Clinical trial NCT03515044
Conditions: Overt Hepatic Encephalopathy
Sponsor: Bausch Health Americas, Inc.
Start date: 2018-09-13; Completion date: 2020-03-12
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to Assess the Efficacy and Safety of Rifaximin Soluble Solid Dispersion (SSD) Tablets Plus Lactulose for the Treatment of Overt Hepatic Encephalopathy (OHE).

Detailed description:
The primary objective of this study is to assess the efficacy of rifaximin SSD plus lactulose versus placebo plus lactulose for the treatment of overt hepatic encephalopathy (OHE). The secondary objectives of this study are to assess the safety of rifaximin SSD in subjects with OHE and to assess the effects of treatment with rifaximin SSD on key secondary endpoints.

Arms: arm 1: 40 mg Rifaximin immediate release (IR) rifaximin SSD once daily (QD) and lactulose arm 2: 40 mg Rifaximin immediate release (IR) rifaximin SSD twice daily (BID) and lactulose arm 3: 80 mg Rifaximin sustained extended release (SER) rifaximin SSD once daily (QD) and lactulose arm 4: 80 mg Rifaximin sustained extended release (SER) rifaximin SSD twice daily (BID) and lactulose arm 5: SSD placebo twice daily (BID) and lactulose
Interventions: intervention 1: 40 mg Rifaximin SSD once daily intervention 2: 40 mg Rifaximin SSD twice daily intervention 3: 80 mg Rifaximin SSD once daily intervention 4: 80 mg Rifaximin SSD twice daily intervention 5: Placebo
Intervention descriptions: intervention 1: SSD once daily (QD) intervention 2: SSD twice daily (BID) intervention 3: SSD once daily (QD) intervention 4: SSD twice daily (BID) intervention 5: Administered twice daily (BID)

Protocol documents:
Prot_SAP_000.pdf: 
1 TITLE PAGE 
 
Clinical Study Protocol 
RNHE2041 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Multicenter Study to Assess the Efficacy and Safety of Rifaximin 
Soluble Solid Dispersion (SSD) Tablets Plus Lactulose for the 
Treatment of Overt Hepatic Encephalopathy (OHE) 
 
IND: 
116602 
Developmental phase: 
Phase 2 
Study design: 
Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Multicenter, 5-Arm 
Original Protocol: 
Amendment 1: 
Amendment 2: 
Amendment 3:  
29 March 2018 
20 September 2018 
05 September 2019 
08 January 2020 
Sponsor: 
Salix Pharmaceuticals, a division of Bausch Health US, LLC 
400 Somerset Corporate Blvd 
Bridgewater, NJ 08807 
Main office: (908) 927-1400 
Fax: (908) 927-1794 
 
CONFIDENTIAL 
Nothing herein is to be disclosed without prior approval of the sponsor. 
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. or its affiliates. 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. 
Study #RNHE2041 – Abbreviated Clinical Study Report
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
 
Study #RNHE2041 – Abbreviated Clinical Study Report


Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 3 
 
Personnel Responsible for Conducting the Study  
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter 
Study to Assess the Efficacy and Safety of Rifaximin Soluble Solid Dispersion (SSD) 
Tablets Plus Lactulose for the Treatment of Overt Hepatic Encephalopathy (OHE) 
PROTOCOL:  RNHE2041 
 
 
 
 
Study #RNHE2041 – Abbreviated Clinical Study Report
Page 16-10


Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 4 
Principal Investigator Protocol Agreement Page 
I agree: 
• 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. 
• 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 (e.g., 
advertisements), and any other written information to be provided to the subjects, 
before initiating this clinical study. 
• 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. 
• To permit direct monitoring and auditing by the sponsor or sponsor’s 
representatives and inspection by the appropriate regulatory authority(ies). 
• 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 Rifaximin 
Investigator Brochure or equivalent document and approved product label (if 
applicable). 
• 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. 
• 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) 
 
 
 
 
Principal Investigator (signature) 
 
Date 
Study #RNHE2041 – Abbreviated Clinical Study Report
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 5 
2.0 
SYNOPSIS 
Name of Sponsor/Company: Salix Pharmaceuticals, a division of Bausch Health US, LLC 
Name of Investigational Product: Rifaximin SSD [40 mg immediate release (IR) and 80 mg 
sustained extended release (SER)] tablets 
Name of Active Ingredient: Rifaximin 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter Study 
to Assess the Efficacy and Safety of Rifaximin Soluble Solid Dispersion (SSD) Tablets Plus Lactulose 
for the Treatment of Overt Hepatic Encephalopathy (OHE). 
Number of clinical sites: Multi-center (approximately 60 US sites; expansion to ex-US countries 
possible) 
Number of Subjects Planned: Approximately 325 subjects (65 subjects per treatment arm) 
Objectives:  
The primary objective of this study is to assess the efficacy of rifaximin SSD plus lactulose versus 
placebo plus lactulose for the treatment of overt hepatic encephalopathy (OHE). 
The secondary objectives of this study are to assess the safety of rifaximin SSD in subjects with OHE 
and to assess the effects of treatment with rifaximin SSD on key secondary endpoints. 
Endpoints: 
Efficacy Phase 
     Primary: 
• 
Time to OHE resolution determined using the Hepatic Encephalopathy Grading Instrument 
(HEGI).  
     Secondary: 
• 
Time to OHE resolution defined as a West Haven Criteria (WHC) score of 0 or 1 
• 
Time to 1 unit decrease in WHC score during the randomized treatment period. 
• 
Change from Baseline in WHC score at Day 15 or end of blinded treatment period, 
whichever occurs first. 
• 
Change from Baseline in HEGI score at Day 15 or end of blinded treatment period, 
whichever occurs first. 
• 
Time to improvement in HEGI score. 
• 
Length of hospitalization from baseline to end of blinded treatment phase. 
      Safety: 
• 
Incidence of treatment-emergent adverse events (TEAEs). 
• 
Change from baseline to OHE resolution  in vital sign measurements and clinical 
laboratory values 
• 
Incidence of infections, (e.g., spontaneous bacterial peritonitis (SBP), urinary tract 
infection, pneumonia, bacteremia, and cellulitis) 
      Open-label Safety Follow-up Phase: 
• 
Reoccurrence of OHE during the 30 day follow-up period. 
• 
Readmission to hospital during the 30 day follow-up period. 
• 
Change from Baseline to study exit in indices of Health Outcome using the Caregiver 
Burden Inventory (CBI) 
• 
Change during Follow-up Phase (from first follow-up visit post OHE resolution to study 
exit) in Chronic Liver Disease Questionnaire (CLDQ). 
  
Study #RNHE2041 – Abbreviated Clinical Study Report
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 6 
Methodology: 
This is a randomized, double-blind, placebo-controlled study of Rifaximin SSD in male and female 
subjects hospitalized with OHE. There will be two treatment phases: (1) a safety and efficacy phase in 
which blinded treatment will be either (a) rifaximin SSD and lactulose or (b) placebo and lactulose; and 
(2) an open-label safety follow-up phase where all subjects will receive 30 days of treatment with 
Xifaxan® 550 mg BID. 
There will be five cohorts of 65 subjects each. 
• 
Cohort 1 (Treatment A) will enroll 65 subjects with OHE, to be administered 40 mg 
immediate release (IR) rifaximin SSD once daily (QD)* and lactulose**. 
• 
Cohort 2 (Treatment B) will enroll 65 subjects with OHE, to be administered 40 mg 
immediate release (IR) rifaximin SSD twice daily (BID) and lactulose**. 
• 
Cohort 3 (Treatment C) will enroll 65 subjects with OHE to be administered 80 mg 
sustained extended release (SER) rifaximin SSD once daily (QD)* and lactulose**. 
• 
Cohort 4 (Treatment D) will enroll 65 subjects with OHE to be administered 80 mg 
sustained extended release (SER) rifaximin SSD twice daily (BID) and lactulose**. 
• 
Cohort 5 (Treatment E) will enroll 65 subjects with OHE, to be administered SSD placebo 
twice daily (BID) and lactulose**.  
All subjects who complete the blinded randomized treatment phase (defined as confirmed resolution of 
OHE), will continue on to the safety follow-up period receive 30 days of open-label treatment with 
Xifaxan® 550 mg upon hospital discharge, regardless of the treatment arm to which they were 
previously randomized. 
An interim analysis will be conducted when at least 10 subjects per treatment group have completed 
participation in the blinded treatment period of the study. The unblinded interim results will be 
reviewed by a few designated members of the Sponsor’s team who do not have direct involvement with 
the ongoing study. The interim results will not be shared outside of the small designated team, and no 
changes will be made to the ongoing study based on the interim study results. 
*Blinding will be maintained in the QD SSD cohorts by administering placebo as the second daily 
dose. All subjects will receive two tablets per day at 12 hour (±2 hour) intervals.   
** The adult, oral dosage is 2 to 3 tablespoons (30 to 45 mL, containing 20 to 30 g of lactulose) three 
times daily. The dosage should be adjusted to produce 2 to 3 soft stools daily or per PI discretion.  
Rectal lactulose may be administered in lieu of oral lactulose. Bristol stool type will still be assessed as 
required by the protocol for subjects dosed with rectal lactulose. Dose amount and frequency for rectal 
lactulose should be administered according to product label or per PI discretion. 
Diagnosis and Main Criteria for Inclusion: 
1. Male or female at least age 18  or older at the time of consent. 
2. Females of childbearing potential, defined as a female who is fertile following menarche, must 
have a negative serum pregnancy test at screening and agree to use an acceptable method of 
contraception throughout their participation in the study.  NOTE: Serum pregnancy tests 
performed upon hospital admission, prior to study consent, may be used at Screening. 
Note: Female subjects who have been surgically sterilized (e.g., hysterectomy or bilateral tubal 
ligation) or who are postmenopausal (defined as total cessation of menses for > 1 year) will not be 
considered “female subjects of childbearing potential”. 
3. Subject is hospitalized with encephalopathy secondary to liver cirrohis and has a confirmed 
diagnosis of OHE at Baseline. . 
4. Subject has a Grade 2 or Grade 3 HE episode according to the HE Grading Instrument (HEGI) 
following: a) at least one lactulose treatment with subsequent bowel movement(s) and b) be 
adequately hydrated (IV fluids at PI discretion).  
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 7 
5. Surrogate decision maker must be able to read, understand and provide written informed consent 
on behalf of the subject on the Institutional Review Board (IRB)/Ethics Committee (EC) approved 
ICF and provide authorization as appropriate per local privacy regulations. 
6. Subject must be able to swallow oral medication (e.g., study drug) without assistance at Baseline. 
Key Exclusion Criteria:  
1. Subject has an uncontrolled major psychiatric disorder including major depression or psychoses as 
determined by the investigator. 
2. Subject has sepsis, as determined by the investigator. 
3. Subject is currently taking oral antibiotics, which cannot be discontinued or changed to parenteral 
at time of enrollment. Note: Subjects currently taking rifaximin who discontinue use at time of 
enrollment are not excluded. 
4. Subject shows presence of intestinal obstruction or has inflammatory bowel disease. 
5. Subject has uncontrolled Type 1 or Type 2 diabetes as determined by the investigator.  Note:  
Subjects with controlled diabetes may be enrolled if they are on stable doses of insulin or oral 
hypoglycemic drugs for at least 3 months prior to screening, and demonstrate clinically acceptable 
blood glucose control at Baseline, as determined by the investigator. 
6. Subject has an active malignancy (exceptions: non-melanoma skin cancers). 
7. Subject has HCC (Hepatocellular carcinoma) , history of  HCC, or reasonable clinical suspicion of 
HCC per PI.  Prior imaging completed within 6 months prior to obtaining consent may be used to 
rule out HCC.  In lieu of recent imaging, if AFP is above the upper limit of normal cross-sectional 
imaging techniques should be used to rule out HCC. 
8. Subject has any condition or circumstance, determined by the investigator, (including alcohol or 
substance abuse) that adversely affects the subject or could cause noncompliance with treatment, 
or may affect the interpretation of clinical data, or may otherwise contraindicate the subject’s 
participation in the study. 
9. If female, subject is pregnant, at risk of pregnancy, or is nursing. 
10. Known human immunodeficiency virus (HIV) infection. 
11. Subject has undergone a liver transplant within 5 years prior to Baseline. 
12. 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. 
13. Subject has a history of hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or 
any of the components of rifaximin SSD. 
14. Subject used any investigational product or device within 30 days or 5 drug half-lives (whichever 
is longer) prior to baseline. 
15. Subject used milk thistle or any known P-gp inhibitor within 30 days prior to Baseline. 
Investigational product, dosage and mode of administration: 
• 
Treatment A:  40 mg immediate release (IR) rifaximin SSD tablet once daily (QD) and 
lactulose*. 
• 
Treatment B:  40 mg immediate release (IR) rifaximin SSD tablet twice daily (BID) and 
lactulose*. 
• 
Treatment C:  80 mg sustained extended release (SER) rifaximin SSD tablet once daily (QD) 
and lactulose*. 
• 
Treatment D:  80 mg sustained extended release (SER) rifaximin SSD tablet twice daily (BID) 
and lactulose*. 
• 
Treatment E:  SSD placebo tablet twice daily (BID) and lactulose*.  
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 8 
 * The adult, oral dosage is 2 to 3 tablespoons (30 to 45 mL, containing 20 to 30 gm of lactulose) three 
times daily (TID). The dosage must be adjusted to produce 2 to 3 soft stools daily or per PI discretion.  
Rectal lactulose may be administered in lieu of oral lactulose. Bristol stool type will still be assessed as 
required by the protocol for subjects dosed with rectal lactulose. Dose amount and frequency for rectal 
lactulose should be administered according to product label or per PI discretion. 
Duration of treatment: 
Subjects will be on treatment for up to 14 days in the blinded, placebo-controlled portion of the study. 
Subjects who continue on to the open-label phase will receive 30 days of open-label treatment with 
Xifaxan® 550 mg upon hospital discharge, regardless of the treatment arm to which they were 
randomized.  
Criteria for Evaluation: 
The primary endpoint in this study is time to resolution of OHE per the HE Grading Instrument 
(HEGI).  OHE status will be evaluated every 12 hours (+/- 2 hours) after randomization.  Resolution is 
defined as a HEGI score < 2. 
Statistical Methods: 
The primary efficacy endpoint is time to OHE resolution. OHE resolution is defined as a HEGI score < 
2. Time to resolution of OHE is defined as the duration between the date/time of first dose of study 
drug and the date/time of first resolution of OHE. Subjects who complete the blinded randomized 
treatment period without experiencing OHE resolution will be censored at 14 days post first dose. 
The primary efficacy analysis of time to OHE resolution between each active rifaximin SSD plus 
lactulose treatment group and the placebo plus lactulose group will be tested using the log-rank test. 
Analysis of primary efficacy endpoint will be tested in intent-to-treat (ITT) and per protocol (PP) 
populations. 
- 
The ITT population will include all randomized subjects who received at least one dose of blinded 
treatment drug. 
- 
The PP population will include all ITT subjects who remain in study through the end of the 
blinded randomized treatment period and who have not deviated from the protocol in any way 
likely to seriously affect the primary outcome of the study. Important protocol deviations will be 
identified prior to locking the study database. 
The incidence of treatment-emergent AEs will be summarized for each treatment group by body 
system and MedDRA preferred term. 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. 
The incidence of treatment-emergent AEs of infections, such as spontaneous bacterial peritonitis 
(SBP), urinary tract infection (UTI), pneumonia, bacteremia and cellulitis, will be summarized by each 
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. Severity and AE leading to 
early termination will also be presented for these infection AEs. 
On-study vital signs assessment will include supine blood pressure (systolic and diastolic), pulse rate, 
respiration rate, and weight and temperature. Vital signs will be summarized at baseline and at each 
time point collected, as well as changes from baseline. For each summary, the N, mean, median, 
standard deviation (SD), minimum, and maximum values will be given by treatment group. 
Pretreatment vital signs obtained closest in time to first dose of study drug will be used for 
summarization and analysis of baseline and change from baseline. 
Similarly, on-study clinical labs will be summarized at baseline and at each time point collected.  
 
