Study to Evaluate the Efficacy and Safety of CC-90001 in Participants With Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis

Study Overview
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Brief Summary
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This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, multinational, dose-finding study evaluating the efficacy of three treatment doses of CC-90001 compared with placebo, in Non-alcoholic Steatohepatitis (NASH) participants with Stage 2, Stage 3 liver fibrosis. This study is designed to assess response to treatment on measures of fibrosis and other efficacy parameters. It will also assess dose response and overall safety.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Finding Study To Evaluate The Efficacy and Safety Of CC-90001 In Subjects With Non-Alcoholic Steatohepatitis (NASH) and Liver Fibrosis

Conditions
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Non-alcoholic Fatty Liver Disease, Liver Cirrhosis

Intervention / Treatment
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* Drug: CC-90001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Key Inclusion Criteria Diagnosis of non-alcoholic steatohepatitis (NASH) with presence of Stage 2, Stage 3 fibrosis based of the non-alcoholic steatohepatitis (NASH) Clinical Research Network (CRN) Histologic Scoring System and a nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) of 4 or higher Exclusion Criteria: - Key Exclusion Criteria History or evidence of decompensated liver disease, Hepatitis and fibrosis more likely related to etiologies other than non-alcoholic steatohepatitis (NASH). Participant has urine ethyl glucuronide (EtG) > 500 ng/mL at Screening. History or positive screen for human immunodeficiency virus (HIV) infection or congenital or human immunodeficiency virus (HIV)-unrelated acquired immunodeficiencies (eg, common variable immunodeficiency [CVID]). History of hepatitis B and/or hepatitis C. History of malignancy within the last 5 years (exceptions: excised and cured basal/squamous cell skin carcinomas and cervical carcinoma in situ). Pregnancy or lactation.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-90001 400 mg once daily (QD)<br>CC-90001 400 mg QD | Drug: CC-90001<br>* oral<br>|
| Experimental: CC-90001 200 mg once daily<br>CC-90001 200 mg QD | Drug: CC-90001<br>* oral<br>|
| Experimental: CC-90001 100 mg once daily<br>CC-90001 100 mg QD | Drug: CC-90001<br>* oral<br>|
| Placebo Comparator: Placebo once daily<br>Placebo QD | Drug: Placebo<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve a ≥1 Stage Improvement in Liver Fibrosis Using the NASH CRN Histological Scoring System at Week 52 | Percentage of participants who achieve a ≥1 stage improvement in liver fibrosis using the NASH CRN Histological Scoring System at Week 52. A participant with a change of ≤ -1 from baseline in fibrosis stage is considered as an improvement responder for this endpoint. The NASH CRN Histologic Scoring System comprised: steatosis (0 to 3) lobular inflammation (0 to 3) hepatocellular ballooning (0 to 2) fibrosis disease stage (0 to 4) Stage 0 - None; Stage 1a - Mild (delicate) zone 3 perisinusoidal fibrosis; Stage 1b - Moderate (dense) zone 3 perisinusoidal fibrosis; Stage 1c - Portal/periportal fibrosis only; Stage 2 - Zone 3 perisinusoidal fibrosis with portal/periportal fibrosis; Stage 3 - Bridging fibrosis; Stage 4 - Cirrhosis. | From baseline up to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With no Worsening of Steatohepatitis and ≥1 Stage Improvement in Liver Fibrosis Score at Week 52 | Percentage of participants with no worsening of steatohepatitis and ≥1 stage improvement in liver fibrosis score at week 52 using the NASH CRN Histological Scoring System at Week 52. A participant with a change of ≥ -1 from baseline in fibrosis stage and no worsening in steatohepatitis is considered as an improvement responder for this endpoint. The NASH CRN Histologic Scoring System comprised: steatosis (0 to 3) lobular inflammation (0 to 3) hepatocellular ballooning (0 to 2) fibrosis disease stage (0 to 4) Stage 0 - None; Stage 1a - Mild (delicate) zone 3 perisinusoidal fibrosis; Stage 1b - Moderate (dense) zone 3 perisinusoidal fibrosis; Stage 1c - Portal/periportal fibrosis only; Stage 2 - Zone 3 perisinusoidal fibrosis with portal/periportal fibrosis; Stage 3 - Bridging fibrosis; Stage 4 - Cirrhosis. | From baseline up to week 52 | 
