Hepatic Cirrhosis, Liver Fibrosis
Conditions
Brief summary
This is a study of experimental medication BMS-986263 in adult patients with advanced hepatic fibrosis (scar tissue in the liver caused by inflammation that is far on in progress) after the patient is cured of hepatitis C (an infection caused by a virus that attacks the liver and leads to inflammation).
Interventions
DRUGBMS-986263
Administered by intravenous (IV) infusion
OTHERPlacebo
Administered by intravenous (IV) infusion
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
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Participants must provide documentation showing a sustained virologic response (SVR) for at least 1 year (52 weeks) prior to the date of screening (SVR is defined as a negative hepatitis C RNA greater than or equal to 12 weeks from the end of therapy) * Participants must have METAVIR Stage 3 or 4 (or equivalent if using other classification; eg, Ishak)
Exclusion criteria
* Other causes of liver disease (eg, alcoholic liver disease, HBV \[serologically positive as determined using United States Centers for Disease Control and Prevention guidance for interpretation of hepatitis B serologic test results\], autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, NASH, hemochromatosis) * Participants having liver diseases associated with infection with any other hepatitis virus * Detectable HCV RNA at screening * Child-Pugh score \> 6 * Model for End-Stage Liver Disease score \>12 * Evidence of HCC at screening based on alpha-fetoprotein (AFP) levels: AFP \> 100 ng/mL (\> 82.6 IU/mL) OR AFP ≥ 50 and ≤ 100 ng/mL (≥ 41.3 IU/mL and ≤ 82.6 IU/ mL) with liver ultrasound showing findings suspicious for HCC, or any imaging technique (eg, magnetic resonance imaging \[MRI\] or computed tomography; based on local assessment), or ultrasound * Blood transfusion in the last 6 months prior to screening due to the risk of re-infection with HCV, HBV, HIV, etc * Participant has any disease or condition which, in the opinion of the investigator, might compromise patient safety (eg, hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, skeletal, central nervous system, or compliment-mediated disease); or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of BMS 986263, or would place the participant at increased risk Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Achieve ≥ 1 Stage Improvement in Liver Fibrosis (METAVIR Score) as Determined by Liver Biopsy After 12 Weeks of Treatment | Week 12 | The number of participants who achieve ≥ 1 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The METAVIR system is used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C virus (HCV). It assesses liver biopsies for activity grade (A0-A3) and fibrosis stage (Stage 1 - 4). Participants without a measurement at Week 12 are considered non-responders. Activity Grade: A0 = no activity; A1 = mild activity; A2 = moderate activity; A3 = severe activity Fibrosis stage: 1 = portal fibrosis without septa ; 2 = portal fibrosis with few septa; 3 = numerous septa without cirrhosis; 4 = cirrhosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With ≥ 1 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | Week 12 | The number of participants with ≥ 1 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The Ishak scoring system is used to grade fibrosis in the histology samples. The Ishak system (0 through 6 scale) was developed to grade portal-based liver fibrosis associated with viral hepatitis: 0: No fibrosis 1. Fibrous expansion of some portal areas, with or without short fibrous septa 2. Fibrous expansion of most portal areas, with or without short fibrous septa 3. Fibrous expansion of most portal areas with occasional portal to portal bridging 4. Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central) 5. Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 6. Cirrhosis, probable or definite |
| The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (METAVIR Score) After 12 Weeks of Treatment | Week 12 | The number of participants with ≥ 2 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The METAVIR system is used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C virus (HCV). It assesses liver biopsies for activity grade (A0-A3) and fibrosis stage (Stage 1 - 4). Participants without a measurement at Week 12 are considered non-responders. Activity Grade: A0 = no activity; A1 = mild activity; A2 = moderate activity; A3 = severe activity Fibrosis stage: 1 = portal fibrosis without septa ; 2 = portal fibrosis with few septa; 3 = numerous septa without cirrhosis; 4 = cirrhosis |
| Change From Baseline in Collagen Proportionate Area (CPA) After 12 Weeks of Treatment | Baseline and Week 12 | The change from baseline measurement in Collagen Proportionate Area (CPA) is used to asses the effects of treatment compared to placebo. Assessment of CPA is a method by which the amount (percentage) of collagen in stained tissue sections is analyzed using morphometric image analysis |