 
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 9 
Sample Size:  
Approximately 325 subjects will be randomized in a 1:1:1:1:1 ratio to rifaximin SSD tablets (40 mg 
immediate release (IR), QD plus lactulose; 40 mg immediate release (IR), BID plus lactulose; 80 mg 
sustained extended release (SER), QD plus lactulose; 80 mg sustained extended release (SER), BID 
plus lactulose, and placebo, BID plus lactulose). 
The sample size estimation is based on cumulative probability distributions of the time from baseline 
until the first OHE resolution (HEGI score < 2) between treatment groups using the log-rank test.  
This sample size estimation is based on a previous study with rifaximin (Sharma 2013). It is assumed 
that approximately 76% of rifaximin plus lactulose subjects and 51% of placebo plus lactulose subjects 
will experience OHE resolution over the course of up to 14 days of treatment. With two-sided type I 
error rate of 0.05, approximately 61 evaluable subjects per treatment group will provide at least 80% 
power to demonstrate the superiority of rifaximin SSD to placebo using the log-rank test. 
 
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Protocol RNHE2041 
 
 
 
 
 
Bausch Health US, LLC 
Clinical Study Protocol, Amendment 3, dated 08 January 2020  
 
CONFIDENTIAL 
Page 10 
Table of Contents  
1 
TITLE PAGE ....................................................................................................................................... 1 
2.0 SYNOPSIS ............................................................................................................................................ 5 
3.0 INTRODUCTION ..............................................................................................................................14 
3.1 DISEASE BACKGROUND AND SCIENTIFIC RATIONALE.......................................................................14 
3.1.1 
Liver Cirrhosis .......................................................................................................................14 
3.1.2 
Pathophysiology of Hepatic Encephalopathy ........................................................................14 
3.2 CURRENT THERAPY FOR MAJOR COMPLICATIONS OF CLD ..............................................................15 
3.3 CLINICAL AND NON-CLINICAL INFORMATION ...................................................................................17 
3.3.1 
Clinical Experience with Rifaximin Soluble Solid Dispersion Tablets .................................17 
3.4 RATIONALE .......................................................................................................................................20 
3.4.1 
Scientific Rationale for the Use of Rifaximin in Preventing Major Complications of Liver 
Cirrhosis: ................................................................................................................................20 
3.4.2 
Study Rationale......................................................................................................................21 
4.0 OBJECTIVES .....................................................................................................................................23 
4.1 EFFICACY OBJECTIVES .....................................................................................................................23 
4.1.1 
Primary Objective ..................................................................................................................23 
4.1.2 
Secondary Objectives ............................................................................................................23 
5.0 STUDY DESIGN .................................................................................................................................23 
5.1 DESCRIPTION OF STUDY DESIGN ......................................................................................................23 
5.2 SELECTION OF STUDY POPULATION ..................................................................................................24 
5.2.1 
Eligibility ...............................................................................................................................24 
5.2.2 
Female Subjects of Childbearing (Reproductive) Potential ...................................................27 
5.3 INVESTIGATORS ................................................................................................................................28 
5.4 STUDY DURATION ............................................................................................................................28 
5.5 TREATMENTS ....................................................................................................................................28 
6.0 STUDY MATERIALS ........................................................................................................................29 
6.1 DESCRIPTION OF TREATMENTS .........................................................................................................29 
6.2 DESCRIPTION OF COMPARATOR TREATMENTS ..................................................................................29 
6.3 DESCRIPTION OF LACTULOSE............................................................................................................29 
6.4 INSTRUCTIONS FOR USE AND ADMINISTRATION ...............................................................................29 
6.5 PACKAGING AND LABELING .............................................................................................................30 
6.6 ACCOUNTABILITY .............................................................................................................................30 
6.7 METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ..........................................................31 
6.8 RANDOMIZATION AND BLINDING......................................................................................................31 
6.9 UNBLINDING .....................................................................................................................................31 
7.0 EFFICACY AND SAFETY ANALYSIS ..........................................................................................32 
7.1 SAFETY AND EFFICACY ENDPOINTS ..................................................................................................32 
7.2 STATISTICAL HYPOTHESIS ................................................................................................................33 
7.3 SAMPLE SIZE ....................................................................................................................................33 
7.4 STUDY POPULATIONS .......................................................................................................................34 
7.5 STATISTICAL ANALYSIS ....................................................................................................................34 
7.5.1 
Methods of Analysis ..............................................................................................................34 
7.5.2 
Subject Disposition ................................................................................................................35 
7.5.3 
Demographics and Baseline Characteristics ..........................................................................35 
7.5.4 
Efficacy Endpoint Analyses ..................................................................................................36 
7.5.5 
Safety Endpoints Analyses ....................................................................................................36 
7.5.6 
Clinical Laboratory Findings .................................................................................................37 
7.5.7 
Vital Signs Measurements .....................................................................................................38 
7.6 INTERIM ANALYSIS ...........................................................................................................................38 
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CONFIDENTIAL 
Page 11 
8.0 STUDY METHODS............................................................................................................................38 
8.1 STUDY VISITS ...................................................................................................................................38 
8.1.1 
Day 1: Screening / Baseline ...................................................................................................41 
8.1.2 
Day 2 up to Day 15: Randomized Treatment Period .............................................................42 
8.1.3 
OHE Resolution .....................................................................................................................42 
8.1.4 
Hospital Discharge Visit ........................................................................................................43 
8.1.5 
Open-label Safety Follow-up / Visit 1 (Day 7 ±2) .................................................................43 
8.1.6 
Open-label Safety Follow-up Visit 2 (Day 14 ±2) .................................................................44 
8.1.7 
Open-label Safety Follow-up / Visit 3 (EOS) (Day 30 ±2) ...................................................44 
8.1.8 
Unscheduled Visits ................................................................................................................45 
8.1.9 
Missed Visits .........................................................................................................................45 
8.2 POST-STUDY FOLLOW-UP .................................................................................................................45 
8.3 STUDY COMPLETION .........................................................................................................................45 
8.3.1 
Early Study Termination ....................................................................................................45 
8.4 CONCOMITANT MEDICATIONS/THERAPY ..........................................................................................46 
8.5 TREATMENT COMPLIANCE ................................................................................................................48 
8.6 PROTOCOL DEVIATIONS ....................................................................................................................48 
9.0 ADVERSE EVENTS ..........................................................................................................................48 
9.1 OPERATING DEFINITIONS FOR ASSESSING SAFETY ...........................................................................49 
9.1.1 
Adverse Event........................................................................................................................49 
9.1.2 
Serious Adverse Event ...........................................................................................................50 
9.2 CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES
 51 
9.3 METHOD, FREQUENCY, AND TIME PERIOD FOR DETECTING AES AND SAES ....................................51 
9.3.1 
Time Period for Detecting and Reporting of AEs and SAEs .................................................51 
9.3.2 
Post-Study SAEs....................................................................................................................52 
9.4 DOCUMENTING AES AND SAES ........................................................................................................52 
9.5 SEVERITY OF ADVERSE EVENTS .......................................................................................................53 
9.6 ASSESSMENT OF CAUSALITY ............................................................................................................53 
9.7 FOLLOW-UP OF AES AND SAES ........................................................................................................53 
9.8 PROMPT REPORTING OF SAES TO CRO/SPONSOR DESIGNEE ...........................................................54 
9.9 PREGNANCY REPORTING ..................................................................................................................54 
9.10 TRANSMISSION OF SAE REPORT FORMS AND PREGNANCY REPORT FORMS .....................................55 
9.11 REGULATORY REPORTING REQUIREMENTS FOR SAES .....................................................................55 
10.0 DATA QUALITY ASSURANCE ......................................................................................................55 
10.1 STUDY MONITORING ........................................................................................................................55 
10.2 SOURCE DOCUMENTATION ...............................................................................................................56 
10.3 RECORDING OF DATA AND RETENTION OF DOCUMENTS...................................................................57 
10.4 AUDITING PROCEDURES ...................................................................................................................58 
10.5 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVAL ....................................................58 
10.6 PUBLICATION OF RESULTS ................................................................................................................59 
11.0 REFERENCES ....................................................................................................................................60 
APPENDICES 
APPENDIX A: 
HE GRADING INSTRUMENT (HEGI) ..................................................................64 
APPENDIX B: 
WEST HAVEN CRITERIA (WHC) ........................................................................65 
APPENDIX C: 
CAREGIVER BURDEN INVENTORY (CBI)........................................................66 
APPENDIX D: 
CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ) .................................67 
APPENDIX E: 
BRISTOL STOOL CHART ......................................................................................69 
 
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CONFIDENTIAL 
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List of Abbreviations and Definitions of Terms 
Abbreviation or Term  Definition or Explanation 
AASLD 
American Association for the Study of Liver Disease 
AE 
Adverse event 
AFP 
Alpha-fetoprotein 
AUC 
Area under the plasma concentration-time curve 
AUCt 
Area under single-dose concentration-time curve 
AUC0-t 
Area under single-dose concentration-time curve from time 0 to time of last detectable 
concentration at time (t) [amount·time/volume] 
AUC0-∞ 
Area under single-dose concentration-time curve from time 0 to infinite time post dose 
[amount·time/volume; concentration time] 
BID 
Twice a day 
BT 
Bacterial translocation 
CBI 
Caregiver Burden Inventory 
CLD 
Chronic liver disease 
CLDQ 
Chronic liver disease questionnaire 
Cmax 
Maximum drug concentration 
CRF 
Case report form 
DR 
Delayed-release 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
EIR 
Extended intestinal release 
EOS 
End of study 
EOT 
End of treatment 
EVB 
Esophageal variceal bleeding 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HE 
Hepatic encephalopathy 
HEGI 
Hepatic encephalopathy grading instrument 
HIV 
Human Immunodeficiency Virus 
HRS 
Hepatorenal syndrome 
Hz 
Hertz 
IBO 
Intestinal bacterial overgrowth 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation 
IR 
Immediate release 
IRB 
Institutional Review Board 
IV 
Intravenous 
MELD 
Model for End-stage Liver Disease 
MMP-9 
Matrix metalloproteinase-9 
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Abbreviation or Term  Definition or Explanation 
NIS 
Nationwide Inpatient Sample 
OHE 
Overt Hepatic Encephalopathy 
PXR 
Pregnane X receptor 
QD 
Once a day 
QHS 
Every bedtime 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SBP 
Spontaneous bacterial peritonitis 
SER 
Sustained Extended Release 
SOP 
Standard Operating Procedure 
SSD 
Soluble Solid Dispersion 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three times a day 
TIPS 
Transjugular intrahepatic portosystemic shunt 
Tmax 
Time taken to reach Cmax 
US 
United States 
 
