A Study of Experimental Medication BMS-986036 in Adults With Nonalcoholic Steatohepatitis (NASH) and Stage 3 Liver Fibrosis

Study Overview
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Brief Summary
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This is a study of experimental medication BMS-986036 given to adults with Nonalcoholic Steatohepatitis (NASH; the buildup of fat and inflammation in the liver that is not caused by alcohol) and stage 3 liver fibrosis (severe fibrosis).

Official Title
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A Phase 2B Randomized Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of BMS-986036 (PEG-FGF21) in Adults With Nonalcoholic Steatohepatitis (NASH) and Stage 3 Liver Fibrosis

Conditions
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Nonalcoholic Steatohepatitis, Liver Fibrosis, Nonalcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Drug: BMS-986036
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver biopsy performed within 6 months (26 weeks) prior to the screening period. If historical biopsy is not available, a liver biopsy will be performed during the screening period. Biopsy must be consistent with NASH, with: a) a score of at least 1 for each NAS component (steatosis, lobular inflammation, and ballooning), as assessed by the central reader, and b) stage 3 liver fibrosis according to the NASH CRN classification, as assessed by the central reader Participants taking anti-diabetic, anti-obesity, or anti-dyslipidemic medications must have been on stable regimens for at least 3 months (12 weeks) (6 weeks for statins) prior to and during the screening period Participants taking vitamin E at doses greater than or equal to (>=) 800 IU/day must have been on stable doses for at least 6 months (26 weeks) prior to and during the Screening Period. Vitamin E treatment (>=800 IU/day) must not have been initiated after the qualifying liver biopsy was performed. Exclusion Criteria: Other causes of liver disease (e.g., alcoholic liver disease, hepatitis B virus infection, chronic hepatitis C virus [HCV] infection, autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, α-1-antitrypsin deficiency, iron overload, and hemochromatosis); participants with HCV sustained viral response (undetectable HCV RNA) for at least 2 years prior to biopsy confirming study eligibility may be eligible Current or past history of hepatocellular carcinoma (HCC) Past or current evidence of hepatic decompensation (e.g., ascites, variceal bleeding, hepatic encephalopathy and/or spontaneous bacterial peritonitis) or liver transplantation Other protocol defined inclusion/exclusion criteria could apply

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BMS-986036 Dose Level 1<br>Administered by subcutaneous injection. | Drug: BMS-986036<br>* Specified dose on specified days.<br>* Other names: Pegbelfermin;|
| Experimental: BMS-986036 Dose Level 2<br>Administered by subcutaneous injection. | Drug: BMS-986036<br>* Specified dose on specified days.<br>* Other names: Pegbelfermin;|
| Experimental: BMS-986036 Dose Level 3<br>Administered by subcutaneous injection. | Drug: BMS-986036<br>* Specified dose on specified days.<br>* Other names: Pegbelfermin;|
| Placebo Comparator: Placebo<br>Administered by subcutaneous injection. | Other: Placebo<br>* Specified dose on specified days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With Improvement in Fibrosis or Nonalcoholic Steatohepatitis (NASH) at Week 24 | The percentage of participants who achieved a ≥1-stage improvement in fibrosis without worsening of NASH or NASH improvement with no worsening of fibrosis at week 24 in liver biopsy. Improvement in fibrosis is defined by the NASH Clinical Research Network (CRN) Fibrosis Score. Improvement in NASH is defined by a ≥2-stage decrease in the nonalcoholic fatty liver disease activity score (NAS). Worsening of NASH is defined as an increase of the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) by ≥1 point. Worsening of fibrosis is defined as an increase of fibrosis by ≥1 point as determined by the NASH CRN Fibrosis Score. NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants Who Achieved an Improvement in Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Score at Week 24 | An improvement in fibrosis is defined as a decrease of ≥ 1-stage in the NASH CRN Fibrosis Score at week 24 in liver biopsy. NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose | 
| The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 24 | An improvement in Ishak fibrosis is defined as a decrease of fibrosis by ≥ 1-stage in the Ishak fibrosis score at week 24 in liver biopsy. ISHAKs uses a 0-6 scale: 1: centrilobular pericellular fibrosis, 2: centrilobular and periportal fibrosis, 3: bridging fibrosis (few bridges), 4: bridging fibrosis (many bridges), 5: early or incomplete cirrhosis, 6: established or advanced cirrhosis. | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 24 | An improvement in CPA is defined as any decrease in CPA at week 24 in liver biopsy. | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis at Week 24 | The percentage of participants with NASH resolution without worsening of fibrosis at week 24 in liver biopsy. NASH resolution defined by the nonalcoholic fatty liver disease activity score (NAS) component of ballooning = 0 and inflammation = 0-1. Worsening of fibrosis is defined as an increase of fibrosis by ≥ 1-stage in the NASH Clinical Research Network (CRN) Fibrosis Score. Ballooning = 0 (none) inflammation = 0 (none) - 1 (Grade <2). NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 24 | NASH resolution defined by the nonalcoholic fatty liver disease activity score (NAS) component of ballooning = 0 and inflammation = 0-1 at week 24 in liver biopsy. Ballooning = 0 (none) inflammation = 0 (none) - 1 (Grade <2). | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement Without Worsening of Fibrosis at Week 24 | The percentage of participants with NASH improvement without worsening of fibrosis at week 24 in liver biopsy. NASH improvement defined as a reduction of nonalcoholic fatty liver disease activity score (NAS) by ≥2 points with contribution from >1 NAS component. Worsening of fibrosis is defined as an increase of ≥1-point in the NASH Clinical Research Network (CRN) Fibrosis Score. NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose | 
| The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 24 | An improvement in fibrosis is defined as a decrease of fibrosis by ≥1-stage in the NASH Clinical Research Network (CRN) Fibrosis Score at week 24 in liver biopsy. Worsening of NASH is defined as an increase of the nonalcoholic fatty liver disease activity score (NAS) by ≥ 1-stage. NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 24 | The percentage of participants with NASH improvement at week 24 in liver biopsy. NASH improvement is defined as a reduction of nonalcoholic fatty liver disease activity score (NAS) by ≥ 2 points with contribution from > 1 NAS component. The NASH CRN system assesses liver biopsies for degree of steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2), and fibrosis (0-4). The 3 categories are added together in an unweighted fashion to determine the NAS, which ranges from 0 to 8. | From first dose to 24 weeks after first dose | 
| The Percentage of Participants With Progression to Cirrhosis at Week 24 | Progression to cirrhosis is defined by the nonalcoholic steatohepatitis clinical research network (NASH CRN) Fibrosis Stage 4 at Week 24 in liver biopsy. NASH CRN Fibrosis is staged on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal fibrosis); 2 (perisinusoidal and portal/periportal fibrosis); 3 (bridging fibrosis); 4 (cirrhosis). | From first dose to 24 weeks after first dose |