| The Number of Participants With ≥ 15% Decrease From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) at Day 85 | Baseline and day 85 | The number of participants with ≥ 15% decrease from baseline in liver stiffness is used to asses the effects of treatment compared to placebo Magnetic resonance elastography (MRE) is a noninvasive medical imaging technique that quantitatively measures the stiffness of soft tissues by introducing shear waves and imaging their propagation using magnetic resonance imaging (MRI). MRE will be used to quantitate liver stiffness as a surrogate biomarker of liver fibrosis. |
| Change From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) Day 85 | Baseline and day 85 | Change from baseline in liver stiffness is used to asses the effects of treatment compared to placebo. Magnetic resonance elastography (MRE) is a noninvasive medical imaging technique that quantitatively measures the stiffness of soft tissues by introducing shear waves and imaging their propagation using magnetic resonance imaging (MRI). MRE will be used to quantitate liver stiffness as a surrogate biomarker of liver fibrosis |
| The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | Week 12 | The number of participants with ≥ 2 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The Ishak scoring system is used to grade fibrosis in the histology samples. The Ishak system (0 through 6 scale) was developed to grade portal-based liver fibrosis associated with viral hepatitis: 0: No fibrosis 1. Fibrous expansion of some portal areas, with or without short fibrous septa 2. Fibrous expansion of most portal areas, with or without short fibrous septa 3. Fibrous expansion of most portal areas with occasional portal to portal bridging 4. Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central) 5. Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 6. Cirrhosis, probable or definite |
Countries
United States
Participant flow
Pre-assignment details
Per sponsor decision, Part 2 of the study was not initiated. 61 subjects were randomized and treated in Part 1
Participants by arm
| Arm | Count |
|---|---|
| BMS-986263 45 mg QW (Once Weekly) BMS-986263 45 mg will be administered as an IV infusion QW for a total of 12 weeks in adults with advanced hepatic fibrosis due to Hepatitis C (HCV) who have achieved sustained virologic response (SVR) | 18 |
| BMS-986263 90 mg QW (Once Weekly) BMS-986263 90 mg will be administered as an IV infusion QW for a total of 12 weeks in adults with advanced hepatic fibrosis due to Hepatitis C (HCV) who have achieved sustained virologic response (SVR) | 28 |
| Placebo QW (Once Weekly) Placebo will be administered as an IV infusion QW for a total of 12 weeks in adults with advanced hepatic fibrosis due to Hepatitis C (HCV) who have achieved sustained virologic response (SVR) | 15 |
| Total | 61 |
Baseline characteristics
| Characteristic | BMS-986263 45 mg QW (Once Weekly) | BMS-986263 90 mg QW (Once Weekly) | Placebo QW (Once Weekly) | Total |
|---|---|---|---|---|
| Age, Continuous | 60.2 Years STANDARD_DEVIATION 7.45 | 59.8 Years STANDARD_DEVIATION 8.24 | 61.8 Years STANDARD_DEVIATION 6.47 | 60.4 Years STANDARD_DEVIATION 7.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 13 Participants | 6 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 15 Participants | 9 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 26 Participants | 13 Participants | 56 Participants |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 11 Participants | 16 Participants | 7 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 28 | 0 / 15 |
| other Total, other adverse events | 10 / 18 | 16 / 28 | 8 / 15 |
| serious Total, serious adverse events | 0 / 18 | 1 / 28 | 0 / 15 |
Outcome results
Primary
The Number of Participants Who Achieve ≥ 1 Stage Improvement in Liver Fibrosis (METAVIR Score) as Determined by Liver Biopsy After 12 Weeks of Treatment
The number of participants who achieve ≥ 1 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The METAVIR system is used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C virus (HCV). It assesses liver biopsies for activity grade (A0-A3) and fibrosis stage (Stage 1 - 4). Participants without a measurement at Week 12 are considered non-responders. Activity Grade: A0 = no activity; A1 = mild activity; A2 = moderate activity; A3 = severe activity Fibrosis stage: 1 = portal fibrosis without septa ; 2 = portal fibrosis with few septa; 3 = numerous septa without cirrhosis; 4 = cirrhosis
Time frame: Week 12
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | The Number of Participants Who Achieve ≥ 1 Stage Improvement in Liver Fibrosis (METAVIR Score) as Determined by Liver Biopsy After 12 Weeks of Treatment | 3 Participants |
| BMS-986263 90 mg QW (Once Weekly) | The Number of Participants Who Achieve ≥ 1 Stage Improvement in Liver Fibrosis (METAVIR Score) as Determined by Liver Biopsy After 12 Weeks of Treatment | 6 Participants |
| Placebo QW (Once Weekly) | The Number of Participants Who Achieve ≥ 1 Stage Improvement in Liver Fibrosis (METAVIR Score) as Determined by Liver Biopsy After 12 Weeks of Treatment | 2 Participants |
95% CI: [0.13, 17.7]
95% CI: [0.26, 20.23]
Secondary
Change From Baseline in Collagen Proportionate Area (CPA) After 12 Weeks of Treatment