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3.0 
INTRODUCTION  
3.1 
Disease Background and Scientific Rationale 
3.1.1 
Liver Cirrhosis 
The magnitude of the health care burden caused by liver disease in the United States (US) 
is significant from both a societal and health economic perspective.  Approximately 
2.6 million people have liver disease in the US (Pleis 2009).  In 2004, 2.3 million 
ambulatory care visits, and 759,000 hospitalizations were needed to care for these 
patients (Everhart 2008).  Cirrhosis is a major cause of much of the chronic liver disease 
(CLD) in the US and is the 12th leading cause of death.  Using data from the Nationwide 
Inpatient Sample (NIS) database from 1998 to 2006, a series of 217,948 hospital 
admissions with a primary diagnosis of cirrhosis was evaluated.  Mortality rates from 
complications of cirrhosis in this series were approximately 8%, 18%, 10%, and 45% for 
ascites, hepatic encephalopathy (HE), variceal bleeding, and hepatorenal syndrome 
(HRS), respectively (Singla 2011).  Similarly, other studies have demonstrated that the 
in-hospital mortality of patients with spontaneous bacterial peritonitis (SBP) ranges from 
10% to 50% (Toledo 1993, Runyon 1991, Rimola 1995, Felisart 1985, Navasa 2013, 
Gines 1990, Tito 1988, Planas 2004).   The incidence of cirrhosis in the US is on the rise 
and will continue to be a major health burden.  The NIS database indicated that cases of 
cirrhosis increased at an annual rate of 3.7% over the 9-year period studied.  It is 
predicted that over the next 20 years, cases of Hepatitis C Virus (HCV)-related cirrhosis 
will double (Davis 2010).  This is not unexpected given the current prevalence of chronic 
HCV infection in the US is 2.7 to 3.9 million people and the fact that the cause of 
cirrhosis is HCV infection in approximately 26% of cases (Wolf 2012). 
3.1.2 
Pathophysiology of Hepatic Encephalopathy  
Hepatic encephalopathy (HE) is a major complication of cirrhosis and the result of a 
cascade of events that begins with hepatocyte death.  Hepatocyte death results in 
inflammation and fibrosis of the hepatic architecture.   
Hepatic encephalopathy (HE) is a reversible neuropsychiatric abnormality that presents in 
30% to 45% of patients with cirrhosis and in 10% to 50% of patients with a transjugular 
intrahepatic portosystemic shunt (TIPS) (Poordad 2007, Amodio 2001, Guevara 2009).  
Alterations in the production, metabolism, and excretion of nitrogenous compounds, 
including ammonia, contribute to the pathogenesis of HE.  Ammonia is a by-product of 
nitrogen metabolism.  Approximately half of the body’s ammonia is produced in the 
portal-drained viscera, and half is produced in the colon.   
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Ammonia is primarily metabolized in the liver to urea and excreted in the urine.  In 
patients with liver disease, this function is diminished or lost, and the skeletal muscle 
becomes a major elimination pathway.  Cirrhotic patients are often muscle wasted, and 
this can lead to toxic accumulation of ammonia.  Metabolism of ammonia in astrocytes in 
the brain can have both excitatory and inhibitory effects on neurotransmission and causes 
the common clinical signs of HE including confusion, coma, asterixis, loss of fine motor 
skills, hyperreflexia, and slow, monotonous speech.  Other gut-derived neurotoxins, 
including mercaptans, phenols, manganese, short chain fatty acids, and bilirubin have 
also been implicated in the pathogenesis of HE.  Precipitating factors for HE include 
gastrointestinal (GI) bleeding, dehydration, excess dietary protein intake, hypokalemic 
alkalosis, infection, and constipation.  Central benzodiazepine receptors also appear to be 
upregulated in the presence of ammonia, making patients with cirrhosis more sensitive to 
the effects of benzodiazepines (Schiano 2010). 
3.2 
Current Therapy for Major Complications of CLD 
The management of cirrhosis and its complications (including HE) is based on disease 
severity and whether or not complications have developed (i.e., decompensated disease).  
The American Association for the Study of Liver Disease (AASLD) Practice Guidelines 
for evaluating patients for liver transplantation recommend that patients with cirrhosis 
should be evaluated for transplant when they develop evidence of liver dysfunction 
defined by a Child- Pugh score of ≥ 7 and model for end-stage liver disease (MELD) 
score ≥ 10 (Murray 2005).  In 2010, a set of quality indicators for use in the management 
of cirrhosis was developed by an 11-member panel of specialists from across the US.  
This panel recommended that patients with a MELD score of ≥ 15 or ≤ 15, with 
complications, be referred to a transplant center (Starr 2011). 
The development of esophageal variceal bleeding (EVB), ascites, SBP, HE, or HRS has a 
profound impact on prognosis.  Despite current medical therapies for EVB, ascites, SBP, 
and HE, patients with compensated disease who develop 1 of these complications have a 
5-year survival rate of 20% to 50% (Gines 1987, Fattovich 1997).  The survival rate of 
patients who develop SBP or HRS is particularly poor.  For SBP, less than half will 
survive 1-year; the median survival rate for patients with type I HRS is less than 2 weeks 
(Andreu 1993; Gines 1993). 
As noted previously for data prior to 2010, HE presents in 30% to 45% of patients with 
cirrhosis and in 10% to 50% of patients with a TIPS procedure despite available 
treatments.   
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Management of patients with chronic HE includes provision of supportive care, 
identification and removal of precipitating factors, and reduction of nitrogenous load 
from the gut (Gines 1993, Romero-Gomez 2010, Wright 2007).  Until 2010, lactulose 
was the only approved therapy for the treatment and prevention of HE in the US.  
Lactulose is a cathartic that is thought to lower plasma levels of ammonia by acidification 
of stools and purging to increase the fecal excretion of nitrogen.  There is no fixed 
recommended dose; the dose is self-titrated by the patient to produce 2 to 3 soft stools per 
day to achieve efficacy (Lactulose Solution PI).  Continuous long-term therapy is 
indicated to lessen the severity and prevent the recurrence of portal-systemic 
encephalopathy (i.e., HE).  HE treatment guidelines from the AASLD/European 
Association for the Study of the Liver (EASL) recognize that putting patients on 
maintenance therapy with lactulose may not be enough to prevent recurrences.  A 
previous study (Sharma 2013) demonstrated that a combination of rifaximin plus 
lactulose was more effective than lactulose alone for improvement of HE and reduction 
in mortality. 
While deemed effective (Sharma 2009), the side effects of lactulose therapy include 
bloating, abdominal cramps, diarrhea, and an unpleasant taste; these side effects are not 
well tolerated and cause poor adherence to long term treatment.  It is important to note 
that in patients with underlying advanced liver disease, complications such as 
dehydration and electrolyte disturbances (e.g., hypokalemia) may occur due to lactulose 
use for which other specific therapy may be required.  Furthermore, lactulose can induce 
diarrhea, a precipitating factor of HE (Bajaj 2010; Bass 2007; Kalaitzakis 2007). 
The mode of action of antibiotics for the treatment of HE is to reduce the number of 
deaminating bacteria and urease producing bacteria, thereby reducing the production of 
ammonia and other potential toxins.  Antibiotics such as neomycin, metronidazole, and 
rifaximin have demonstrated efficacy and have been used with or without lactulose. 
Neomycin sulfate is an aminoglycoside antibiotic that is approved for acute treatment as 
adjunctive therapy in hepatic coma at total daily doses of 4 g to 12 g.  However, 
neomycin use is only recommended for short-term therapy in the treatment of HE due to 
the risk of nephrotoxicity and ototoxicity (Neo-Fradin PI®).  Although oral neomycin is 
commonly considered a nonabsorbed antibiotic, it has significant oral absorption 
(approximately 3%) and systemic exposure, especially in patients with renal 
insufficiency.  Neomycin accumulates in soft tissues after repeated dosing, particularly in 
the renal cortex and inner ear.   
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It is effective primarily against Gram-negative bacilli with some activity against Gram-
positive organisms, and no activity against anaerobic bowel flora (Neo-Fradin PI®).  
Mainly due to these limitations, neomycin is a poor choice for long term therapy. 
Since Gram-negative anaerobic bacteria are major contributors to ammonia generation in 
the gut, metronidazole, an antibiotic effective against anaerobic bacteria has been 
considered and used in the treatment of HE (Morgan 1982).  However, metronidazole is 
not approved for the treatment of HE and is not recommended for long term treatment 
due to central nervous system toxicity, risk of convulsive seizures, and peripheral 
neuropathy, particularly in patients with severe hepatic disease (Flagyl (metronidazole) 
capsules [package insert]). 
3.3 
Clinical and Non-clinical Information 
3.3.1 
Clinical Experience with Rifaximin Soluble Solid Dispersion Tablets 
The pharmacokinetics of rifaximin were evaluated in four Phase 1 studies and one Phase 
2 study after administration of the rifaximin soluble solid dispersion (SSD) formulation in 
either healthy volunteers or subjects with impaired liver function. 
Study RFPK1042 was a 2-part study evaluating the pharmacokinetics of rifaximin SSD at 
different doses and the regional absorption and bioavailability of rifaximin following 
targeted release at prespecified locations in the GI tract.  Study RNPK1002 evaluated the 
pharmacokinetics of the 80 mg rifaximin SSD tablet using 3 different release 
formulations.  Study RNDI1005 is a drug-drug interaction study that evaluated whether 
esomeprazole, which raises GI pH, alters the PK of the IR and SER formulation of 
rifaximin when administered concomitantly.  Study RNPK1003 evaluated the single-dose 
PK of rifaximin 80 mg IR and 80 mg SER dispersion tables, as well as 80-mg and 80-mg 
SER administered together in subjects with mild, moderate, and severe hepatic 
impairment and in healthy subjects.  Study RNLC2131 evaluated the population 
pharmacokinetics of rifaximin SSD tablets in subjects with liver cirrhosis who 
participated in the randomized, double-blind, placebo-controlled, dose-ranging, 
multicenter study to assess the efficacy and safety of rifaximin SSD tablets for the 
prevention of complications in subjects with early decompensated liver cirrhosis. 
Overall, the results of the early Phase 1 studies demonstrated the safety and formulation 
performance of rifaximin SSD.  Progressive decreases in systemic exposure as a function 
of increasing delays in intestinal release were observed for rifaximin SSD tablets.   
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Mean Cmax values ranged from 1.41 ng/mL to 5.20 ng/mL [for the sustained extended 
release (SER) and immediate release (IR) formulations, respectively]; corresponding 
mean AUC0-∞ values were 10.2 ng.h/mL and 24.9 ng.h/mL (RNPK1002 CSR, Table 6).  
Compared with the current 550 mg tablet formulation, rifaximin IR and SER tablet 
formulations provide similar or lower Cmax and AUC values systemically, accompanied 
by prolonged half-lives that may indicate increased GI residence times.  The data 
demonstrate the feasibility of a single daily rifaximin IR or SER dose.   
Phase 2 Program 
Study RNLC2131 was a Phase 2, randomized, double-blind, placebo-controlled, 
multicenter study evaluating the efficacy (prevention of hospitalization for complications 
of liver cirrhosis or all-cause mortality in subjects with early decompensation) and safety 
of rifaximin SSD tablets in subjects with early decompensated liver cirrhosis.  Subjects 
with documented medically non-refractory ascites who had not previously experienced 
spontaneous bacterial peritonitis (SBP), esophageal variceal bleeding (EVB), or 
hepatorenal syndrome (HRS) were enrolled in the study.  Subjects completed a 1 to 21-
day Screening Period, a 24-week Treatment Period, and a 2-week Follow-up Period.  A 
total of 518 subjects who successfully completed the Screening Period entered the 
Treatment Period and were randomized in a 1:1:1:1:1:1 allocation to 1 of 6 treatment 
groups.  All treatments were administered once daily at bedtime (QHS). 
Subjects were treated QHS with rifaximin SSD, 40 mg or 80 mg tablets, in 1 of 2 
formulations of IR and SER. 
The active treatment groups were as follows: 
- 
Treatment A: rifaximin SSD 40 mg QHS (IR tablet) 
- 
Treatment B: rifaximin SSD 80 mg QHS (IR tablet) 
- 
Treatment C: rifaximin SSD 40 mg QHS (SER tablet) 
- 
Treatment D: rifaximin SSD 80 mg QHS (SER tablet) 
- 
Treatment E: rifaximin SSD 80 mg (IR tablet) and SSD 80 mg (SER tablet) QHS 
Overall, the mean MELD score was 11.5, with the majority of subjects (280 subjects; 
54.3%) scoring between 11 and 18.  The overall mean MELD score was 12.9, with the 
majority of subjects (327 subjects; 63.4%) again scoring between 11 and 18.  Most 
subjects (416 subjects; 80.6%) had a class B Child-Pugh classification and a Conn score 
category of 0 (317 subjects; 61.4%).  The mean time since first diagnosis of liver 
cirrhosis score was 1665.5 days.   
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Hepatitis C was the most common liver cirrhosis etiologic category (242 subjects; 46.9%) 
with “alcoholic liver disease” reported as the second most common (220 subjects; 
42.6%).  The majority of subjects did not have HE or diabetes at Screening (364 subjects; 
70.5%).  In general, the balance in baseline disease characteristics across all 6 treatment 
groups was consistent. 
The primary objective of this study was to assess the efficacy of rifaximin SSD versus 
placebo in preventing complications of liver cirrhosis and all-cause mortality in subjects 
with early liver decompensation.   
Treatment with rifaximin IR and SER SSD was shown to be safe and well-tolerated and 
demonstrated potential therapeutic utility, particularly the IR 40 mg QHS and SER 80 mg 
QHS formulas, in preventing complications of liver cirrhosis and all-cause mortality in 
patients with early liver decompensation.  
While the primary analysis did not demonstrate statistically significant differences in 
time to composite endpoint of hospitalization for the liver cirrhosis complications or 
mortality up to 24 weeks for the combined rifaximin SSD groups versus placebo (p = 
0.8062) or any pairwise comparison, in a post-hoc analyses there was a consistent pattern 
of benefit with rifaximin SSD IR 40 mg and SSD SER 80 mg. 
The IR 40 mg group post-hoc analysis revealed a statistically significant difference 
versus placebo (p = 0.0297) for the composite endpoint of all-cause hospitalization/all-
cause mortality (primary endpoint of the study was hospitalization for any of the liver 
cirrhosis complications (HE, EVB, SBP, or HRS) (RNLC2131 CSR Appendix 16.1.13).  
In addition, subjects in the alcohol-induced only subgroup had a statistically significant 
difference in time to All-cause Hospitalization/All-cause Mortality versus placebo when 
treated with rifaximin IR 40 mg QHS (p = 0.0298).  Furthermore, subjects with a Conn 
score of 0 demonstrated a statistically significant difference for both the overall treatment 
comparison of any rifaximin SSD treatment versus placebo and predominantly in favor of 
the IR 40 mg formulation. 
Results of the sensitivity analysis on the PP population demonstrated a statistically 
significant difference in the time to hospitalization for any of the liver cirrhosis 
complications or all-cause mortality up to 24 weeks that was in favor of the SER 80 mg 
QHS treatment group versus placebo (p = 0.0464).  Based on the Kaplan-Meier estimates, 
the SER 80 mg QHS group presented with the highest survival rate of all treatment 
groups for Time to Hospitalization for Any of the Liver Cirrhosis Complications by 
Treatment Group, however this effect was not statistically significant.   
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A trend was observed in the time to hospitalization for any of the liver cirrhosis 
complications or all-cause mortality during the 24 week period within the ≥ 947 days 
subgroup in favor of the SER 80 mg QHS group versus placebo (stratified log-rank p = 
0.0517).  In addition, subjects in the alcohol-induced only subgroup had a statistically 
significant difference in time to All-cause Hospitalization/All-cause Mortality versus 
placebo when treated with rifaximin SER 80 mg QHS (p = 0.0166). 
The safety outcomes were consistent with the known safety profile of rifaximin.  
Treatment-emergent AEs, SAEs, severe TEAEs, and drug-related TEAEs occurred most 
frequently in the GI disorder System Organ Class (SOC).   
Hepatic encephalopathy was the most common preferred term (PT) followed by ascites, 
edema peripheral, and diarrhea.  No deaths were related to study drug.  Overall, there 
were no clinically relevant differences observed at SOC and PT levels between groups. 
3.4 
Rationale 
3.4.1 
Scientific Rationale for the Use of Rifaximin in Preventing Major 
Complications of Liver Cirrhosis: 
Multiple lines of clinical and experimental evidence support the use of rifaximin in 
preventing complications of cirrhosis through mechanisms that: 
• decrease serum neurotoxin production 
• decrease endotoxin production and absorption 
• reduce intestinal bacterial translocation (BT) 
• reduce intestinal permeability 
• decrease portal venous pressures through reduction in endotoxin concentrations 
• activate the nuclear pregnane X receptor (PXR) 
Rifaximin is a nonaminoglycoside, semisynthetic antibiotic derived from rifamycin.  It is 
a non-systemic, poorly-absorbed, oral antibiotic specific for enteric pathogens of the GI 
tract (Xifaxan® PI, Gerard 2005, Gillis 1995, Hoover 1993).  Rifaximin has potentially 
important advantages in preventing the complications of cirrhosis relative to orally 
bioavailable, broad-spectrum antibiotics.  For example, rifaximin has minimal systemic 
exposure regardless of food intake or presence of GI disease which mitigates the risk of 
systemic side effects.  Neither a reduction in overall colonic bacteria nor an increase in 
antimicrobial resistance in the colonic bacteria occurs to a clinically significant extent.   
 
