Open-Label Study to Evaluate the Safety, Tolerability, and PK of Aramchol in Subjects With Hepatic Impairment

Study Overview
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Brief Summary
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Phase 1, multicenter, open-label, 2-part, single- and multiple-dose study designed to assess the effect of hepatic insufficiency on the PK of aramchol

Detailed Description
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Each of the 2 parts of the study will consist of a screening period, a check in day, a treatment period, and an end of study (EOS) visit. In Part 1 (single-dose): up to 48 subjects are planned: 8 subjects each in the mild (Cohort A), moderate (Cohort B), and severe (Cohort C) hepatic impairment cohorts and 8 to 24 healthy control subjects with normal hepatic function (Cohort D). Enrollment of 8 subjects with mild hepatic impairment (Cohort A) will proceed only if there is evidence of reduced clearance of aramchol in Cohort B. Assignment to cohorts A to C, will be according to Child Pugh classification system. Serial blood samples for PK analysis of aramchol concentrations in plasma will be collected before dosing (0 hour) and up to 168 hours for healthy subjects and 240 hours for hepatically impaired subjects after administration of aramchol. In Part 2 (multiple-dose), a cohort of at least 8 subjects comprising of mild, moderate or severe hepatic impaired subjects, as well as a cohort of up to 8 healthy volunteers will be administered aramchol as multiple doses to obtain the PK profile of aramchol at steady state. Aramchol will be given twice daily for 12 days. Trough blood samples for analysis of aramchol plasma concentrations will be collected before the AM dose on several days and at intervals to 12 hours after the AM dose on Day 12.

Official Title
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A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aramchol in Subjects With Hepatic Impairment

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Aramchol 600mg single dose
* Drug: Aramchol 300mg, bid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject is male or female 18 to 79 years of age, inclusive. The subject has a body mass index of 19 to 40 kg/m2, inclusive, at screening. Females of childbearing potential must practice a highly effective method of contraception throughout the study period and for 1 month after treatment discontinuation. Male subjects with female partners of childbearing potential must be vasectomized, be willing to use an acceptable method of birth control, or practice abstinence during the study. The subject has a resting pulse rate of ≥40 and <100 beats per minute with no clinically significant deviation as judged by the investigator. The subject has a QT interval corrected for heart rate using Fridericia's formula of <500 msec. The subject agrees to comply with all protocol requirements. The subject is able to provide written informed consent. Additional Inclusion Criteria for Healthy Subjects Only (Cohort D): The subject has normal hepatic function. The subject has a resting blood pressure of 90 to 150 mm Hg (systolic) and 50 to 100 mm Hg (diastolic). The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings. Additional Inclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, B, and C): The subject has cirrhosis with evidence of impaired liver function. The etiology of the cirrhosis may be alcoholic, autoimmune, nonalcoholic steatohepatitis, or chronic viral hepatitis type B or C. The subject has chronic (more than 6 months) and stable hepatic impairment (ie, no acute episodes of illness within 30 days before screening due to deterioration of hepatic function) as assessed by a Child-Pugh classification score of mild (5 to 6 points), moderate (7 to 9 points), or severe (10 to 15 points). The subject has a resting blood pressure of 90 to 155 mm Hg (systolic) and 50 to 100 mm Hg (diastolic). The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings, except for findings that, as judged by the investigator, are consistent with the subject's hepatic impairment or other stable concomitant medical conditions. Exclusion Criteria: The subject has a history or clinical manifestations of a significant neurological, renal, cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric disease that would preclude study participation, as judged by the investigator. The subject has a positive test result for human immunodeficiency virus type 1 or 2 antibodies at screening. The subject has a history of drug abuse within 3 months before screening. The subject has a history of alcoholism within 3 months before screening, or excessive alcohol consumption (regular alcohol intake >15 units per week) (1 unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits). The subject smokes >10 cigarettes daily and is unwilling to reduce to <5 daily from the time of screening through the last PK sample. The subject is unable or unwilling to abstain from alcohol, caffeine, xanthine containing beverages or food (eg, coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit, grapefruit juice, Seville oranges, or products containing any of these, from 48 hours prior to study drug dosing until discharge. The subject is involved in strenuous activity or contact sports within 24 hours of the first dose of study drug or during the study. The subject has donated blood or blood products >450 mL within 3 months before the first dose of study drug. The subject has a presence or history of relevant drug and/or food allergies (ie, allergy to aramchol, cholic acid, or any excipients, or any significant food allergy. The subject has received study drug in another investigational study within 30 days of dosing. In the opinion of the investigator, the subject is not suitable for entry into the study. For additional exclusion criteria specific to hepatic impaired subjects and healthy volunteers, see protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Mild Hepatic Impairment (Cohort A)<br>8 mild hepatic impaired subjects | Drug: Aramchol 600mg single dose<br>* aramchol acid tablet 600mg, single dose<br>|
| Experimental: Part 1: Moderate Hepatic Impairment (Cohort B)<br>8 moderate hepatic impaired subjects | Drug: Aramchol 600mg single dose<br>* aramchol acid tablet 600mg, single dose<br>|
| Experimental: Part 1: Severe Hepatic Impairment (Cohort C)<br>8 severe hepatic impaired subjects | Drug: Aramchol 600mg single dose<br>* aramchol acid tablet 600mg, single dose<br>|
| Experimental: Part 1: Healthy Volunteers (Cohort D)<br>up to 24 matched healthy volunteers | Drug: Aramchol 600mg single dose<br>* aramchol acid tablet 600mg, single dose<br>|
| Experimental: Part 2: Hepatic Impairment cohort<br>up to 8 hepatic impaired subjects (mild, moderate or severe) | Drug: Aramchol 300mg, bid<br>* aramchol acid tablet 300mg, bid for 12 days<br>|
| Experimental: Part 2: Healthy Volunteers cohort<br>up to 8 matched healthy volunteers | Drug: Aramchol 300mg, bid<br>* aramchol acid tablet 300mg, bid for 12 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral Clearance, single dose | CL/F measured after single dose during part 1 | Day 11 | 
| Oral Clearance, steady state | CL/F measured at steady state during part 2 | Day 12 | 
| AUC0-tau, steady state | AUC from time 0 to the dosing interval tau measured at steady state during part 2 | Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with clinically significant TEAEs that are considered related to treatment as assessed by CTCAE v4.0 |  | Part 1: up to 22 days; Part 2: up to 27 days | 
| Number of subjects with clinically significant changes in liver function tests |  | Part 1: up to 22 days; Part 2: up to 27 days | 
| ECG QTc interval using Fridericia correction |  | Part 1: up to 22 days; Part 2: up to 27 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics