Hepatic Cirrhosis, Liver Fibrosis, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis
Conditions
Brief summary
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 liver cirrhosis (liver damage characterized by normal liver tissue being replaced by scar tissue).
Interventions
DRUGBMS-986036
Specified dose on specified days.
OTHERPlacebo
Specified dose on specified days.
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 and cirrhosis according to the NASH CRN classification, as assessed by the central reader * Must be 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 infection \[HCV\], 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 * Medical history of gastroesophageal varices, except if esophagogastroduodenoscopy \[EGD\] performed within 12 months prior to the Screening Period has shown \<= Grade 1 varices Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48 | From first dose to 48 weeks after first dose | 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 48 in liver biopsy. Worsening of NASH is defined as an increase of the nonalcoholic fatty liver disease activity score (NAS) by ≥ 1-stage. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48 | From first dose to 48 weeks after first dose | 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 48 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). 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). |
| The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48 | From first dose to 48 weeks after first dose | An improvement in fibrosis is defined as a decrease of ≥ 1-stage in the non-alcoholic steatohepatitis clinical research network (NASH CRN) Fibrosis Score at week 48 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). |
| The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48 | From first dose to 48 weeks after first dose | An improvement in Ishak fibrosis is defined as a decrease of fibrosis by ≥ 1-stage in the Ishak fibrosis score at week 48 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. |
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48 | From first dose to 48 weeks after first dose | NASH resolution defined by the nonalcoholic fatty liver disease activity score (NAS) component of ballooning = 0 and inflammation = 0-1 at week 48 in liver biopsy. Ballooning = 0 (none) inflammation = 0 (none) - 1 (Grade \<2). |
| The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48 | From first dose to 48 weeks after first dose | The percentage of participants with NASH improvement at week 48 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. |
| The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48 | From first dose to 48 weeks after first dose | An improvement in CPA is defined as any decrease in CPA at week 48 in liver biopsy. |
Countries
Japan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BMS-986036 10 mg BMS-986036 10 mg administered subcutaneously once weekly | 39 |
| BMS-986036 20 mg BMS-986036 20 mg administered subcutaneously once weekly | 38 |
| BMS-986036 40 mg BMS-986036 40 mg administered subcutaneously once weekly | 39 |
| Placebo Placebo matching BMS-986036 administered subcutaneously once weekly | 39 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Randomized (Pre-Treatment) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 1 | 1 | 0 |
| Treatment Period | Lost to Follow-up | 1 | 0 | 0 | 2 |
| Treatment Period | Other Reasons | 0 | 2 | 1 | 1 |
| Treatment Period | Withdrawal by Subject | 3 | 3 | 3 | 2 |
Baseline characteristics
| Characteristic | BMS-986036 10 mg | BMS-986036 20 mg | BMS-986036 40 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 8 Participants | 9 Participants | 14 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 30 Participants | 30 Participants | 25 Participants | 112 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 6 Participants | 7 Participants | 11 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 30 Participants | 31 Participants | 28 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 7 Participants | 4 Participants | 3 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 30 Participants | 31 Participants | 34 Participants | 33 Participants | 128 Participants |
| Sex: Female, Male Female | 28 Participants | 26 Participants | 21 Participants | 24 Participants | 99 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 18 Participants | 15 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 39 | 0 / 38 | 0 / 39 | 1 / 39 |
| other Total, other adverse events | 27 / 39 | 36 / 37 | 29 / 39 | 33 / 39 |
| serious Total, serious adverse events | 7 / 39 | 7 / 37 | 8 / 39 | 3 / 39 |
Outcome results
Primary
The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48
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 48 in liver biopsy. Worsening of NASH is defined as an increase of the nonalcoholic fatty liver disease activity score (NAS) by ≥ 1-stage. 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.