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Furthermore, in vitro studies have demonstrated that rifaximin interferes with the transfer 
of and promotes the elimination of plasmids from various Gram-positive and 
Gram-negative bacterial hosts, suggesting that rifaximin is capable of limiting the transfer 
of antibiotic-resistance plasmids and the diffusion of virulence factors in bacteria 
(Debbia 2008). 
The use of rifaximin in the treatment of complications of cirrhosis is supported by 
microbiological and pharmacodynamic evidence which suggests both effects on bacteria 
and on host inflammatory response as mechanisms of action as outlined below: 
Rifaximin is active against the bacteria that have been investigated as possible pathogenic 
agents for SBP (Xifaxan® PI, Gerard 2005, Gillis 1995, Hoover 1993). 
Rifaximin affects bacterial translocation to mesenteric lymph nodes (Fiorucci, 2002). 
Rifaximin induces in enteroaggregative and enterotoxigenic Escherichia coli a loss of 
virulence factors such as enterotoxins, surface adhesion factors and matrix 
metalloproteinase-9 (MMP-9), and changes in epithelial cell physiology associated with 
reduction in bacterial attachment/internalization (Brown 2010; Fiorucci 2002). 
Data indicate that the anti-inflammatory activity of rifaximin is due to its gut-specific 
human PXR activation (Ma 2007).  Activation of PXR, such as that observed with 
rifaximin in the intestinal lumen, results in upregulation of metabolic enzymes and 
transporters (e.g., CYP3A, sulfotransferases, and P-glycoprotein) that may result in 
increased epithelial cell protection against bacterial metabolic products. 
3.4.2 
Study Rationale 
Cirrhosis is a major cause of CLD in the US and is the 12th leading cause of death.  The 
incidence of cirrhosis in the US is increasing and will continue to be a major health 
burden from an economic and societal/caregiver perspective.  While liver transplant is the 
only curative therapy for cirrhosis; safe, effective, and cost-efficient therapies for the 
prevention of the major complications of cirrhosis including mortality, and to bridge a 
patient to transplant are needed.  These therapies must arrest the hemodynamic and 
infectious etiologies of cirrhosis complications, and improve the morbidity, mortality, 
and quality of life of the patient. 
Rifaximin is approved by the United States Food and Drug Administration (FDA) to 
reduce the risk of OHE recurrence in patients ≥ 18 years of age.  It is not indicated for 
primary prophylaxis of HE events.   
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The current literature supports the potential therapeutic utility of rifaximin in treating 
complications of cirrhosis with ascites such as SBP, HE, EVB, and HRS through multiple 
mechanisms including direct suppression of intestinal bacterial overgrowth (IBO) and 
bacterial translocation (BT) that leads to a reduction in endotoxemia, bacteremia, and 
bacterial seeding of ascitic fluid, and indirect improvement in portal hemodynamics.  
While the efficacy of broad spectrum antibiotics for the treatment and prophylaxis of 
cirrhosis complications such as SBP is well documented, they have high systemic 
exposures and there is concern over the emergence of drug-resistant organisms. 
The new rifaximin SSD IR and SER are novel formulations of rifaximin that are designed 
to improve luminal solubility to increase the availability of soluble rifaximin to the gut 
lumen and epithelia, while minimizing systemic exposure.  Its unique formulation greatly 
improves its water solubility without the need for bile acids, an important determination 
of solubility of the current approved formulation (Darkoh 2010).   
This characteristic makes the new SSD formulation particularly attractive for use in a 
population with significantly impaired hepatic function.  Data from early phase trials with 
the SSD formulation support the safety, solubility and potential clinical utility of 
rifaximin in preventing complications of cirrhosis in patients with early liver 
decompensation.  Based on these data and the medical need for safe and effective 
treatments for OHE, the Sponsor is seeking to initiate clinical development of Rifaximin 
SSD in OHE. 
The current standard of care for patients with hepatic encephalopathy is treatment with 
nonabsorbable disaccharides lactulose or lactitol, which decreases the absorption of 
ammonia through cathartic effects and by altering colonic pH.  In addition to lactulose, 
oral antibiotics have been used in OHE to reduce ammonia-producing enteric bacteria.  
However, because of side effects these agents are only infrequently used at present. 
Rifaximin is currently approved for reduction in risk of OHE recurrence, but not for the 
treatment of OHE.  Randomized clinical trials showing the superiority of rifaximin plus 
lactulose versus lactulose alone suggest that rifaximin may be useful in the treatment of 
OHE.  Based on these data and the need for safe and effective alternatives to systemic 
broad spectrum antibiotics used to treat complications of cirrhosis, this Phase 2 
dose-ranging trial will be conducted to assess the viability of rifaximin SSD for the 
prevention of complications in cirrhosis patients with early decompensation. 
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4.0 
OBJECTIVES 
4.1 
Efficacy Objectives 
4.1.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of rifaximin SSD [40 mg 
immediate release (IR) and 80 mg sustained extended release (SER)] plus lactulose 
versus placebo plus lactulose for the treatment of OHE. 
4.1.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Assess the safety of rifaximin SSD in subjects with OHE. 
• Assess the effects of treatment with rifaximin SSD on key secondary endpoints. 
5.0 
STUDY DESIGN 
5.1 
Description of Study Design 
Study RNHE2041 is a Phase 2, randomized, double-blind, placebo controlled, 
multicenter study evaluating the efficacy and safety of rifaximin SSD tablets (40 mg IR 
and 80 mg SER) plus lactulose in subjects hospitalized with OHE.  Subjects who have 
liver cirrhosis and OHE, defined as a score of 2 or 3 on the Hepatic Encephalopathy 
Grading Instrument [(HEGI); Appendix A], are eligible for enrollment.  Subjects who 
successfully meet the inclusion/exclusion criteria will enter the treatment period and will 
be randomized in a 1:1:1:1:1 ratio into 1 of 5 treatment groups as noted below.  The 
blinded treatment period starts upon randomization following hospital admission.  
Subjects will be on blinded treatment for up to 14 days.  All subjects who complete the 
blinded randomized treatment phase (defined as confirmed resolution of OHE), will 
continue on to the safety follow-up period and receive 30 days of open-label treatment 
with Xifaxan® 550 mg upon hospital discharge, regardless of the treatment arm to which 
they were previously randomized.  If subjects remain hospitalized following OHE 
resolution, standard of care treatment (which may include Xifaxan® 550 mg) should be 
given until hospital discharge.   Open-label drug should only be dispensed to subjects 
upon hospital discharge.  Please note this may be on a different day than OHE resolution. 
• Treatment A: 40 mg immediate release (IR) rifaximin SSD tablet once daily (QD) 
and lactulose*. 
• Treatment B: 40 mg immediate release (IR) rifaximin SSD tablet twice daily 
(BID) and lactulose*. 
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• Treatment C: 80 mg sustained extended release (SER) rifaximin SSD tablet once 
daily (QD) and lactulose*. 
• Treatment D: 80 mg sustained extended release (SER) rifaximin SSD tablet twice 
daily (BID) and lactulose*. 
• Treatment E: SSD placebo tablet twice daily (BID) and lactulose*.  
*Oral Lactulose will be administered according to the product label, with dosage adjusted 
to produce 2 to 3 soft stools daily or per PI discretion.  Rectal lactulose may be 
administered in lieu of oral lactulose. Bristol stool type will still be assessed as required 
by the protocol for subjects dosed with rectal lactulose. Dose amount and frequency for 
oral and rectal lactulose should be administered according to the product label or per PI 
discretion. 
An interim analysis will be conducted when at least 10 subjects per treatment group have 
completed participation in the blinded treatment period of the study. The unblinded 
interim results will be reviewed by a few designated members of the Sponsor’s team who 
do not have direct involvement with the ongoing study. The interim results will not be 
shared outside of the small designated team, and no changes will be made to the ongoing 
study based on the interim study results. 
5.2 
Selection of Study Population  
Approximately 325 subjects (65 subjects per arm), from approximately 60 study sites in 
the US, hospitalized for liver cirrhosis and OHE, with a HEGI score of 2 or 3 following 
adequate hydration and lactulose treatment, will be enrolled in this clinical investigation.  
Expansion to other countries may be considered. 
5.2.1 
Eligibility 
 
Inclusion Criteria 
A subject will be eligible for inclusion in this study if he/she meets all of the following 
criteria: 
1. Male or female at least age 18 or older at the time of consent. 
2. Female subjects of childbearing potential, defined as fertile following menarche, must 
have a negative serum pregnancy test at screening and agree to use an acceptable 
method of contraception throughout their participation in the study.  NOTE: Serum 
pregnancy tests performed upon hospital admission, prior to time of consent, may be 
used at Screening.  Acceptable methods of contraception include double barrier 
methods (condom with spermicidal jelly or a diaphragm with spermicide), hormonal 
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methods (e.g., oral contraceptives, patches or medroxyprogesterone acetate), or an 
intrauterine device (IUD) with a documented failure rate of less than 1% per year.  
Abstinence or partner(s) with a vasectomy may be considered an acceptable method of 
contraception at the discretion of the investigator.  See Section 5.2.2 for additional 
information. 
Note: Female subjects who have been surgically sterilized (e.g., hysterectomy or 
bilateral tubal ligation) or who are postmenopausal (defined as a total cessation of 
menses for > 1 year) will not be considered “female subjects of childbearing 
potential”. 
3. Subject is hospitalized with encephalopathy secondary to liver cirrohis and has a 
confirmed diagnosis of OHE at Baseline. . 
4. Subject has a Grade 2 or Grade 3 HE episode according to the HEGI (Appendix A) 
following: a) at least one lactulose treatment with subsequent bowel movement(s) and 
b)  be adequately hydrated (IV fluids at PI discretion). 
 
