
12.7.1 Adjustment for Covariates 
Not Applicable. 
12.7.2 Handling of Dropouts or Missing Data 
Subjects who discontinue from the study will not be replaced.  No imputations will be made 
for missing data.    
12.7.3 Interim Analysis and Data Monitoring 
No interim analysis is planned. 


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13 Quality Control and Quality Assurance 
13.1 Investigator Information and Training 
The investigators and essential support staff will be trained by the Sponsor (or designee) in 
regards to Good Clinical Practices (GCPs) and all aspects of protocol execution.  It is the 
responsibility of the investigator to train ancillary study staff. 
13.2 Study Monitoring 
This study will be monitored by the Sponsor (or designee) in accordance with GCPs and 
applicable regulations.  By signing this protocol, the investigator agrees to periodic, onsite 
monitoring of all appropriate study documentation. 
The progress of the study will be monitored by periodic onsite visits and frequent 
communications between the Sponsor (or designee) and the investigator (either by phone, 
fax, email, or post). 
During these contacts, the monitor will: 
x Check and assess the progress of the study; 
x Review study data collected; 
x Conduct source document verification; and 
x Identify any issues and address their resolution. 
The objectives of monitoring procedures are to verify that data is authentic, accurate, and 
complete; that the safety and rights of subjects are being protected; and that the study is 
conducted in accordance with the currently approved protocol (and any amendments), GCP 
and all applicable regulatory requirements. 
13.3 Audits and Inspections 
At its discretion, the Sponsor (or designee) may conduct a quality assurance audit of this 
study.  If such an audit occurs, the investigator agrees to allow the auditor direct access to all 
relevant documents and to schedule his/her time and the time of his/her staff to permit 
meetings with the auditor to discuss findings and any relevant issues. 
In addition, regulatory agencies may conduct a regulatory inspection of this study.  If the 
investigator is notified of an inspection by a regulatory authority, the investigator agrees to 
notify the Sponsor immediately.  The investigator agrees to allow the inspector direct access 


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to all relevant documents and to schedule his/her time and the time of his/her staff to permit 
meetings with the inspector to discuss findings and any relevant issues. 
13.4 Data Quality Assurance 
All assessments performed will be accurately documented in the subject’s source documents 
and CRFs. The investigator or designee will enter the information required by the protocol 
into the source documents and CRFs provided by the Sponsor or designee. 
The investigators must read the protocol thoroughly and follow the instructions exactly. Any 
deviations should be agreed to by prior discussion between the Sponsor and the investigator, 
with appropriate written protocol amendments made prior to implementing the agreed 
changes. Any amendment containing major modifications, particularly if it may involve an 
increased risk to the subjects, will be approved by the IRB before it may be implemented. No 
change in the conduct of the study may be instituted without written approval from the 
Sponsor. 
14 Ethics and Administrative Issues 
The investigator and the study staff are responsible for conducting this study in accordance 
with the applicable principles which have their origins in the Declaration of Helsinki, ICH, 
GCPs, and all other applicable laws and regulations. 
14.1 Institutional Review Board (IRB) Approval 
This protocol, the informed consent document, relevant supporting information, and all types 
of subject recruitment or advertisement information must be approved by the appropriate IRB 
before the study is initiated.  Any amendments to the protocol also must be approved, where 
necessary, by the IRB prior to implementing changes in the study.  Documentation of these 
approvals must be provided to the Sponsor prior to the initiation of the amendment.   
The investigator’s responsibilities regarding the IRB are as follows:  
x Obtain IRB approval of the protocol, informed consent document, and any 
advertisements for subject recruitment prior to their use. 
x Obtain IRB approval for any protocol amendments and revisions to the informed 
consent document before implementing the changes. 
x Provide the IRB with any required information before or during the study. 


