A Study of CRV431 Dosed Once Daily in NASH Induced F2 and F3 Subjects

Study Overview
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Brief Summary
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This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects.

Detailed Description
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This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects. Study will evaluate the safety and tolerability of a once daily 75mg dose and 225mg of CRV431 compared to placebo over 28 days of dosing. Pharmacokinetic parameters of CRV431 and its major metabolites and fraction unbound will also be evaluated. Non-invasive antifibrotic bio-markers will be collected and quantified from presumed NASH F2/F3 subjects dosed with 75mg CRV431 or placebo.

Official Title
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AMBITION: A Phase 2A, Multiple-Center, Single-Blind, Placebo-Controlled Study To Evaluate The Safety and Tolerability of CRV431 Dosed Once Daily in NASH Induced F2 and F3 Subjects

Conditions
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NASH - Nonalcoholic Steatohepatitis, Fibrosis, Liver, NAFLD - Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: CRV431 75mg
* Drug: Placebo (1 softgel)
* Drug: CRV431 225mg
* Drug: Placebo (3 softgels)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female between 18 and 75 years of age (inclusive). Capable of giving written informed consent and able to effectively communicate with the investigator and study personnel. Presumed F2/F3 NASH to include: AST >20 IU/L, Pro-C3 >15.5 ng/mL, enhanced liver fibrosis (ELF) score >9.8, and FibroScan >8.5 kPa values. Key Exclusion Criteria: Pregnant or breastfeeding or planning to become pregnant during the study period. Known allergy to CRV431, cyclosporine, or any of their inactive ingredients. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus antibodies (HIVAb). Well documented causes of chronic liver disease according to standard diagnostic procedures to include any history or presence of decompensated cirrhosis. Subjects with a platelet count <150,000/mL. Subjects with hemoglobin A1c(HbA1c) >9.5%. Weight loss of more than 5% within 3 months prior to randomization. Subjects with a blood pressure to include a systolic pressure >150 or a diastolic pressure >90. At Screening, an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 mL (calculated by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] method) and/or a Kidney Disease Improving Global Outcomes (KDIGO) category of >G2. Subjects with a history of organ transplantation. Corneal transplantation will be allowed.

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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No

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, multi-center, single-blind
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CRV431 75mg<br>CRV431, softgel capsule, 75mg, QD, 28 days, fasted conditions | Drug: CRV431 75mg<br>* 1 x 75mg softgel capsule<br>|
| Placebo Comparator: Placebo, 75mg<br>Placebo, softgel capsule, QD, 28 days, fasted conditions | Drug: Placebo (1 softgel)<br>* 1 x placebo softgel capsule<br>|
| Experimental: CRV431 225mg<br>CRV431, softgel capsule, 225mg, QD, 28 days, fasted conditions | Drug: CRV431 225mg<br>* 3 x 75mg softgel capsule<br>|
| Placebo Comparator: Placebo, 225mg<br>CRV431, 3 softgel capsules, 225mg, QD, 28 days, fasted conditions | Drug: Placebo (3 softgels)<br>* 3 x placebo softgel capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Safety and Tolerability Events of CRV431 Versus Placebo. | Number of adverse events, serious adverse events, and clinical laboratory abnormalities. | Time from informed consent to study day 42. | 
| Tmax, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | The Tmax value is defined as time to reach maximum whole blood concentration. Each value is a median for the cohort along with the standard deviation presented in hours for Day 1 and Day 28. | Day 1 and Day 28 | 
| Cmax, of Once Daily (QD) 75mg and 22mg mg Doses of CRV431 is Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | The Cmax value is defined as the maximum whole blood concentration presented as ng/mL. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28. | Day 1 and Day 28 | 
| AUC 0-last, of Once Daily (QD) 75mg and 225mg mg Doses of CRV431 in Presumed Non-alcoholic Steatohepatitis F2/F3 Fibrosis Subjects. | The AUC 0-last value is defined as the area under the whole blood concentration time curve from time 0 to the time of the last measurable concentration. Each value is a geometric mean for the cohort along with the standard deviation for Day 1 and Day 28. | Timepoints for data collection include 0, 2.0 hours, 4.0 hours, 8 hours on both Day 1 and Day 28. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-fibrotic