5. Surrogate decision-maker must be able to read, understand, and provide written 
informed consent on behalf of the subject on the Institutional Review Board 
(IRB)/Ethics Committee (EC) approved ICF and provide authorization as appropriate 
per local privacy regulations. 
6.  Subject must be able to swallow oral medication (e.g., study drug) without assistance 
at Baseline. 
 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria are 
met: 
Current or Past Medical History 
1. Subject has an uncontrolled major psychiatric disorder including major depression or 
psychoses, as determined by the investigator (Diagnostic and Statistical Manual of 
Mental Disorders, 5th., American Psychiatric Association, 2013). 
2. Subject has sepsis, as determined by the investigator. 
3. Subject is currently taking oral antibiotics, which cannot be discontinued or changed to 
parenteral at time of enrollment. Note: Subjects currently taking rifaximin who 
discontinue use at time of enrollment are not excluded. 
4. Subject shows presence of intestinal obstruction or has inflammatory bowel disease. 
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5. Subject has uncontrolled Type 1 or Type 2 diabetes as determined by the investigator.  
Note: Subjects with controlled diabetes may be enrolled if they are on stable doses of 
insulin or oral hypoglycemic drugs for at least 3-months prior to screening, and 
demonstrate clinically acceptable blood glucose control upon admission in the opinion 
of the investigator. 
6. Subject has an active malignancy (exceptions: non-melanoma skin cancers). 
7. Subject has HCC, history of  HCC, or reasonable clinical suspicion of HCC per PI.  
Prior imaging completed within 6 months prior to obtaining consent may be used to 
rule out HCC.  In lieu of recent imaging, if AFP is above the upper limit of normal 
cross-sectional imaging techniques should be used to rule out HCC.. 
8. Subject has any condition or circumstance, as determined by the investigator, 
(including alcohol or substance abuse) that adversely affects the subject or could cause 
noncompliance with treatment, or may affect the interpretation of clinical data, or may 
otherwise contraindicate the subject’s participation in the study. 
9. If female, subject is pregnant, at risk of pregnancy, or is nursing. 
10. Known human immunodeficiency virus (HIV) infection. 
11. Subject has undergone a liver transplant within 5 years prior to Baseline. 
12. 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. 
13. Subject has a history of hypersensitivity to rifaximin, rifampin, rifamycin 
antimicrobial agents, or any of the components of rifaximin SSD. 
14. Subject used any investigational product or device within 30 days or 5 drug half-lives 
(whichever is longer) prior to Baseline. 
15. Subject used milk thistle or any known P-gp inhibitor within 30 days prior to Baseline. 
Subject Withdrawal Criteria 
All premature discontinuations and their reasons must be carefully documented by the 
investigator on the final eCRF, and if need be, on the AE form.  Reasons for study 
completion/discontinuation as listed on the report form are described as follows: 
• Normal Study Completion – subject completes study as planned per the 
protocol 
• Adverse Event – complete AE form 
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• Subject Request – consent withdrawal (i.e. subject moved, schedule 
conflicts) 
• Protocol Violation – contact the Sponsor or Sponsor’s designee prior to 
making decision 
• Lost to Follow-Up – document with two phone calls and a certified letter 
• Pregnancy – subject will discontinue study drug immediately, but will be 
followed to term; pregnancy form must be completed 
• Worsening Condition – subject requires alternate treatment prior to 
completing the study and the investigator determines it is not due to lack of 
efficacy (i.e. requires liver transplant during the study). 
• Other – specify in the comments section of final eCRF 
Subjects who terminate treatment early will be asked to complete all end of study visit 
assessments (see Section 8.3.1 for additional information) prior to commencement of any 
alternative medication or therapy (if possible).  Subjects who discontinue from the study 
during the treatment period will be asked to come back for the 30 day post-treatment 
cessation follow-up visit. 
All subjects are free to withdraw from participating in this study at any time and for 
whatever reason, specified or unspecified, and without prejudice.  No constraints will be 
placed on ordinary subject management, and subjects, when appropriate, will be placed 
on other conventional therapy upon request or whenever clinically necessary as 
determined by their physician. 
5.2.2 
Female Subjects of Childbearing (Reproductive) Potential 
Rifaximin is a Pregnancy Category C drug with no adequate and well controlled studies 
in pregnant women, and has been shown to be teratogenic in rats and rabbits at doses that 
caused maternal toxicity.  Please refer to the Rifaximin Investigator Brochure and 
Xifaxan® complete prescribing information for additional information on rifaximin 
(Xifaxan® PI).  
Female study subjects of childbearing (reproductive) potential must have a negative 
serum pregnancy test at Screening and agree to use an acceptable method of 
contraception throughout their participation in the study (see details in Section 5.2.1.1, 
Inclusion Criteria).  If a female subject becomes pregnant while on this study, the study 
drug will be immediately discontinued and the subject will be followed until the outcome 
of the pregnancy is known.  The pregnancy will be reported to the Sponsor using the 
guidelines provided in Section 9.9 and Section 9.10. 
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5.3 
Investigators 
The study will be conducted at approximately 60 investigative sites.  The study will be 
conducted by Investigators who are determined by the Sponsor to be suitably qualified by 
training and experience to conduct this study in compliance with all applicable ICH 
GCPs guidelines and FDA Federal Regulations or Local Regulations. 
In the event that the participating sites do not meet full enrollment in a timely manner, the 
Sponsor may decide to increase enrollment at other active participating sites and/or 
activate additional site(s) as needed to satisfy the enrollment requirements of the study. 
5.4 
Study Duration 
Subjects will be enrolled in the double-blind, placebo-controlled phase during 
hospitalization, up to 14 days, and in the open-label, safety follow-up phase for 30 days. 
5.5 
Treatments 
In the double-blind phase, subjects will be randomized (1:1:1:1:1) to the following 
treatment groups: 
• Treatment A: 40 mg IR rifaximin SSD tablet once daily (QD)* and lactulose**. 
• Treatment B: 40 mg IR rifaximin SSD tablet twice daily (BID) and lactulose**. 
• Treatment C: 80 mg SER rifaximin SSD tablet once daily (QD)* and lactulose**. 
• Treatment D: 80 mg SER rifaximin SSD tablet twice daily (BID) and lactulose**. 
• Treatment E: SSD placebo tablet twice daily (BID) and lactulose**.  
* Blinding will be maintained in the QD SSD cohorts by administering placebo as the 
second daily dose.  All subjects will receive two tablet per day at 12-hour (±2 hour) 
intervals based on the time of the first dose following randomization. 
** The adult, oral dosage is 2 to 3 tablespoonfuls (30 to 45 mL, containing 20 to 30 gm 
of lactulose) TID. The dosage must be adjusted to produce 2 to 3 soft stools daily or per 
PI discretion.  Rectal lactulose may be administered in lieu of oral lactulose. Bristol stool 
type will still be assessed as required by the protocol for subjects dosed with rectal 
lactulose. Dose amount and frequency for rectal lactulose should be administered 
according to product label or per PI discretion.  
After completion of the blinded randomized treatment phase, defined as OHE resolution, 
subjects who continue on to the open-label safety follow-up period will receive  30 days 
of open-label treatment with Xifaxan® 550 mg upon hospital discharge, regardless of the 
treatment arm in which they were previously randomized.  Open-label drug should only 
be dispensed upon hospital discharge.  Please note this may be on a different day than 
OHE resolution. If subjects remain hospitalized following OHE resolution, standard of 
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care treatment (which may include Xifaxan® 550 mg) should be given until hospital 
discharge. 
6.0 
STUDY MATERIALS 
6.1 
Description of Treatments 
Rifaximin SSD will be supplied as light blue-colored, coated, round, biconvex tablets 
each containing 40 mg or 80 mg of rifaximin.  Inactive ingredients include: hypromellose 
acetate succinate, poloxamer 407, croscarmellose sodium (CCS), microcrystalline 
cellulose, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium 
dioxide, polyethylene glycol, talc and FD&C Blue #2.  The concentration of the 
intragranular excipient CCS controls the drug release rate.   
Two tablet formulations have been formulated with varying concentrations of 
intragranular CCS: immediate release (IR) with 10% w/w CCS, and sustained extended 
release (SER) with 0% w/w CCS. 
6.2 
Description of Comparator Treatments 
Placebo will be supplied as tablets that look like the rifaximin SSD tablets but only 
containing inactive ingredients.  The components used in the manufacture of the placebo 
are hypromellose acetate succinate, poloxamer 407, croscarmellose sodium, 
microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, polyvinyl 
alcohol, titanium dioxide, polyethylene glycol, talc and FD&C Blue #2. 
6.3 
Description of Lactulose 
Lactulose will be supplied by the hospital and dosed in accordance with label 
instructions.  The adult, oral dosage is 2 to 3 tablespoonfuls (30 to 45 mL, containing 20 
to 30 gm of lactulose) TID. The dosage must be adjusted to produce 2 to 3 soft stools 
daily or per PI discretion.  Rectal lactulose may be administered in lieu of oral lactulose. 
Bristol stool type will still be assessed as required by the protocol for subjects dosed with 
rectal lactulose. Dose amount and frequency for rectal lactulose should be administered 
according to product label or per PI discretion. Use of lactulose (dosing time and amount) 
as well as stool appearance as assessed by the Bristol Stool Chart (Appendix E) will be 
documented in the eCRF.  
6.4 
Instructions for Use and Administration  
Doses of rifaximin SSD and placebo will be taken orally with water, and tablets will be 
swallowed whole. 
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The study drug should be stored at controlled room temperature, 20°C to 25°C (68°F to 
77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F). 
6.5 
Packaging and Labeling  
The study drug will be packaged and labeled in a manner consistent with the study 
design. 
Each multi-use blister pack of rifaximin SSD 40 mg IR tablets, rifaximin SSD 80 mg 
SER tablets, and SSD placebo tablets will bear a label that meets applicable laws for an 
investigational drug, which includes, but is not limited to, the following information: 
• Protocol Number 
• Kit Number 
• Space for entry of the subject’s initials 
• Space for the entry of date dispensed 
• A statement reading: “Caution: New Drug Limited by Federal Law to 
Investigational Use” 
• A statement reading, “Manufactured for Salix Pharmaceuticals, Inc., a wholly-
owned subsidiary of Valeant Pharmaceuticals NA LLC” 
• A statement indicating the quantity of product contained 
• A statement reading, “Keep out of the Reach of Children” 
• A statement reading, “Store at controlled room temperature 20 to 25°C (68 to 
77°F) with excursions permitted 15 to 30°C (59 to 86°F)” 
6.6 
Accountability 
The Investigator is responsible for ensuring that the designated investigational center 
staff member will conduct a complete inventory of study materials and assume 
responsibility for their storage and dispensing.  In accordance with federal regulations, 
the investigators must agree to keep all study materials in a secure location with restricted 
access.  The investigator will keep a record of the inventory and dispensing of all study 
drug.  This record will be made available to the site’s monitor for the purpose of 
accounting for all clinical supplies.  Any significant discrepancy and/or deficiency must 
be recorded with an explanation. 
All supplies sent to the investigators will be accounted for and, in no case, used in any 
unauthorized situation.  Upon receipt, all shipment supplies must be acknowledged and 
documented, stored and/or returned appropriately. Following verification, and as directed 
by the Sponsor, all used and unused product must be returned to the Sponsor or, with the 
Sponsor’s permission, disposed of at the site in an appropriate manner. The procedure for 
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documenting and performing drug return or destruction will be provided to the site by the 
Sponsor designee.   
6.7 
Methods of Assigning Subjects to Treatment Groups 
This is a double-blind study, in which the identity of the study drug will be unknown to 
both investigator/evaluator and subjects, as well as all individuals closely associated with 
the study.  Subjects will be randomized to 1 of 5 treatment groups in a 1:1:1:1:1 ratio 
[rifaximin SSD 40 mg IR (QD and BID), rifaximin SSD 80 mg (QD and BID), and 
placebo BID].  Each screened subject will be assigned a screening number by the 
investigational center, which will consist of the XX-digit site number (pre-assigned by 
Sponsor/designee) and the 3-digit chronological order screening number, starting with 
‘001’ (e.g., XX-001, XX-002).   
The study drug kit will be assigned to the subject based on a randomization code and kits 
will be dispensed to the subjects by the randomization system at the Day 2 visit.  
6.8 
Randomization and Blinding 
The study drugs will be packaged and labeled identically.  In the SSD QD cohorts 
blinding will be maintained by administering placebo as the second daily dose.  Study 
drug kits will be numbered sequentially and dispensed randomly to the subjects entering 
the study within each investigational center.  Study drug supplies will be distributed to 
the investigational sites to maintain the randomization ratio within each investigational 
center. 
As a double-blinded study, the investigators, the site staff, the sponsor, and the clinical 
monitors will not be aware of the treatment assigned to the individual study subjects.  
Delegated staff members at each investigational center will dispense the study drugs and 
will collect all used and unused study drug containers as scheduled. 
6.9 
Unblinding 
A few designated members of the Sponsor’s team not involved in the ongoing activities 
of the study will be unblinded as a result of the interim analysis performed when at least 
10 subjects per treatment group have completed participation in the blinded treatment 
period of the study.  Otherwise, the treatment assignments for all enrolled subjects will be 
unblinded only after completion of the 30 day open-label safety follow-up period.  
Specifically, the blind will be broken only after all subject data are entered and cleaned 
according to the study Data Management Plan and the study database is locked. 
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In the case of a medical emergency, the investigator can break the blind for the subject 
involved preferably by first discussing the situation with the medical monitor and the 
sponsor (or designee) immediately.  After confirmation, the investigator will be contacted 
with unblinding information by a sponsor representative.  The investigator will record the 
code break in the subject’s source documents. 
7.0 
EFFICACY AND SAFETY ANALYSIS  
7.1 
Safety and Efficacy Endpoints 
Primary Efficacy Endpoints 
The primary efficacy variable is the time to OHE resolution as measured by the Hepatic 
Encephalopathy Grading Instrument (HEGI; Appendix A).  Using an iterative Delphi 
method, Steering Committee and international hepatologist panel, the West Haven 
Criteria (WHC; Appendix B) scale was modified to develop a clinician tool for OHE 
identification and grading. Major diagnostic criteria include: disorientation (time, place, 
and/or person), presence of both lethargy and asterixis, and somnolence coma.  
Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When 
applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, 
HEGI demonstrated excellent concordance with investigator judgment (Bajaj et al, 2016). 
The HEGI is used to standardize investigator determination as to whether a patient with a 
documented history of cirrhosis and HE is experiencing or has experienced an Overt HE 
episode. The patient is considered to be having an Overt HE episode if at least one of the 
following applies: 1) Disorientated to time or place or person; 2) Lethargic and has 
asterixis and/or 3) Inability to assess the patient due to disorientation to time and place 
and person; and/or somnolence, and/or coma.  Clinical findings must have been present 
for at least 1 hour to be considered an OHE episode.  Resolution of OHE must be 
confirmed with a repeat evaluation using the HEGI at least 3 and no more than 12 hours 
after the initial evaluation to demonstrate persistence of resolution.  NOTE: Subjects 
should continue to dose on blinded study medication until OHE resolution is confirmed. 
Secondary Efficacy Endpoints: 
The following secondary efficacy variables will also be assessed: 
• Time to OHE resolution defined as a West Haven Criteria (WHC) score of 0 or 1 
• Time to 1 unit decrease in WHC score during the randomized treatment period. 
• Change from Baseline in WHC score at Day 15 or end of blinded treatment period, 
whichever occurs first. 
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• Change from Baseline in HEGI score at Day 15 or end of blinded treatment period, 
whichever occurs first. 
• Time to improvement in HEGI score. 
• Length of hospitalization from Baseline to End of Blinded Treatment Phase. 
Safety Endpoints: 
Safety assessments will include the following: 
• Incidence of treatment-emergent adverse events (TEAEs). 
• Change from baseline to OHE resolution in vital sign measurements and clinical 
laboratory values. 
• Incidence of infections, such as spontaneous bacterial peritonitis (SBP), urinary 
tract infection, pneumonia, bacteremia, and cellulitis. 
Open-label Safety Follow-up Phase:  
• Reoccurrence of OHE during the 30 day follow-up period.  
• Readmission to hospital during the 30 day follow-up period. 
• Change from Baseline to study exit in indices of Health Outcome using the 
Caregiver Burden Inventory (CBI; Appendix C) 
• Change during Follow-up Phase (from first follow-up visit post OHE resolution to 
study exit) in Chronic Liver Disease Questionnaire (CLDQ; Appendix D). 
7.2 
Statistical Hypothesis 
The log-rank test is a statistical method for comparing distributions of time until the 
occurrence of an event of interest among independent groups. The null hypothesis tested 
by the log-rank test is that of equal time distribution among groups. Rejection of the null 
hypothesis indicates that the event rates differ among groups at one or more time points 
during the study. 
 
