Dose-ranging Study of Rifaximin Soluble Solid Dispersion (SSD) Tablets for the Prevention of Complications of Early Decompensated Liver Cirrhosis

Phase 2

Completed

Conditions: Liver Cirrhosis

Interventions: Drug: Rifaximin SSD 40 mg SER tablet
Drug: Rifaximin SSD 80 mg IR tablet
Drug: Rifaximin SSD 80mgIR/80mgSER tablet
Drug: Rifaximin SSD 80 mg SER tablet
Drug: Rifaximin SSD 40 mg IR tablet
Drug: Placebo

Registration Number: NCT01904409

Lead Sponsor: Bausch Health Americas, Inc.

Brief Summary: The primary objective of this study is to assess the efficacy of rifaximin SSD versus placebo in preventing complications of liver cirrhosis, such as all-cause mortality (death due to all causes) or hospitalization, in subjects with early decompensated liver cirrhosis.

Rifaximin, a non-systemic antibacterial agent, is currently marketed as a 550 mg tablet for the reduction in risk of recurrent overt hepatic encephalopathy, a complication of liver cirrhosis. The rifaximin SSD tablet was formulated to maximize the efficacy of rifaximin.

Subjects will receive 1 of 5 doses of rifaximin SSD tablets or placebo tablets every day for 24 weeks.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 420

Inclusion Criteria

Diagnosis of liver cirrhosis and documented ascites.
Model End Stage Liver Disease (MELD) score of at least 12, MELD Na of at least 12, or Child-Pugh B (score of 7 - 9).
If applicable, has a close family or other personal contacts who can provide continuing oversight to the patient and will be available to the patient during the conduct of the trial.
If female of childbearing potential, have a negative serum pregnancy test at study start and agree to use an acceptable method of contraception during the study.

Exclusion Criteria

History of a major psychiatric disorder including uncontrolled major depression or controlled or uncontrolled psychoses within the past 24 months prior to study start.
History of alcohol abuse or substance abuse within the past 3 months prior to study start.
Documented cholestatic liver disease such as primary sclerosing cholangitis.
Had prophylactic variceal banding within 2 weeks or is scheduled to undergo prophylactic banding during the study.
Diagnosed with an infection for which the patient is currently taking oral or parenteral antibiotics.
Significant hypovolemia, or any electrolyte abnormality that can affect mental function (eg, serum sodium < 125 mEq/L, serum calcium > 10 mg/dL).
Severe hypokalemia, defined as serum potassium concentration < 2.5 mEq/L.
Anemic, defined as hemoglobin concentration ≤ 8 g/dL.
Renal insufficiency with a creatinine of ≥ 1.5 mg/dL.
Presence of intestinal obstruction or inflammatory bowel disease.
Uncontrolled Type 1 or Type 2 diabetes.
History of seizure disorders.
Unstable cardiovascular or pulmonary disease, categorized by a worsening in the disease condition that requires a change in treatment or medical care within 30 days of study start.
Active malignancy within the last 5 years (exceptions: basal cell carcinomas of the skin, or if female, in situ cervical carcinoma that has been surgically excised).
Has hepatocellular carcinoma.
Known human immunodeficiency virus, varicella, herpes zoster, or other severe viral infection within 6 weeks of study start.
Positive stool test for Yersinia enterocolitica, Campylobacter jejuni, Salmonella, Shigella, ovum and parasites, and/or Clostridium difficile (C. difficile); determined during the screening period prior to study start.
History of tuberculosis infection and/or has received treatment for a tuberculosis infection.
History of hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any of the components of rifaximin soluble solid dispersion.
Used any investigational product or device, or participated in another research study within 30 days prior to study start.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rifaximin SSD 40 mg SER tablet	Rifaximin SSD 40 mg SER tablet	Rifaximin soluble solid dispersion (SSD) 40 mg sustained extended release (SER) tablet once daily.
Rifaximin SSD 80 mg IR tablet	Rifaximin SSD 80 mg IR tablet	Rifaximin soluble solid dispersion (SSD) 80 mg immediate release (IR) tablet once daily.
Rifaximin SSD 80mgIR/80mgSER tablet	Rifaximin SSD 80mgIR/80mgSER tablet	Rifaximin soluble solid dispersion (SSD) 80 mg immediate release (IR) tablet + rifaximin SSD 80 mg sustained extended release (SER) tablet once daily.
Rifaximin SSD 80 mg SER tablet	Rifaximin SSD 80 mg SER tablet	Rifaximin soluble solid dispersion (SSD) 80 mg sustained extended release(SER) tablet once daily.
Rifaximin SSD 40 mg IR tablet	Rifaximin SSD 40 mg IR tablet	Rifaximin soluble solid dispersion (SSD) 40 mg immediate release (IR) tablet once daily.
Placebo	Placebo	Placebo tablets once daily.

Primary Outcome Measures

Name	Time	Method
Time to all-cause mortality or hospitalization that is attributable to complications of liver disease.	Weeks 1 through 24	The primary outcome measure will evaluate the time from start of the treatment period to death due to any cause (all-cause mortality) or hospitalization due to complications of liver disease for each patient during the 24-week treatment period.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics of rifaximin and its metabolite.	Weeks 1 through 24	This outcome will measure the plasma levels of rifaximin and its metabolite (25-desacetyl rifaximin) for each patient during the 24-week treatment period.
Overall hospitalization rate due to each complication of liver disease or all-cause mortality over the 24-week treatment period.	Weeks 1 through 24	This outcome measure will determine the rate of hospitalization (percentage of patients who are hospitalized) due to each complication of liver disease or all-cause mortality over the 24-week treatment period.
Changes in indices of health outcomes	Weeks, 4, 8, 12, 16, and 24	This outcome will evaluate each patient's responses on questionnaires that assess health status.
Incidence of treatment-emergent adverse events.	Weeks 1 through 24	This outcome will evaluate the incidence of treatment-emergent adverse events (percentage of patients who experience adverse events following the start of the treatment period).
Change in clinical laboratory parameters.	Weeks 1 through 24	This outcome will measure the changes in each patient's clinical laboratory test results during the treatment period.
Changes in electrocardiogram measurements	Weeks 1 through 24	This outcome will measure the changes in measurements obtained from 12-lead electrocardiograms for each patient during the treatment period.