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x Submit progress reports to the IRB, as required, during the conduct of the study; 
request re-review and approval of the study, as needed; provide copies of all IRB re-
approvals and relevant communication to the Sponsor. 
x Notify the IRB within 10 days (unless required sooner by IRB) of all serious and 
unexpected AEs related to the study medications that are reported to you by the Sponsor. 
The investigator is responsible for updating the IRB on the progress of the study and of 
any changes made to the protocol at least once a year or at regular intervals as deemed 
appropriate. The investigator must also keep the IRB informed of any AEs, according to 
the IRB policy. 
x Notify the Sponsor within 24 hours of awareness and the IRB within in 10 days (unless 
required sooner by IRB) of all unanticipated problems involving risk to subjects or 
others. For the purposes of this study, an Unanticipated Problem is defined as any 
incident, experience, or outcome that meets all of the following criteria: 
o Unexpected in nature, severity, or frequency (i.e., not described in study-
related documents, such as the IRB-approved protocol, informed consent 
document, US Prescribing Information (USPI) 
o Related or possibly related to participation in the research (i.e., possibly 
related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
o Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
14.2 Subject Information and Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation in layman’s terms regarding the nature 
of the study, along with the aims, methods, objectives, and any potential risks.  The informed 
consent document must be appropriately signed and dated by the subject or the subject’s 
legally authorized representative and the person obtaining the consent (if required by the 
IRB) prior to conducting/obtaining any study-related assessments, including the 
discontinuation of any medications prohibited for the study. 
If the informed consent document is amended during the study, the investigator must follow 
all applicable regulatory requirements pertaining to approval of the amended informed 
consent document by the IRB and use of the amended document (including for ongoing 
subjects, as directed by the IRB). 


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The informed consent document also shall contain the subject's authorization for the use and 
disclosure of his/her protected health information (PHI) in connection with the study as 
defined by Health Insurance Portability and Accountability Act of 1996 (HIPAA) or 
equivalent local regulations in studies conducted outside the United States.  The 
authorization shall include at a minimum a clear description of the following: the duration of 
the authorization, the subject's right of access to the PHI (or any suspension thereof during 
the course of the study), type of information to be used/disclosed in the study, the names or 
classes of parties that may use or disclose the PHI, the purpose of the use/disclosure of PHI, 
the extent of the subject's right to revoke the authorization, the extent to which participation 
in the study is conditioned on signing the authorization, and the potential for redisclosure of 
PHI or other such information as may be required by local regulations outside of the United 
States. 
The original and any amended signed and dated informed consent documents must be 
retained at the study site; and a copy must be given to the subject or subject’s legally 
authorized representative(s). 
14.3 Study and Site Closure or Discontinuation 
Upon completion of the study, the following activities, when applicable, must be conducted 
by the monitor in conjunction with the investigator, as appropriate: 
x Return of all study data to the Sponsor (or designee). 
x Data clarifications and/or resolutions. 
x Accounting, reconciliation, and final disposition of used and unused study drug. 
x Review of site study records for completeness. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single site or at all sites at any time and for any reason.  If such action is 
taken, the Sponsor will discuss this with the investigator (including the reasons for taking 
such action) at that time.  The Sponsor will promptly inform all other investigators and/or 
institutions conducting the study if the study is suspended or terminated for safety reasons, 
and also will inform the regulatory authorities of the suspension or termination of the study 
and the reason(s) for the action.  If required by applicable regulations, the investigator must 
inform the IRB promptly and provide the reason for the suspension or termination. 
14.3.1 Study Discontinuation 
Should the investigator, the Sponsor, the FDA, or local regulatory authorities become aware 
of conditions arising during the conduct of this study that may warrant the cessation of the 


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study, such action may be taken.  Prior to such action, consultation between the Sponsor, the 
investigator, and, as appropriate, the FDA and/or local regulatory authorities will take place.  
Conditions that may result in the termination of the study or parts thereof include, but are not 
limited to, the following: 
x The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.  
x A decision on the part of the Sponsor to alter, suspend, or discontinue the development 
of the investigational product. 
14.3.2 Study Site Discontinuation 
The study site can be discontinued at the request of the Sponsor, the investigator, or by the 
FDA or local regulatory authorities. 
Conditions that may warrant discontinuation of the study site include, but are not limited to, 
any of the following: 
x Failure of the investigator to accrue subjects into the study at an acceptable rate. 
x Failure of the investigator to comply with current GCPs and/or applicable regulations. 
x Submission of knowingly false information from the research facility to the FDA or 
other regulatory authorities. 
x Insufficient adherence to protocol requirements and procedures. 
If the study is prematurely discontinued at a study site, all study data must be returned to the 
Sponsor or designee.  In addition, the site must conduct final disposition of all used and 
unused study drug in accordance with the Sponsor’s procedures for the study.  Study 
termination and follow-up will be performed in compliance with the conditions set forth in 
GCPs and applicable regulations. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the Sponsor. 
14.4 Data Handling and Record Keeping 
14.4.1 Case Report Forms and Database Processing 
Subject data will be collected in an eCRF using Electronic Data Capture (EDC).  The EDC 
system will be Part 11 compliant and will have a documented audit trail for all changes made 
to the eCRF.   