H0: S1(t) =S2(t) 
versus the alternative: 
HA: S1(t) ≠ S2(t)Where S1(t) and S2(t) represent the cumulative probability 
distributions of the times from baseline until the first OHE resolution for each 
SSD group and the placebo group, respectively. 
7.3 
Sample Size 
Approximately 325 subjects will be randomized in 1:1:1:1:1 ratio to rifaximin SSD 
tablets [40 mg immediate release (IR)] QD plus lactulose, rifaximin SSD tablets [40 mg 
immediate release (IR)] BID plus lactulose, rifaximin SSD tablets [80 mg sustained 
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extended release (SER)] QD plus lactulose, rifaximin SSD tablets [80 mg sustained 
extended release (SER)] BID plus lactulose and placebo BID plus lactulose. 
The sample size estimation is based on cumulative probability distributions of the times 
from baseline until the first OHE resolution (HEGI score <2) between treatment groups 
using the log-rank test. 
This sample size estimation is based on a previous study with rifaximin (Sharma 2013).  
It is assumed that approximately 76% of rifaximin plus lactulose subjects and 51% of 
placebo plus lactulose subjects will experience OHE resolution over the course of up to 
14 days of treatment.  With two-sided type I error rate of 0.05, approximately 61 
evaluable subjects per treatment group will provide at least 80% power to demonstrate 
the superiority of rifaximin SSD to placebo using the log-rank test.  
7.4 
Study Populations 
Intent to Treat (ITT):  The ITT population will include all randomized subjects who 
received at least one dose of study drug.   
Analysis on the ITT sample will be used as the primary efficacy analysis and will be 
performed for all efficacy endpoints.  Subjects will be analyzed in the treatment group to 
which they were randomized. 
Per Protocol (PP):  The PP population will include all ITT subjects who remain in the 
study through the end of the blinded randomized treatment period and who have not 
deviated from the protocol in any way likely to seriously affect the primary outcome of 
the study. Important protocol deviations will be identified prior to locking the study 
database. 
Safety:  The safety population will include all subjects who received at least 1 dose of 
study drug.  All subjects in the safety population will be analyzed according to the 
treatment they actually received. 
7.5 
Statistical Analysis 
7.5.1 
Methods of Analysis 
All continuous variables will be summarized using descriptive statistics including the 
sample size (N), mean, SD, median, minimum, and maximum.  All categorical variables 
will be summarized using frequency counts and percentages. 
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7.5.2 
Subject Disposition 
Subject disposition will be summarized for all randomized subjects and will include the 
number of subjects randomized; number and percentage of subjects who completed or 
prematurely discontinued the study, classified by reasons for premature discontinuation; 
the number of subjects randomized at each study site; and the number and percentage of 
subjects who completed or discontinued the study at each study site. 
7.5.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment 
using the ITT, PP, and safety populations.  Demographic characteristics include age, 
gender, race, ethnicity and weight. 
Baseline characteristics include: 
• HEGI grade (Appendix A) 
• WHC score (Appendix B) 
• Serum ammonia levels 
• Comprehensive Metabolic/Liver Panel (including ALT, AST, ALP, DBil, TBil, 
ProTime, INR; total serum protein) 
• Hematology: CBC w/Differential 
• Alpha fetoprotein (AFP) only in lieu of recent HCC imaging at screening only 
• Serum pregnancy test. NOTE: Serum pregnancy tests performed upon hospital 
admission, prior to study consent, may be used at Screening. 
• Urinalysis 
• Current Rifaximin use at screening (Yes vs. No) 
• Current lactulose use for maintenance of remission at screening (Yes vs. No) and 
dosage 
• Time since first diagnosis of advanced liver disease, defined as first dose date minus 
date of first diagnosis of advanced liver disease + 1 
(randomization date will be used if first dose date is missing) 
• Time since first diagnosis of hepatic encephalopathy, defined as first dose date 
minus date of first diagnosis of hepatic encephalopathy + 1 
(randomization date will be used if first dose date is missing) 
• Number of HE episodes within the past 6 months 
• Factors contributing to HE episodes 
• Diabetes at Screening (Yes vs. No) 
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7.5.4 
Efficacy Endpoint Analyses 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to OHE resolution as measured by the HEGI, a 
modified West Haven Criteria scale.  OHE resolution is defined as a HEGI grade of < 2.  
Resolution of OHE must be confirmed with a repeat evaluation using the HEGI at least 3 
and no more than 12 hours after the initial evaluation to demonstrate persistence of 
resolution.  Time to resolution of OHE is defined as the duration between the date/time of 
first dose of study drug (baseline) and the date/time of first documented resolution of 
OHE via the HEGI.  Subjects who complete the 14 day randomized treatment period 
without experiencing OHE resolution will be censored at 14 days.   
The primary efficacy analysis of time to OHE resolution between each active rifaximin 
SSD plus lactulose treatment group and the placebo plus lactulose group will be tested 
using the log-rank test. 
Analysis of primary efficacy endpoint will be tested in ITT and PP populations.  
Analysis of Secondary Efficacy Endpoints 
Analyses of secondary efficacy endpoints will be based on the ITT population.  
• Time to OHE resolution defined as a WHC score of 0 or 1 
• Time to 1 unit decrease in WHC score during the randomized treatment period. 
• Change from Baseline in WHC score at Day 15 or end of blinded treatment period, 
whichever occurs first. 
• Change from Baseline in HEGI score at Day 15 or at end of blinded treatment 
period, whichever occurs first. 
• Time to improvement in HEGI score. 
• Length of hospitalization from Baseline to End of Blinded Treatment Phase. 
7.5.5 
Safety Endpoints Analyses 
All safety analyses will be performed for the Safety Population. Each analysis will 
consist of a summary of data within each treatment group. 
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 initial treatment (baseline visit) or, if pre-existing, 
worsening after initial treatment (baseline). 
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The incidence of treatment-emergent AEs will be summarized for each treatment group 
by body system and MedDRA preferred term.  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: 
• Number and percentage of subjects experiencing TEAEs; 
• Number and percentage of TEAEs by relationship to study treatment (i.e. related 
or unrelated); 
• Number and percentage of TEAEs by severity (i.e., mild, moderate or severe); 
• Number and percentage of subjects experiencing serious AEs (SAEs); 
• Number and percentage of subjects experiencing study drug-related SAEs; 
• TEAE leading to permanent treatment discontinuation; 
• TEAEs with an outcome of death. 
The incidence of treatment-emergent AEs of infections, such as SBP, UTI, pneumonia, 
bacteremia and cellulitis will be summarized by each 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.  Severity and AE 
leading to early termination will also be presented for these infection AEs. 
All SAEs and AEs leading to premature withdrawal from the study, and all deaths, will 
be listed. 
7.5.6 
Clinical Laboratory Findings 
Laboratory data will be summarized at baseline and at each visit, as well as changes from 
baseline in laboratory parameters.  For each summary the N, mean, median, SD, 
minimum, and maximum values will be given by treatment group.  Pretreatment 
laboratory values obtained closest in time to first dose of study drug will be used for 
summarization of baseline and change from baseline. Clinical laboratory tests performed 
during the study will be analyzed by a local clinical laboratory.  To standardize the 
laboratory reference values the normal laboratory values listed in the Merck Manual will 
be used. 
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• Serum ammonia levels 
• Comprehensive Metabolic/Liver Panel (including ALT, AST, ALP, AFP, DBil, 
TBil, ProTime, INR; total serum protein) 
• Hematology: CBC w/Differential 
• Alpha fetoprotein (AFP) only in lieu of recent HCC imaging at screening only 
• Serum pregnancy test. NOTE: Serum pregnancy tests performed upon hospital 
admission, prior to study consent, may be used at Screening. 
• Urinalysis 
• Urine pregnancy test 
7.5.7 
Vital Signs Measurements 
Vital signs will be summarized at baseline and at each visit, as well as changes from 
baseline in vital sign measurements.  For each summary the N, mean, median, SD, 
minimum, and maximum values will be given by treatment group.  Pretreatment vital 
signs obtained closest in time to first dose of study drug will be used for summarization 
and analysis of baseline and change from baseline vital signs. 
Vital signs will include supine blood pressure (mmHg), heart rate (beats per minute), 
respiratory rate, weight and temperature. Height (cm) will be collected at Screening only. 
Vital sign measurements will be collected at every visit.  Supine blood pressure 
measurements should be measured on the same arm throughout the study. 
7.6 
Interim Analysis 
An interim analysis will be conducted when at least 10 subjects per treatment group have 
completed participation in the blinded treatment period of the study. The CRO/Sponsor 
designee will remain blinded, whereas a few designated members of the Sponsor’s team 
who do not have direct involvement with the ongoing study will be unblinded at the interim 
analysis stage. The interim results will not be shared outside of the small designated team, 
and no changes will be made to the ongoing study based on the interim study results. 
8.0 
STUDY METHODS 
8.1 
Study Visits  
Following identification of a potential subject, the Investigator (or designee) will explain 
the purpose of the study, procedures, risks/benefits, and subject responsibilities to the 
potential subject’s caregiver.  The subject’s ability to meet the requirements of the study 
will be determined in discussions with the caregiver.  If the caregiver consents on behalf 
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of the subject the person obtaining written consent will sign and date the IRB/EC-
approved ICF, at which point the subject is considered part of the study population.  The 
original signed document will be retained in the subject records, and a copy will be 
provided to the subject/caregiver.  In addition, the applicable privacy regulation 
requirements must be met. 
Study Visit procedures are outlined in Table 1. 
 
 
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Table 1:  Study Design and Schedule of Assessments 
 
Blinded Randomized Treatment 
Period 
 
Open-label Safety Follow-up Period 
GENERAL & SAFETY 
ASSESSMENTS: 
Screening & 
Baseline 
Treatment Period  
Hospital 
Discharge  
Follow-up4 Visit 
1 
Follow-up4 
Visit 2 
Follow-up4 
Visit 3/ EOS8 
Study Day 
Study Day 1 
Study Day 2 Up to 
Study Day 15 
 
 Day 7 Post 
Resolution (±2)   
Day 14 Post 
Resolution 
(±2)  
Day 30 Post 
Resolution 
(±2)   
Informed Consent 
X 
 
 
 
 
 
Review inclusion / exclusion criteria 
X 
 
 
 
 
 
Medical History and Demographics 
X 
 
 
 
 
 
Record Concomitant Medications 
X 
X 
X 
X 
X 
X 
Discontinue use of prohibited 
medications 
X 
 
 
 
 
 
Vital Signs and Weight (kg) 
X 
X 
 
X 
X 
X 
Height (cm) 
X 
 
 
 
 
 
Physical Examination 
X 
X2 
 
X 
X 
X 
Clinical Laboratory Tests/ Urinalysis 
X5 
X 
 
X 
X 
X 
Serum/Urine Pregnancy Test 
X6 
 
 
 
 
X6 
HEGI1 
X 
X2 
 
X 
X 
X 
WHC1 
X 
X2 
 
X 
X 
X 
CBI1 
X 
 
 
X 
X 
X 
Randomize Subject in EDC 
X 
 
 
 
 
 
Dispense/Administer 1st Dose of 
Blinded Study Drug 
 
X2 
 
 
 
 
Record dates/times of study drug 
dosing 
 
X 
 
 
 
 
Record Bristol Stool Appearance  
 
X 
 
 
 
 
Record lactulose use (dosing time and 
amount) dates/times of lactulose use 
X 
X 
 
X3 
X3 
X3 
Assess Open-Label Dosing 
Compliance 
 
 
 
X3 
X3 
X3 
Record Adverse Events 
X 
X 
X 
X 
X 
X 
Dispense Open Label Xifaxan® 
550mg and Review Dosing 
Instructions 
 
 
 
X7 
 
 
 
CLDQ1 
 
 
 
X 
X 
X 
Abbreviations: EOS = end of study 
All Subject assessments will be performed by a trained and qualified Evaluator. Efforts should be made to have the same evaluator assess the same Subject 
for as many HEGI assessments as possible. Every effort must be made for the same Evaluator to conduct the HEGI assessments at both the resolution of 
OHE and the confirmation of resolution assessed 3 to 12 hours later.  
1Evaluator, defined by only licensed physicians, physician’s assistants or nurse practitioners, who are trained in these instruments may conduct the 
assessment.    
2Assessments are conducted twice per day, approximately 12 hours (±2 hours) apart.  Following resolution of OHE,  a confirmatory HEGI (3 to 12 hours 
post initial resolution) must be done to complete the blinded randomized treatment phase.. Subjects should continue to dose on blinded study medication 
until OHE resolution is confirmed. 
3Subject will report on lactulose use (if any) and open-label dosing compliance from previous visit to current visit.  Diary cards are not being used on this 
study.   
4Open-label Safety Follow-up visits will be conducted by a study investigator. 
5Clinical laboratory tests run within 24 hours of consent, may be used in place of drawing new labs at Screening provided all protocol required labs are 
present. Note: AFP is only required at Screening.   
6 Serum pregnancy test is done at Screening and urine pregnancy test at EOS visit (open-label safety follow-up Visit 3) 
7 Open-label drug should only be dispensed to subjects upon hospital discharge.  Please note this may be on a different day than OHE resolution. 
8 If a subject early terminates/discontinues during the study, the visit schedule at the end of the that treatment phase should be followed for their ET visit. 
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8.1.1 
Day 1: Screening / Baseline 
The following procedures are to be completed at the Screening/Baseline visit, prior to 
randomization: 
• Informed consent is to be signed by the subject’s caregiver prior to performing any 
study evaluations or procedures, including discontinuing any prohibited medications. 
• Allocate subject screening identification number to eligible subjects in ascending 
order using the next available consecutive number on the list. 
• Review Inclusion/Exclusion criteria to ensure subject qualifies for the study. 
• Conduct serum pregnancy test (for female subjects of childbearing potential) and 
confirm that it is negative. Note: Serum pregnancy tests performed upon hospital 
admission, prior to study consent, may be used at Screening. 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Collect demographic information, significant medical history, and hospital admission 
data including diagnosis of liver cirrhosis and OHE and HEGI grade. 
• Collect vital sign measurements (include weight, height, supine blood pressure, heart 
rate, respiration rate and temperature).  Height will only be collected at Screening. 
• Record all concomitant medications administered within the 30 days prior to 
screening visit, and ensure that all prohibited medications are discontinued 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). Labs drawn within 24 hours of consent may be used at Screening 
provided all protocol required labs are present. 
• Subject must have a Grade 2 or Grade 3 HEGI score (Appendix A) following 
lactulose treatment and adequate hydration (IV fluids at PI discretion). NOTE: 
Duration of hospital admission prior to enrollment is not restricted provided the 
hydration and lactulose treatment occurred within a reasonable timeframe to subject 
randomization. 
• Determine and record WHC score. (Appendix B) 
• Assess Caregiver Burden Index (CBI; Appendix C).  
After all Screening/Baseline procedures have been completed and necessary information 
has been collected: 
• Randomize subject onto study using a randomization code obtained from the IRT. 
• Record date, time(s) and dose(s) of lactulose. 
• Record all AEs. 
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8.1.2 
Day 2 up to Day 15: Randomized Treatment Period 
The following are to be conducted each day the subject is hospitalized.  
Conducted Daily 
• Record all concomitant medications and AEs. 
• Collect vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate and temperature). 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). 
• Dispense study drug and administer dose to subject.  
• Record date and times of study drug dose.  
• Record date, time(s) and dose(s) of lactulose. 
• Record frequency of bowel movements and stool appearance. (Bristol, Appendix E) 
Conducted TWICE Daily at 12 Hour (±2 Hr) Intervals (approx. 7AM and 7PM) 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Determine and record HEGI score. (Appendix A) 
• Determine and record WHC score. (Appendix B) 
Criteria for OHE Resolution 
For the purposes of this clinical study, OHE resolution is determined solely on the HEGI 
score.  A HEGI score of < 2 indicates resolution of OHE, whereas a HEGI score of ≥2 
indicates a continuation of the OHE episode. 
Resolution of the OHE episode (HEGI score of < 2) must be confirmed by a repeat 
evaluation (HEGI) at least 3 and no more than 12 hours after the initial evaluation to 
demonstrate persistence of the OHE resolution.   
- 
If the OHE resolution is not confirmed by this repeat evaluation, the subject 
continues in the study until OHE resolution occurs again and is subsequently 
confirmed by a repeat evaluation 3-12 hours following.  
- 
If the OHE resolution is confirmed by this repeat evaluation, the subject is 
considered resolved.  Resolution of OHE will be recorded as the date/time of the 
HEGI assessment immediately prior to the confirmation evaluation. NOTE: 
Subjects should continue to dose on blinded study medication until OHE 
resolution is confirmed. 
8.1.3 
OHE Resolution 
The following procedures will occur upon OHE resolution with confirmatory HEGI.  
• Record all concomitant medications and AEs. 
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• Collect vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate, and temperature). 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). 
• Determine and record HEGI score. (Appendix A) 
• Determine and record WHC score. (Appendix B) 
• Dispense Xifaxan® 550mg (BID dosing) and review dosing instructions with subject. 
• Schedule and review the open-label safety follow-up visits with subject.  
• Record stool appearance. (Bristol, Appendix E) 
 
If the subject discontinues or early terminates from the study prior to starting the open-
label safety follow-up period, the OHE Resolution visit assessments are to be done as the 
subjects early termination/discontinuation visit and the subject exited from study. Please 
refer to Section 8.3.1 for a list of early termination/discontinuation procedures to be 
conducted.  
8.1.4 
Hospital Discharge Visit 
The following procedures will occur if the subject is not discharged from the hospital on 
the same day as OHE resolution:  
• Record all concomitant medications and AEs. 
• Dispense Xifaxan 550 mg (BID dosing) and review instructions with subject.  
• Schedule and review the open-label safety follow-up visits with subject. 
8.1.5 
Open-label Safety Follow-up / Visit 1 (Day 7 ±2)  
Follow-up Visit 1 will occur 7 days (± 2 days) following a confirmed resolution of OHE.  
Note that OHE resolution and subject discharge may not occur on the same day.  
• Record all concomitant medications and AEs. 
• Collect vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate and temperature). 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). 
• Record date, time(s) and dose(s) of lactulose, if taken. 
• Determine and record HEGI score. (Appendix A) 
• Determine and record WHC score. (Appendix B) 
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• Assess health outcomes indices via CBI (Appendix C) and CLDQ (Appendix D). 
8.1.6 
Open-label Safety Follow-up Visit 2 (Day 14 ±2)  
Follow-up Visit 2 will occur 14 days (± 2 days) following a confirmed resolution of OHE.  
Note that OHE resolution and subject discharge may not occur on the same day.  
• Record all concomitant medications and AEs. 
• Collect vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate and temperature). 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). 
• Record date, time(s) and dose(s) of lactulose, if taken. 
• Determine and record HEGI score. (Appendix A) 
• Determine and record WHC score. (Appendix B) 
• Assess health outcomes indices via CBI (Appendix C) and CLDQ (Appendix D). 
8.1.7 
Open-label Safety Follow-up / Visit 3 (EOS) (Day 30 ±2)  
Visit 3 (EOS) Visit will occur 30 days (± 2 days) following a confirmed resolution of OHE.  
Note that OHE resolution and subject discharge may not occur on the same day.  
• Record all concomitant medications and AEs. 
• Collect vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate and temperature). 
• Complete a full physical examination, including evaluation for complications of liver 
cirrhosis. 
• Collect blood and urine for clinical laboratory tests (hematology, blood chemistry, 
and urinalysis). 
• Record date, time(s) and dose(s) of lactulose, if taken. 
• Determine and record HEGI score. (Appendix A) 
• Determine and record WHC score. (Appendix B) 
• Assess health outcomes indices via CBI (Appendix C) and CLDQ (Appendix D). 
• Conduct urine pregnancy test. 
 