| Percentage of Participants With Improvement in Total NAS | Percentage of participants with an improvement of ≥ 2 points in the total NAS with improvement in more than one category of steatosis, lobular inflammation, and hepatocellular ballooning, and no worsening of liver fibrosis at Week 52. A participant with a change of ≤ -2 from baseline in total NAS, a change of ≤ -1 from baseline in more than one subscore, and a change of ≤ 0 from baseline in fibrosis stage is considered as a responder for this endpoint. | From baseline up to week 52 | 
| Percentage of Participants With Resolution of NASH | Percentage of participants who demonstrate absence of ballooning, and lobular inflammation score of 0 or 1 at Week 52. Absence of ballooning is defined as a score of 0 in hepatocellular ballooning. A participant with a score of 0 in ballooning, a score of 0 or 1 in lobular inflammation is considered as a responder for this endpoint. | From baseline up to week 52 | 
| Percentage of Participants With Resolution of NASH With no Worsening of Liver Fibrosis | Percentage of participants who demonstrate absence of ballooning, and lobular inflammation score of 0 or 1 and no worsening of liver fibrosis at Week 52 Absence of ballooning is defined as a score of 0 in hepatocellular ballooning. Worsening of fibrosis stage was defined as progression of NASH CRN fibrosis stage. A participant with a score of 0 in ballooning, a score of 0 or 1 in lobular inflammation, and a change of ≤ 0 from baseline in fibrosis stage is considered as a responder for this endpoint. | From baseline up to week 52 | 
| Percentage of Participants Who Progressed to Cirrhosis | Percentage of participants who progressed to cirrhosis | From baseline up to week 52 | 
| Mean Change From Baseline in Liver Biochemistry | Mean change from Baseline in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) | From baseline up to week 52 | 
| Mean Change From Baseline in Metabolic Parameters | Mean change from baseline in total low density cholesterol (LDL) high density cholesterol (HDL), and triglycerides | From baseline up to week 52 | 
| Cmax | Cmax is defined as maximum plasma concentration of the drug | Day 1 and at Week 4 | 
| Tmax | Tmax is defined is the time to maximum plasma concentration | Day 1 and at Week 4 | 
| AUC (0-t) | Area under the plasma concentration time-curve. AUC from time 0 to the last time of quantifiable concentration | Day 1 and at Week 4 | 
| AUC t | Area under the plasma concentration time-curve. AUC over the dosing interval. | Day 1 and at Week 4 | 
| Apparent Total Body Clearance of the Drug | Apparent total body clearance of the drug (CL/F) | At Week 4 | 
| Number of Participants With Treatment Related Safety Events | Number of participants with treatment related safety events | From baseline up to week 52 | 
| Mean Change From Baseline of ECG Results - PR Intervals | Mean change from baseline in PR interval PR Interval: Atrial depolarization and conduction through the AV node Normal Range: 0.12 - 0.20 (120 to 200 msec) | From baseline up to week 52 | 
| Mean Change From Baseline of ECG Results - QRS Duration | Mean change from baseline in QRS duration QRS Duration: Ventricular depolarization and atrial repolarization Normal Range: 0.08 to 0.10 (80 to 100 msec) | From baseline up to week 52 | 
| Mean Change From Baseline of ECG Results - QT Interval | Mean change from baseline in QT interval QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec | From baseline up to week 52 | 
| Mean Change From Baseline of ECG Results - QTcB Interval | Mean change from baseline in QTcB interval QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec QTc: QT interval corrected based on the patient's heart rate QTcB: An electrocardiographic finding in which the QT interval corrected for heart rate using Bazzett's formula. QTc = QT/√(RR) RR= Respiration Rate | From baseline up to week 52 | 
| Mean Change From Baseline of ECG Results - QTcF Interval | Mean change from baseline in QTcF interval QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec QTc: QT interval corrected based on the patient's heart rate QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia's formula. QTc = QT/∛(RR) RR = Respiration rate | From baseline up to week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Alcoholic Steatohepatitis, NASH, Non-Alcoholic Fatty Liver, Liver Fibrosis, CC-90001