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The investigator or designee must enter all required subject data using the specified data 
collection method defined by the Sponsor.  The investigator must complete a declaration on 
the eCRF attesting to his/her responsibility for the quality of all data entered, and that the 
data represents a complete and accurate record of each subject's participation in the study. 
Electronic CRF data will be provided to the investigator at the end of the study and will need 
to be retained by the investigator. 
14.4.2 Source Documents 
Source documents consist of, but are not limited to, subject hospital charts, clinic notes, 
subject medical records, original test results, laboratory data, worksheets, drug accountability 
records, consent forms, etc.  Source documents must be available for review and inspection 
during onsite monitoring of the study by the Sponsor, their designees, IRB and/or appropriate 
regulatory authorities. 
14.4.3 Subject Tracking 
A drug accountability log, subject identification log (to be retained by the investigator only), 
and subject screening/enrollment log will be used to track subject participation in the study. 
14.4.4 Study Files 
The investigator study file and all source data will be maintained by the investigator as 
required by applicable federal and local regulations.  These files are subject to inspection as 
described under Section 13.3 of this protocol.  If an investigator moves, withdraws from an 
investigation or retires, the investigator must notify the Sponsor.  The investigator 
understands and agrees to maintain study files for the required retention period, as defined in 
applicable federal and local regulations. 
14.4.5 Data Management 
Data management will be performed in accordance with the standard operating procedures of 
the Sponsor or its designee.  
14.5 Confidentiality 
The anonymity of subjects participating in this study will be maintained.  The investigator 
will only provide subject initials and subject number on study documents submitted to the 
Sponsor.  The investigator will make every effort to maintain the confidentiality of 
documents that identify the subject by name (e.g., signed informed consent documents, 
laboratory reports, clinic charts), except to the extent necessary to allow inspection by the 
FDA or other regulatory authorities.  Should the name and/or address of a subject 
participating in this trial be on a document for submission to the FDA or other regulatory 


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authorities (e.g., laboratory report), the name and/or address will be completely blocked out 
and replaced with the subject initials and number prior to submission. 
The investigator and other study site personnel will keep confidential any information 
provided by the Sponsor (including this protocol) related to this study and all data and 
records generated in the course of conducting the study, and will not use the information, 
data, or records for any purpose other than conducting the study.  These restrictions do not 
apply to: (1) information which becomes publicly available through no fault of the 
investigator or study site personnel; (2) information which it is necessary to disclose in 
confidence to an IRB solely for the evaluation of the study; (3) information which it is 
necessary to disclose in order to provide appropriate medical care to a study subject, or (4) 
study results which may be published as described in Section 14.8. If a written contract for 
the conduct of the study which includes confidentiality provisions inconsistent with this 
statement is executed, that contract’s confidentiality provisions shall apply rather than this 
statement. 
14.6 Record Retention 
The investigator should properly store and maintain all study records in accordance with 
Sponsor directives. All records relating to the conduct of this study are to be retained by the 
investigator until notified by the sponsor in writing that the records may be destroyed. 
The investigator will allow representatives of the sponsor’s monitoring team, the governing 
IRB/IEC, the FDA, and other applicable regulatory agencies to inspect all study records, 
CRFs, and corresponding portions of the subject’s clinic and/or hospital medical records at 
regular intervals throughout the study. These inspections are for the purpose of verifying 
adherence to the protocol, completeness and accuracy of the data being entered onto the 
eCRF, and compliance with FDA or other regulatory agency regulations. 
14.7 Financing and Insurance 
14.7.1 Finance 
The study is supported by Salix Pharmaceuticals, Inc., a a division of VPNA. 
14.7.2 Insurance and Indemnification 
Documentation of product liability insurance is on file at the Sponsor and is available upon 
request. 