 
 
If the subject discontinues or early terminates from the study during the open-label safety 
follow-up period, the Visit 3 (EOS) visit assessments will be followed as the subject early 
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termination/discontinuation visit and the subject exited from study. Please refer to 
Section 8.3.1 for a list of early termination/discontinuation procedures to be conducted. 
8.1.8 
Unscheduled Visits 
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of 
subjects.  All additional exams should be fully documented in the source documents and 
on Unscheduled Visit CRFs, as appropriate.  Visits intended to fulfill scheduled visit 
requirements that fall outside the designated scheduled visit range, are not Unscheduled 
Visits.  In these cases, the visit data will be collected and transcribed to the appropriate 
scheduled visit CRF. 
If a subject is seen for multiple visits during a given visit timeframe, the data from the 
visit that is intended to meet the protocol requirements for the scheduled visit, should be 
captured on the visit CRF.  Where such a determination cannot be made, the first visit 
within the scheduled visit interval will be used for completion of the protocol required 
scheduled visit CRF.  Data from any additional visits within a scheduled visit interval 
will be captured on an Unscheduled Visit CRF.  
8.1.9 
Missed Visits  
If a subject misses any scheduled follow-up visit and cannot be seen prior to the start of 
the visit range for the next scheduled follow-up visit, the visit is considered missed. 
8.2 
Post-Study Follow-up  
If a subject requires further follow-up of AEs upon discontinuation or completion of the 
study, the Investigator should schedule post-study follow-up visits, as necessary.  Refer 
to for follow-up of AEs following study exit. 
8.3 
Study Completion  
The Sponsor will notify the Investigator when to contact the IRB to inform them that the 
study is complete. 
8.3.1 
Early Study Termination 
If the subject discontinues or early terminates from the study during the blinded treatment 
period, the following assessments are to be collected:  
• All concomitant medications and AEs. 
• Vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate, and temperature). 
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• Complete physical examination, including evaluation for complications of liver 
cirrhosis. 
• Blood and urine for clinical laboratory tests (hematology, blood chemistry, and 
urinalysis). 
• HEGI score. (Appendix A)       
• WHC score. (Appendix B) 
 
If the subject discontinues or early terminates from the study during the open-label safety 
follow-up period, the following visit assessments are to be collected:  
• All concomitant medications and AEs. 
• Vital sign measurements (include weight, supine blood pressure, heart rate, 
respiration rate and temperature). 
• Complete physical examination, including evaluation for complications of liver 
cirrhosis. 
• Blood and urine for clinical laboratory tests (hematology, blood chemistry, and 
urinalysis). 
• Record date, time(s) and dose(s) of lactulose, if taken. 
• HEGI score. (Appendix A)       
• WHC score. (Appendix B) 
• Assess health outcomes indices via CBI (Appendix C) and CLDQ (Appendix D). 
• Urine pregnancy test.      
 
If during the study it becomes evident to the Sponsor that the study should be stopped 
prematurely, the study will be terminated and appropriate notification will be given to the 
Investigators, IRB, and FDA, as applicable.  The Sponsor will instruct the Investigators 
to stop dispensing study materials/treatment and to arrange for study closeout at each site. 
8.4 
Concomitant Medications/Therapy  
All concomitant medications administered within 30 days of Day 1 (Screening/Baseline) 
will be recorded in the subject’s medical records and case report form (CRF). 
Permitted Therapy 
1. Direct-acting antivirals and hepatitis B virus suppression therapy permitted following 
AASLD guidelines. 
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2. Stable dose of antidepressants and/or benzodiazepines if the dose and regimen are 
expected to remain unchanged throughout the trial. 
3. Prescription and non-prescription sleep aids [e.g., Lunesta (eszopiclone) and 
Intermezzo or Ambien (zolpidem tartrate)]. 
4. Stable dose of Neurontin (gabapentin) and Lyrica (pregabalin) if the dose and regimen 
are expected to remain unchanged throughout the trial. 
5. Diuretics (including diuretics for the management of ascites). 
Prohibited Therapy 
Any prohibited medications used during the study will be recorded on the concomitant 
medication page of the CRF. 
1. Non-study rifaximin (e.g., commercial rifaximin, Xifaxan® 550 mg tablets), Rifampin 
or other rifamycin derivatives are prohibited upon subject consent to the study. 
Note: After completion of the blinded randomized treatment phase, defined as 
OHE resolution, subjects will who continue on to the open-label safety follow-up 
period will receive 30 days of open-label treatment with Xifaxan® 550 mg upon 
hospital discharge, regardless of the treatment arm in which they were previously 
randomized.  Open-label drug should only be dispensed upon hospital discharge.  
Please note this may be on a different day than OHE resolution. 
 
If subjects remain hospitalized following OHE resolution, standard of care 
treatment (which may include Xifaxan® 550 mg) should be given until hospital 
discharge,, at which time the subjects will receive 30 days of open-label 
Xifaxan® 550 mg. 
 
The following concomitant medications are prohibited within 30 days of Day 1 
(Screening/Baseline) and throughout the study: 
 
1. Milk thistle. 
2. Investigational drug product or device used within 30 days or 5 drug half-lives 
(whichever is longer) prior to Baseline. 
3. P-glycoprotein inhibitors: including but not limited to cyclosporine A, non-selective 
beta blockers (excluding nadolol), HIV protease inhibitors, azole antifungals, 
macrolide antibiotics, non-dihydropyridine calcium channel blockers. NOTE: This is 
NOT A COMPLETE LIST. 
The following concomitant medications are prohibited after Day 1 (Screening/Baseline) 
through the EOS visit: 
1. P-glycoprotein inhibitors. 
2. Coumadin (warfarin) or coumarin derivatives. 
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3. Alternative, natural, herbal, and/or dietary supplements that may affect the course of 
the liver disease (including but not limited to: Milk Thistle, St John’s Wort, Echinacea, 
etc.). 
8.5 
Treatment Compliance 
Any subject, who does not follow instructions to a degree that, in the Sponsor or 
Investigator’s opinion, jeopardizes the subject’s well-being, may be discontinued. 
8.6 
Protocol Deviations 
The date of and reason for deviations, will be documented for all cases.  Significant or 
major protocol deviations impacting the safety of the subject or the integrity of the study 
must be reported by the Investigator to the IRB/EC immediately.  Reporting of all other 
protocol deviations must adhere to the requirements of the governing IRB/EC.  
Protocol assessments will continue until the end of the study, unless the protocol 
deviations put the subject at risk or the subject’s condition requires that he/she be 
discontinued from the study. 
9.0 
ADVERSE EVENTS 
Salix 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: 
• Identify a potential new safety signal. 
• Ensure that an investigational product’s risks are adequately assessed and 
communicated to investigators, IRBs/IECs, and regulatory bodies during clinical 
development. 
For this study, safety monitoring activities will include but are not limited to:  
• Review and evaluation of single SAE occurrences in real-time as reported through 
the SAE reporting process as outlined in this section of the protocol; 
• Review and evaluation, in real-time, of 1 or more occurrences of an uncommon 
SAE that is not commonly associated with product exposure; 
• Findings and/or safety data obtained during this study will provide information 
for the overall review of safety that is conducted by Salix on a routine basis.  
Salix will report expeditiously any findings from clinical trials (ongoing or 
completed), epidemiological studies,  pooled analysis of multiple studies, and 
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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 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 8.1), AE or 
SAE. 
9.1 
Operating Definitions for Assessing Safety 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a subject 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). 
An AE does include the following: 
• 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. 
• Increase in frequency or intensity of a pre-existing episodic event or condition. 
• Condition detected or diagnosed after study product administration even though it 
may have been present prior to the start of the study. 
• Symptom associated with disease not previously reported by the subject.  
 
An AE does not include the following: 
• 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. 
• Situations where an untoward medical occurrence has not occurred 
(e.g., hospitalization for cosmetic elective surgery; and social and/or convenience 
admissions).  
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• Overdose of either study product or concurrent medication without any signs or 
symptoms. 
• 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. 
9.1.2 
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): 
• Results in death 
• 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
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 for more than 
24 hours.  It does not include presentation at a casualty or emergency room. 
• 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. 
• A congenital anomaly or birth defect in the offspring of a subject who received 
study product. 
• 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 
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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. 
Additionally, an AE meeting any of the serious outcomes previously defined above that is 
assessed by the investigator as resulting from study participation (regardless of 
relationship to study drug) should be treated as a SAE for this protocol (e.g., 
complications resulting from the taking of a blood sample or performance of a protocol 
required procedure). 
Medical and scientific judgment should be used in deciding whether prompt reporting is 
appropriate in case of events that do not meet the serious criteria above. 
9.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, vital signs, hematology) or other 
abnormal assessments (e.g., abnormal findings during examinations) 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 is clinically significant. 
9.3 
Method, Frequency, and Time Period for Detecting AEs and SAEs 
At each assessment, after the subject (or caregiver) has had an opportunity to 
spontaneously mention any problems, the investigator should inquire about AEs by 
asking the following standard questions: 
1. "Have there been any (other) medical problems since your last visit/assessment?" 
2. "Have any new medications been taken, other than those given to you in this study, 
since your last visit/assessment?" 
9.3.1 
Time Period for Detecting and Reporting of AEs and SAEs 
From the time of informed consent through study completion/early termination, including 
the 30-day open-label safety follow-up period.  
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9.3.2 
Post-Study SAEs 
If at any time after 30 days post last study dose, the investigator becomes aware of an 
SAE which he/she feels is related to study drug or procedure, this must also be reported 
immediately (within 24 hours of knowledge of occurrence) by telephone and confirmed 
facsimile transmission/email to CRO/Sponsor designee. 
9.4 
Documenting AEs and SAEs 
All AEs that occur after the subject has signed the ICF 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 CRF.  In addition, SAEs must be documented on the paper 
SAE Report Form.  Should the investigator become aware of an SAE (regardless of its 
relationship to study drug) that occurs within 30 days after stopping the study drug, the 
SAE must be reported in accordance with procedures specified in this protocol. 
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 
(such as vital signs) 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 Assesments’ 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 Sponsor designee.  It is very 
important that the investigator provide his/her assessment of causality to study product. 
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9.5 
Severity of Adverse Events 
The investigator is to classify the severity of an AE according to the following 
definitions: 
• Mild: Awareness of a sign or symptom but is easily tolerated, requires no 
treatment and does not interfere with subject’s daily activities. 
• Moderate: Low level of concern to the subject and may interfere with daily 
activities, but can be relieved by simple therapeutic care. 
• Severe: Interrupts the subject’s daily activity and requires systemic therapy or 
other treatment. 
9.6 
 Assessment of Causality 
The investigator should assess the relationship of the AE, if any, to the study drug as 
either “Related” or “Not Related.”  The following should be taken into account when 
assessing AE/SAE causality: 
• Related:  There is at least a reasonable possibility that the AE/SAE is related 
to the study drug.  Reasonable possibility means that there is evidence to 
suggest a causal relationship between the drug and the AE. 
• Not Related:  There is little or no reasonable possibility that the AE/SAE is 
related to the study drug.  This assessment implies that the AE/SAE has little 
or no temporal relationship to the study drug and/or a more likely or certain 
alternative etiology exists. 
9.7 
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. 
CRO/Sponsor designee 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, CRO/Sponsor 
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designee should be provided with a copy of any postmortem findings, including 
histopathology. 
For SAEs, new or updated information (follow-up information) should be recorded on a 
new SAE Report Form and the corresponding follow-up number entered must be entered 
on the form.  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/IEC must be notified about SAEs 
in accordance with the requirements of the governing IRB/IEC.  
9.8 
Prompt Reporting of SAEs to CRO/Sponsor Designee 
SAEs must be reported promptly to CRO/Sponsor designee once the investigator 
determines that the event meets the protocol definition of a SAE. 
Prompt reporting of a SAE requires: 
• Completion and transmission of the SAE Report Form to CRO/Sponsor designee via 
email/fax 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 CRF 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 CRF (as applicable) should be updated to ensure all data points 
documented in the AE CRF are aligned with the matching data points on the paper 
SAE Report Form. 
9.9 
Pregnancy Reporting 
Pregnancies detected in subjects assigned to study treatment should be reported to 
CRO/Sponsor designee via email/fax within 24 hours of the investigator’s awareness, 
using the Salix Pregnancy Report 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.  (Refer to the ‘Females of Reproductive Potential’ 
section). 
CRO/Sponsor designee should be notified via email/fax of any updates on the status of 
the pregnancy within 24 hours of the information becoming available by updating and/or 
amending the initial pregnancy report form.  If a pregnancy is associated with an SAE, an 
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SAE Report form along with the Salix Pregnancy form should be completed and reported 
to CRO/Sponsor designee. 
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. 
9.10 
Transmission of SAE Report Forms and Pregnancy Report Forms 
Completed SAE Report Forms and completed pregnancy report forms should be 
transmitted to Sponsor designee via the email/fax number provided below: 
 
