Rifaximin Soluble Solid Dispersion (SSD) Tablets Plus Lactulose for the Treatment of Overt Hepatic Encephalopathy (OHE)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Overt Hepatic Encephalopathy

Intervention / Treatment
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* Drug: 40 mg Rifaximin SSD once daily
* Drug: 40 mg Rifaximin SSD twice daily
* Drug: 80 mg Rifaximin SSD once daily
* Drug: 80 mg Rifaximin SSD twice daily
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 18 to 75 years of age (inclusive) at the time of screening. 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: 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. Subject is hospitalized with liver cirrhosis and/or OHE and has a confirmed diagnosis of OHE at Baseline. Subject has a Grade 2 or Grade 3 HE episode according to the HE Grading Instrument (HEGI) following 8 to 12 hours of intravenous (IV) hydration and lactulose treatment. Exclusion Criteria: Subject has an uncontrolled major psychiatric disorder including major depression or psychoses as determined by the investigator. Subject has been diagnosed with an infection for which they are currently taking oral or parenteral antibiotics, which cannot be discontinued at time of enrollment. Note: Subjects currently taking Rifaximin are not excluded Subject shows presence of intestinal obstruction or has inflammatory bowel disease. Subject has uncontrolled Type 1 or Type 2 diabetes. Note: Subjects with controlled diabetes may be enrolled if they are on stable doses of 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. Subject has an active malignancy (exceptions: non-melanoma skin cancers).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter Study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 40 mg Rifaximin SSD once daily<br>40 mg Rifaximin immediate release (IR) rifaximin SSD once daily (QD) and lactulose | Drug: 40 mg Rifaximin SSD once daily<br>* SSD once daily (QD)<br>|
| Experimental: Cohort 2 40 mg Rifaximin SSD twice daily<br>40 mg Rifaximin immediate release (IR) rifaximin SSD twice daily (BID) and lactulose | Drug: 40 mg Rifaximin SSD twice daily<br>* SSD twice daily (BID)<br>|
| Experimental: Cohort 3 80 mg Rifaximin SSD once daily<br>80 mg Rifaximin sustained extended release (SER) rifaximin SSD once daily (QD) and lactulose | Drug: 80 mg Rifaximin SSD once daily<br>* SSD once daily (QD)<br>|
| Experimental: Cohort 4 80 mg Rifaximin SSD twice daiy<br>80 mg Rifaximin sustained extended release (SER) rifaximin SSD twice daily (BID) and lactulose | Drug: 80 mg Rifaximin SSD twice daily<br>* SSD twice daily (BID)<br>|
| Experimental: Cohort 5 Placebo twice daily<br>SSD placebo twice daily (BID) and lactulose | Drug: Placebo<br>* Administered twice daily (BID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Overt Hepatic Encephalopathy (OHE) Resolution Determined Using the Hepatic Encephalopathy Grading Instrument (HEGI), Defined as HEGI Score < 2 | A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome). | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Improvement in Hepatic Encephalopathy Grading Instrument (HEGI) Score, Defined as at Least One Grade Decrease (Improvement) | A participant was considered to have an overt HE episode if at least one of the following applied: (1) Disorientated to time or place or person, (2) Lethargic and has asterixis, (3) Inability to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma. Severity of OHE episodes was graded using the HEGI scale, where Grade 1 is no clinical findings of OHE, and Grade 4 is comatose. Higher scores on the scale have higher severity (worse outcome). | 14 days | 
| Time to Hospital Discharge | Time in days until discharge from the hospital | 14 days |