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14.8 Publication Policy 
All data furnished to the investigator and his/her staff and all data obtained through this 
protocol will be regarded as confidential and proprietary in nature and will not be disclosed 
to any third party, except for the FDA or other regulatory body, without written consent from 
the Sponsor. 
15 References 
Bajaj JS. Review article: the modern management of hepatic encephalopathy. [Review]. 
Alimentary Pharmacology & Therapeutics 2010;31(5):537-47. 
Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in 
hepatic encephalopathy. N Engl J Med 2010 Mar 25;362(12):1071-81. 
Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic 
significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999 
May;30(5):890-5. 
Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in 
nonsystemic gastrointestinal infections. Expert Rev Anti Infect Ther 2005 Apr;3(2):201-11. 
Gillis JC, Brogden RN. Rifaximin. A review of its antibacterial activity, pharmacokinetic 
properties and therapeutic potential in conditions mediated by gastrointestinal bacteria. Drugs 
1995 Mar;49(3):467-84. 
Hoover WW, Gerlach EH, Hoban DJ, Eliopoulos GM, Pfaller MA, Jones RN. Antimicrobial 
activity and spectrum of rifaximin, a new topical rifamycin derivative. Diagn Microbiol 
Infect Dis 1993 Feb;16(2):111-8. 
Leevy CB, Phillips JA. Hospitalizations During the Use of Rifaximin Versus Lactulose for 
the Treatment of Hepatic Encephalopathy. Dig Dis Sci 2007 Mar;52(3). 
Miyazaki ET, Dos SR, Jr., Miyazaki MC, Domingos NM, Felicio HC, Rocha MF, et al. 
Patients on the waiting list for liver transplantation: caregiver burden and stress. Liver 
Transpl 2010 Oct;16(10):1164-8. 
Pleis JR, Lucas JW. Summary Health Statistics for U.S. Adults: National Health Interview 
Survey, 2007.  2009. Hyattsvile, MD, National Center for Health Statistics.  


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Poordad F. Review article: the burden of hepatic encephalopathy. Alimentary Pharmacology 
& Therapeutics 2007;25(s1):3-9. 
Product Information for Xifaxan® (rifaximin) Tablets [package insert], Salix 
Pharmaceuticals, Inc. Raleigh, NC; 2014 Mar 12.  
Stewart CA, Malinchoc M, Kim WR, kamath P. Hepatic encephalopathy as a predictor of 
survival in patients with endstage liver disease. Liver Int 2009;29:1365-71. 


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16 Appendices 
16.1 Overall Time and Events Schedule 
 
Screening 
CRU 
Admission Baseline 
Treatment 
Follow-
Up 
Study Assessments 
Day -21 to 
Day -2 
Day -1 
Day 1 
Pre-
dose 
Day 1 
Post-dose 
Days 
2-6 
Day 7 
EOT b/ 
Early Term 
Day 8 
3 days 
(+1) from 
EOT 
Informed consent 
X 
 
 
 
 
 
 
 
Assign subject number 
X 
 
 
 
 
 
 
 
Medical history/ 
demographics 
X 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 
X 
 
 
 
 
 
MELD/Child-Pugh 
assessment 
X 
 
X 
 
 
X 
 
 
Physical Examination a 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Vital signs c 
X 
X 
X 
X 
 
X 
 
 
12-lead ECG d 
X 
 
 
 
 
 
 
 
Clinical chemistry / 
hematology /coagulation 
X 
 
X 
 
 
X 
 
 
HIV, hepatitis (B & C) 
X 
 
 
 
 
 
 
 
Tuberculosis test 
X 
 
 
 
 
 
 
 
Pregnancy test 
X (urine, 
serum) 
 
X (urine, 
serum) 
 
 
X(serum) 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
Urine drug/nicotine/alcohol 
X 
 
X 
 
 
 
 
 
AEs and SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Serum cystatin C 
 
 
X 
 
 
 
 
 
Drug Administration 
 
 
 
X 
X 
X 
 
 
PK blood samples e 
 
 
X 
 
X 
X 
X 
 
Stool sample for enteric 
infections 
X 
 
 
 
 
 
 
 
Stool sample for microbiome 
X 
 
 
 