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48 | 28.2 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48 | 24.3 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48 | 28.2 Percentage of Participants |
| Placebo | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 48 | 30.8 Percentage of Participants |
p-value: 0.77395% CI: [0.3, 2.62]Cochran-Mantel-Haenszel
p-value: 0.54495% CI: [0.23, 2.23]Cochran-Mantel-Haenszel
p-value: 0.81195% CI: [0.3, 2.62]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48
An improvement in Ishak fibrosis is defined as a decrease of fibrosis by ≥ 1-stage in the Ishak fibrosis score at week 48 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.
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48 | 38.5 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48 | 32.4 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48 | 33.3 Percentage of Participants |
| Placebo | The Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Ishak Fibrosis Score at Week 48 | 35.9 Percentage of Participants |
p-value: 0.83695% CI: [0.4, 3.09]Cochran-Mantel-Haenszel
p-value: 0.76395% CI: [0.3, 2.46]Cochran-Mantel-Haenszel
p-value: 0.82195% CI: [0.32, 2.51]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48
An improvement in fibrosis is defined as a decrease of ≥ 1-stage in the non-alcoholic steatohepatitis clinical research network (NASH CRN) Fibrosis Score at week 48 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).
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48 | 35.9 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48 | 29.7 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48 | 28.2 Percentage of Participants |
| Placebo | The Percentage of Participants Who Achieved >=1 Point Improvement in Fibrosis at Week 48 | 33.3 Percentage of Participants |
p-value: 0.86495% CI: [0.4, 3.16]Cochran-Mantel-Haenszel
p-value: 0.74395% CI: [0.29, 2.49]Cochran-Mantel-Haenszel
p-value: 0.6395% CI: [0.27, 2.29]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48
An improvement in CPA is defined as any decrease in CPA at week 48 in liver biopsy.
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48 | 61.8 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48 | 54.2 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48 | 41.9 Percentage of Participants |
| Placebo | The Percentage of Participants With Any Improvement in Collagen Proportionate Area (CPA) at Week 48 | 53.1 Percentage of Participants |
p-value: 0.47795% CI: [0.48, 4.25]Cochran-Mantel-Haenszel
p-value: 0.81495% CI: [0.32, 3.44]Cochran-Mantel-Haenszel
p-value: 0.36795% CI: [0.21, 1.93]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48
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 48 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). 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).
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48 | 33.3 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48 | 40.5 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48 | 35.9 Percentage of Participants |
| Placebo | The Percentage of Participants With Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) or NASH Improvement at Week 48 | 30.8 Percentage of Participants |
p-value: 0.83795% CI: [0.39, 3.25]Cochran-Mantel-Haenszel
p-value: 0.35995% CI: [0.54, 4.4]Cochran-Mantel-Haenszel
p-value: 0.62795% CI: [0.44, 3.61]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48
The percentage of participants with NASH improvement at week 48 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.
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48 | 15.4 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48 | 24.3 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48 | 12.8 Percentage of Participants |
| Placebo | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Improvement at Week 48 | 2.6 Percentage of Participants |
p-value: 0.05495% CI: [0.76, 325.97]Cochran-Mantel-Haenszel
p-value: 0.00495% CI: [1.5, 549.08]Cochran-Mantel-Haenszel
p-value: 0.08795% CI: [0.57, 271.11]Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48
NASH resolution defined by the nonalcoholic fatty liver disease activity score (NAS) component of ballooning = 0 and inflammation = 0-1 at week 48 in liver biopsy. Ballooning = 0 (none) inflammation = 0 (none) - 1 (Grade \<2).
Time frame: From first dose to 48 weeks after first dose
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMS-986036 10 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48 | 2.6 Percentage of Participants |
| BMS-986036 20 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48 | 5.4 Percentage of Participants |
| BMS-986036 40 mg | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48 | 2.6 Percentage of Participants |
| Placebo | The Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution at Week 48 | 0.0 Percentage of Participants |
p-value: 0.309Cochran-Mantel-Haenszel
p-value: 0.146Cochran-Mantel-Haenszel
p-value: 0.317Cochran-Mantel-Haenszel