9.11 
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/IEC.  
10.0 DATA QUALITY ASSURANCE  
10.1 
Study Monitoring 
The Sponsor’s representatives must be allowed to visit all study site locations to assess 
the data, quality, and study integrity in a manner consistent with applicable health 
authority regulations and the procedures adopted by the Sponsor. 
Prior to the start of the study, the Sponsor (or designees) will review the protocol, CRF, 
regulatory obligations, and other material or equipment relevant to the conduct of the 
study with the Investigator and relevant study site personnel. 
Monitoring visits and telephone consultations will occur as necessary during the course 
of the investigation to verify the following: 
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• the rights and well-being of subjects are protected 
• the conduct of the investigation is in compliance with the currently approved 
protocol/amendment, ICH GCPs, and IRB/EC requirements 
• the integrity of the data, including adequate study documentation 
• the facilities remain acceptable 
• the Investigator and site personnel remains qualified and able to conduct the study 
• test article accountability 
During the course of the study, if the Sponsor determines that an Investigator is 
non-compliant with the study plan and/or applicable regulatory requirements, the Sponsor 
will take action to secure compliance.  In addition, the Sponsor may terminate the 
Investigator’s participation in the study if appropriate, or if the Investigator remains 
non-compliant despite the Sponsor’s actions. 
10.2 
Source Documentation 
All medical information obtained at each study visit must be recorded in the subject’s 
record (source documentation) in real time as it is collected.  Source documentation 
consists of original subject documents, as well as data and records with information 
relevant to the subject and his/her participation in the study. 
Examples of source documents include;  hospital records, clinical and office charts, 
laboratory notes, memoranda, signed ICFs, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, laboratories, and 
medico-technical departments involved in the clinical investigation.  Source 
documentation worksheets may be provided by the Sponsor to record pertinent 
information.  Source data may also include information initially recorded in an electronic 
format. 
Specific to this study, the eCRF is acceptable as a source document for the following 
variables and information can be recorded directly onto the eCRF by site personnel: 
• subject weight and height 
• physical examination 
• respiratory rate 
• blood pressure 
• pulse rate 
• body temperature 
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• time of dosing 
• real time of each examination 
Subject and/or caregiver completed forms are also considered source data. Only subjects 
and caregivers are to record information in questionaires. In no instance, should an 
Investigator or study site personnel record any data or make changes to subject completed 
forms.  The Investigator or designee should review subject/caregiver completed forms.  If 
an entry is found to be illegible or a mistake is found the subject should be instructed to 
edit the entry by drawing a single line through the original entry, entering the new 
information, and dating and initialing the change. 
Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded on eCRFs.  The Investigator and 
his/her study site personnel will be responsible for completing the eCRFs.  The 
Investigator is required to verify that all of the requested information is accurately 
recorded on the eCRFs.  All information requested on the eCRFs needs to be supplied, 
including subject identification and initials, date(s), assessment values, etc., and any 
omission or discrepancy will require explanation.  All information on eCRFs must be 
traceable to source documents. 
The study monitor will be responsible for reviewing and verifying the data recorded on 
the eCRFs, utilizing the original source documentation and will query discrepant 
findings.  The Investigator and study site personnel will be responsible for answering all 
queries.  The eCRFs will be submitted to the Sponsor for quality assurance review, data 
entry, and statistical analysis. 
A copy of the eCRFs will be retained by the Investigator, who must ensure that it is 
stored in a secure place. 
10.3 
Recording of Data and Retention of Documents 
Subject data recorded on eCRFs during the study will be documented in a coded fashion.  
The subject will only be identified by the subject number.  Confidentiality of subject 
records must be maintained to ensure adherence to applicable local privacy regulations. 
The Investigator must retain essential documents (indefinitely or specify time, if 
required) after the completion of the study, unless otherwise notified by the Sponsor.  The 
Investigator agrees to adhere to the document retention procedures when signing the 
protocol Investigator Statement of Approval. 
Essential documents include but are not limited to the following: 
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• IRB/EC approvals for the study protocol, all amendments, ICF(s), and 
advertisements 
• IRB/EC annual study review 
• IRB/EC correspondence and reports (eg, SAE reports, protocol deviations, and 
safety updates) 
• regulatory documents (e.g., financial disclosure and delegation of authority forms) 
• all source documents  
• eCRFs 
• subject’s signed ICF 
• accountability records for the test article(s) 
• correspondence from and to the Sponsor 
• any other documents relevant to the conduct of the study 
In the event that the Investigator withdraws from the study (e.g., retirement, relocation), 
study records will be transferred to a mutually agreed upon designee (e.g., another 
Investigator, site IRB/EC).  The Investigator will provide notice of such transfer in 
writing to the Sponsor. 
10.4 
Auditing Procedures 
Audits of clinical research activities in accordance with the Sponsor’s internal Standard 
Operating Procedures (SOPs) to evaluate compliance with the principles of GCP may 
take place.  A regulatory authority may also wish to conduct an inspection (during the 
study or after its completion).  If an inspection is requested by a regulatory authority 
and/or IRB/EC, the Investigator must inform the Sponsor immediately that this request 
has been made. 
10.5 
Institutional Review Board/Ethics Committee Approval 
The Investigator should ensure that his/her participation in the study, in addition to the 
protocol, subject recruitment materials (written information or materials including web 
pages, radio advertisements, television spots or written text developed to encourage 
subject enrollment) and the ICF to be used in this study are approved by their institution 
IRB/EC, or if not using their institution's IRB/EC, approved by the reviewing central 
IRB/EC prior to entering any subjects in the study.  Documentation of IRB/EC approval 
of the study protocol and informed consent must be provided to the Sponsor prior to 
initiation of the study.  In addition, the Investigator must ensure that the reviewing 
IRB/EC has provided approval for any protocol amendments prior to implementation.   
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If the amendment necessitates a revision to the ICF, the Investigator should ensure the 
revised form is also submitted to and approved by the Sponsor and the IRB/EC prior to 
implementation.  
10.6 
Publication of Results 
All study data generated as a result of this study will be regarded as confidential, until 
appropriate analysis and review by the Sponsor or its designee and the Investigator(s) are 
completed.  The results of the study may be published or presented by the Investigator(s) 
after the review by, and in consultation and agreement with the Sponsor, and such that 
confidential or proprietary information is not disclosed. 
Prior to publication or presentation, a copy of the final text should be forwarded by the 
Investigator(s) to the Sponsor or its designee, for comment.  Such comments shall aim to 
ensure the scientific integrity of the proposed publications and/or presentations and 
ensure that the data and material referring to Salix Pharmaceuticals, Inc. products and 
activities receive fair, accurate, and reasonable presentation. 
 
 
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11.0 REFERENCES 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 
Amodio P, Del PF, Petteno E, Mapelli D, Angeli P, Iemmolo R, et al. Prevalence and 
prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic 
patients. J Hepatol 2001 Jul;35(1):37-45. 
Andreu M, Sola R, Sitges-Serra A, Alia C, Gallen M, Vila M, Coll S, Oliver M. Risk 
factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. 
Gastroenterology. 1993 Apr;104(4):1133-8. 
Bajaj JS, Hafeezulla M, Franco J, Varma R, Hoffmann R, Knox J, Hischkel D, 
Hammekeh T, Pinkerton S, and Saeian K. Inhibitory Control Test for the Diagnosis of 
Minimal Hepatic Encephalopathy.  Gastroenterology 2008; 135: 1591-1600. 
Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of 
hepatic encephalopathy in lactulose-treated patients.  Aliment Pharmacol Ther. 2010 
May;31(9):1012-7.  
Bajaj, Thacker, Heuman, Fuchs, Sterling, Sanyal, Puri, Siddiqui, Stravitz, Bouneva, 
Luketic, Noble, White, Monteith, Unser, Wade. The Stroop Smartphone Application Is a 
Short and Valid Method to Screen for Minimal Hepatic Encephalopathy. 
HEPATOLOGY, Vol. 58, No. 1, 2013  HEPATOLOGY 2013;58:1122-1132. 
Bajaj JS, Frederick RT, Bass NM, Ghabril M, Coyne K, Margolis MK, Santoro M, 
Coakley DF, Mokhtarani M, Jurek M, Scharschmidt BF. Overt hepatic encephalopathy: 
development of a novel clinician reported outcome tool and electronic caregiver diary. 
Metab Brain Dis. 2016 Oct;31(5):1081-93.Bass NM.  Review article: the current 
pharmacological therapies for hepatic encephalopathy.  Aliment Pharmacol Ther. 2007 
Feb;25 Suppl 1:23-31. 
Brown EL, Xue Q, Jiang ZD, Xu Y, Dupont HL. Pretreatment of epithelial cells with 
rifaximin alters bacterial attachment and internalization profiles. Antimicrob Agents 
Chemother. 2010 Jan;54(1):388-96.  
Caserta M, Lund D, Wright S. Exploring the Caregiver Burden Inventory (CBI): Further 
Evidence for a Multi-dimensional View of Burden. J Aging Hum Dev 1996;43(1):21-34. 
Darkoh C, Lichtenberger LM, Ajami N, Dial EJ, Jiang ZD, DuPont HL.  Bile acids 
improve the antimicrobial effect of rifaximin. Antimicrob Agents Chemother. 2010 
Sep;54(9):3618-24. doi: 10.1128/AAC.00161-10. Epub 2010 Jun 14. 
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Davis GL, Alter M, El-Serag H, Poynard T, Jennings L. Aging of Hepatitis C Virus 
(HCV)-infected Persons in the United States: A Multiple Cohort Model of HCV 
Prevalence and Disease Progression. Gastroenterology 2010;138:513-21. 
Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence 
mechanisms at supra- and sub-inhibitory concentrations. J Chemother. 2008 
Apr;20(2):186-94. 
Everhart J. The Burden of Digestive Diseases in the United States. Washington, DC: US 
Department of Health and Human Services, Public Health Service, National Institutes of 
Health, National Institutes of Diabetes and Digestive and Kidney Diseases.; 2008. Report 
No.: NIH Publication No. 09-6443. 
Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P. Morbidity and 
Mortality in Compensated Cirrhosis Type C: a Retrospective Follow-up Study of 384 
Patients. Gastroenterology 1997;112:463-72. 
Felisart J, Rimola A, Arroyo V, et al. Cefotaxime is More Effective than is Ampicillin-
Tobramycin in Cirrhotics with Severe Infections. Hepatology 1985;5:457-62. 
Fiorucci S, Distrutti E, Mencarelli A, Barbanti M, Palazzini E, Morelli A.  Inhibition of 
intestinal bacterial translocation with rifaximin modulates lamina propria monocytic cells 
reactivity and protects against inflammation in a rodent model of colitis.  Digestion. 
2002;66(4):246-56 
 Flagyl (metronidazole) capsules [package insert]. New York, NY: GD Searle; 2018. 
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. 
Gines A, Escorsell A, Gines P, Salo J, Jimenez W, Inglada L, et al. Incidence, Predictive 
Factors, and Prognosis of the Hepatorenal Synodrome in Cirrhosis with Ascites. 
Gastroenterology 1993;105:229-36. 
Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al. Compensated 
Cirrhosis: Natural History and Prognostic Factors. Hepatology 1987;7(1):122-8. 
Gines P, Rmola A, Planas R, et al. Norfloxacin Prevents Spontaneous Bacterial 
Peritonitis Recurrence in Cirrhosis: Results of a Double-Blind, Placebo-Controlled Trial. 
Hepatology 1990;12:716-24. 
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Guevara M, Baccaro M, torre A, Gomez-Anson B, Rios J, Torres F, et al. Hyponatremia 
is a Risk Factor of Hepatic Encephalopathy in Patients with Cirrhosis: a Prospective 
Study with Time-dependent Analysis. Am J Gastroenterol 2009;104:1382-9. 
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. 
Kalaitzakis E, Olsson R, Henfridsson P, Hugosson I, Bengtsson M, Jalan R, Björnsson E.  
Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with 
liver cirrhosis.  Liver Int. 2007 Nov;27(9):1194-201. 
Ma X, Shah YM, Guo GL, Wang T, Krausz KW, Idle JR, Gonzalez FJ. Rifaximin is a 
gut-specific human pregnane X receptor activator. J Pharmacol Exp Ther. 2007 
Jul;322(1):391-8. Epub 2007 Apr 18. 
Merck Manual: Normal Laboratory Values. 
https://www.merckmanuals.com/professional/appendixes/normal-laboratory-values  
Morgan MH, Read AE, Speller DC.  Treatment of hepatic encephalopathy with 
metronidazole.  Gut. 1982 Jan;23(1):1-7. 
Murray K, Carithers R. American Association for the Study of Liver (AASLD) 
Guidelines, Evaluation of the Patient for Liver Transplantation. Hepatology 
2005;41(6):1407-32. 
Navasa M, Follo A, Llovet J, et al. Randomized, Comparative Study of Oral Ofloxacin 
versus Intravenous Cefotaxime in Spontaneous Bacterial Peritonitis. Gastroenterology 
2013;111:1011-7. 
Neo-Fradin (neomycin sulfate) [package insert]. X-Gen Pharmaceuticals, Inc. 2012. 
(discontinued) 
Novak M, Guest C. Application of a Multidimensional Caregiver Burden Inventory. 
Gerontologist 1989;29(6):789-803. 
Planas R, Balleste B, Alvarez MA, Rivera M, Montoliu S, Galeras J, et al. Natural 
History of Decompensated Hepatitis C Virus-related Cirrhosis.  A Study of 100 Patients. 
Journal of Hepatology 2004;40:823-30. 
Pleis JR, Lucas JW. Summary Health Statistics for US Adults: National Health Interview 
Survey, 2007.  National Center for Health Statistics; 2009. Report No.: 10. 
Poordad F. Review Article: the Burden of Hepatic Encephalopathy. Alimentary 
Pharmacology Therapeutics 2007;25(s1):3-9. 
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Rifaximin Investigator Brochure 
Rimola A, Salmeron J, clemente G, et al. Two Different Dosages of Cefotaxime in the 
Treatment of Spontaneous Bacterial Peritonitis in Cirrhosis: Results of a Prospective, 
Randomized, Multicenter Study. Hepatology 1995;21:674-9. 
Romero-Gomez M. Pharmacotherapy of hepatic encephalopathy in cirrhosis. Expert Opin 
Pharmacother 2010 Jun;11(8):1317-27. 
Runyon B, McHutchinson J, Antillon M, et al. Short-course versus Long-course 
Antibiotic Treatment of Spontaneous Bacterial Peritonitis: A Randomized, Controlled 
Study of 100 Patients. Gastroenterology 1991;100:1737-42. 
Schiano TD. Clinical Management of Hepatic Encephalopathy. Pharmacotherapy 2010 
May;30(5, part 2):10S-5S. 
Sharma BC, Sharma P, Agrawal A, Sarin SK.  Secondary prophylaxis of hepatic 
encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.  
Gastroenterology. 2009 Sep;137(3):885-891.  Epub 2009 Jun 6. 
Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, 
double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in 
treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013 Sep;108(9):1458-
1463. 
Singla A, Hart J, Youfu L, Tseng J, Shah S. Hospitalization for Complications of 
Cirrhosis: Does Volume Matter. J Gastrointest Surg 2011;15:330-5. 
Starr S, Raines D. Cirrhosis: Diagnosis, Management and Prevention. Am Fam Physician 
2011;84(12):1353-9. 
Tito L, Rimola A, Gines P, et al. Recurrence of Spontaneous Bacterial Peritonitis in 
Cirrhosis: Frequency and Predictive Factors. Hepatology 1988;8:27-31. 
Toledo C, Salmeron J, Rimola A, et al. Spontaneous Bacterial Peritonitis in Cirrhosis; 
Predictive Factors of Infection Resolution and Survival in Patients Treated with 
Cefotaxime. Hepatology 1993;17:251-7. 
Wolf D. Cirrhosis. Medscape Reference: Drugs, Diseases & Procedures 20. 10-18-2012. 
Wright G, Jalan R.  Management of hepatic encephalopathy in patients with cirrhosis. 
[Review] [76 refs].  Best Practice & Research in Clinical Gastroenterology 
2007;21(1):95-110. 
Xifaxan® PI 
 
 
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