 
X f 
X f 
 
CRU check-in 
 
X 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
X 
 
Follow-up Phone Call 
 
 
 
 
 
 
 
X 
a. 
A full physical examination will be conducted at Screening. A symptom-driven physical exam will be performed at any 
time during the study as deemed necessary by the investigator. 
b. 
EOT=End of Treatment 
c. 
Seated blood pressure, pulse, and oral temperature will be obtained at Screening, after CRU Check-in on Day -1, prior 
to dosing on Day 1, 6 hours post-dose on Day 1, and at Day 7/Early Termination. 
d. 
Both hepatically impaired and healthy subjects will undergo an ECG recording.  
e. 
Plasma for PK will not be collected from subjects who terminate early from the study. 
f. 
Subjects must provide a stool sample on Day 7 or 8 prior to discharge from the CRU. 
  
 


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16.2 CYTOCHROME P450 ENZYME INDUCER/INHIBITOR COMPOUNDS* 
*Adapted from http://medicine.iupui.edu/clinpharm/ddis/main-table 
Inducers 
1A2 
2C19 
2C9 
2D6 
2E1 
3A4,5,7 
broccoli  
carbamazepine  
rifampin  
dexamethasone  
ethanol  
efavirenz 
brussel sprouts 
norethindrone  
secobarbital 
rifampin 
isoniazid 
nevirapine  
char-grilled meat  prednisone  
 
 
 
barbiturates  
insulin  
rifampin 
 
 
 
carbamazepine  
Methyl 
 
 
 
 
glucocorticoids  
cholanthrene  
 
 
 
 
phenobarbital  
nafcillin  
 
 
 
 
phenytoin  
beta-
naphthoflavone  
 
 
 
 
pioglitazone  
omeprazole  
 
 
 
 
rifampin  
tobacco  
 
 
 
 
St.  John's Wort  
 
 
 
 
 
troglitazone 
Inhibitors 
1A2 
2C19 
2C9 
2D6 
2E1 
3A4,5,7 
amiodarone  
cimetidine  
amiodarone  
amiodarone  
disulfiram 
delaviridine 
cimetidine  
felbamate  
fluconazole  
celecoxib  
diethyl-
dithiocarbamate 
indinavir 
fluoroquinolones  
fluoxetine  
fluvastatin  
chlorpheniramine   
nelfinavir 
fluvoxamine 
fluvoxamine  
fluvoxamine  
cimetidine  
 
ritonavir 
furafylline  
indomethacin  
isoniazid  
clomipramine  
 
saquinavir  
Interferon 
ketoconazole  
lovastatin  
cocaine 
 
amiodarone  
methoxsalen  
lansoprazole  
paroxetine  
doxorubicin  
 
cimetidine  
mibefradil  
omeprazole  
phenylbutazone  
fluoxetine  
 
ciprofloxacin  
ticlopidine 
paroxetine  
probenicid  
halofantrine  
 
clarithromycin  
 
probenicid  
sertraline  
haloperidol  
 
diltiazem  
 
ticlopidine  
sulfaphenazole 
levomepromazine   
erythromycin  
 
topiramate 
teniposide  
methadone  
 
fluconazole  
 
 
trimethoprim  
mibefradil  
 
fluvoxamine  
 
 
zafirlukast 
moclobemide  
 
gestodene ++  
 
 
 
paroxetine  
 
grapefruit juice  
 
 
 
quinidine 
 
itraconazole  
 
 
 
ranitidine  
 
ketoconazole  
 
 
 
ritonavir  
 
mifepristone  
 
 
 
terbinafine 
 
nefazodone  
 
 
 
 
 
norfloxacin  


Protocol RFPK4045 
Valeant Research & Development 
Clinical Study Protocol  
Amendment 1 08Oct2018 
 
CONFIDENTIAL 
63 
16.2 CYTOCHROME P450 ENZYME INDUCER/INHIBITOR COMPOUNDS* 
(CONT'D) 
Inhibitors 
1A2 
2C19 
2C9 
2D6 
2E1 
3A4,5,7 
 
 
 
 
 
norfluoxetine  
 
 
 
 
 
mibefradil  
 
 
 
 
 
troleandomycin 
 
 
 
 
 
diethyl- 
dithiocarbamate