The change from baseline measurement in Collagen Proportionate Area (CPA) is used to asses the effects of treatment compared to placebo. Assessment of CPA is a method by which the amount (percentage) of collagen in stained tissue sections is analyzed using morphometric image analysis
Time frame: Baseline and Week 12
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | Change From Baseline in Collagen Proportionate Area (CPA) After 12 Weeks of Treatment | -0.68 Percent | Standard Deviation 2.479 |
| BMS-986263 90 mg QW (Once Weekly) | Change From Baseline in Collagen Proportionate Area (CPA) After 12 Weeks of Treatment | 1.36 Percent | Standard Deviation 2.946 |
| Placebo QW (Once Weekly) | Change From Baseline in Collagen Proportionate Area (CPA) After 12 Weeks of Treatment | -0.21 Percent | Standard Deviation 1.646 |
Secondary
Change From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) Day 85
Change from baseline in liver stiffness is used to asses the effects of treatment compared to placebo. Magnetic resonance elastography (MRE) is a noninvasive medical imaging technique that quantitatively measures the stiffness of soft tissues by introducing shear waves and imaging their propagation using magnetic resonance imaging (MRI). MRE will be used to quantitate liver stiffness as a surrogate biomarker of liver fibrosis
Time frame: Baseline and day 85
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | Change From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) Day 85 | -0.162 Change in kPa | Standard Deviation 0.5807 |
| BMS-986263 90 mg QW (Once Weekly) | Change From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) Day 85 | -0.064 Change in kPa | Standard Deviation 0.7384 |
| Placebo QW (Once Weekly) | Change From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) Day 85 | -0.049 Change in kPa | Standard Deviation 0.5801 |
Secondary
The Number of Participants With ≥ 15% Decrease From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) at Day 85
The number of participants with ≥ 15% decrease from baseline in liver stiffness is used to asses the effects of treatment compared to placebo Magnetic resonance elastography (MRE) is a noninvasive medical imaging technique that quantitatively measures the stiffness of soft tissues by introducing shear waves and imaging their propagation using magnetic resonance imaging (MRI). MRE will be used to quantitate liver stiffness as a surrogate biomarker of liver fibrosis.
Time frame: Baseline and day 85
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | The Number of Participants With ≥ 15% Decrease From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) at Day 85 | 4 Participants |
| BMS-986263 90 mg QW (Once Weekly) | The Number of Participants With ≥ 15% Decrease From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) at Day 85 | 6 Participants |
| Placebo QW (Once Weekly) | The Number of Participants With ≥ 15% Decrease From Baseline in Liver Stiffness as Measured by Magnetic Resonance Elastography (MRE) at Day 85 | 3 Participants |
Secondary
The Number of Participants With ≥ 1 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment
The number of participants with ≥ 1 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The Ishak scoring system is used to grade fibrosis in the histology samples. The Ishak system (0 through 6 scale) was developed to grade portal-based liver fibrosis associated with viral hepatitis: 0: No fibrosis 1. Fibrous expansion of some portal areas, with or without short fibrous septa 2. Fibrous expansion of most portal areas, with or without short fibrous septa 3. Fibrous expansion of most portal areas with occasional portal to portal bridging 4. Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central) 5. Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 6. Cirrhosis, probable or definite
Time frame: Week 12
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | The Number of Participants With ≥ 1 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 4 Participants |
| BMS-986263 90 mg QW (Once Weekly) | The Number of Participants With ≥ 1 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 7 Participants |
| Placebo QW (Once Weekly) | The Number of Participants With ≥ 1 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 4 Participants |
Secondary
The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment
The number of participants with ≥ 2 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The Ishak scoring system is used to grade fibrosis in the histology samples. The Ishak system (0 through 6 scale) was developed to grade portal-based liver fibrosis associated with viral hepatitis: 0: No fibrosis 1. Fibrous expansion of some portal areas, with or without short fibrous septa 2. Fibrous expansion of most portal areas, with or without short fibrous septa 3. Fibrous expansion of most portal areas with occasional portal to portal bridging 4. Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal to central) 5. Marked bridging (portal-portal and/or portal-central) with occasional nodules (incomplete cirrhosis) 6. Cirrhosis, probable or definite
Time frame: Week 12
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 0 Participants |
| BMS-986263 90 mg QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 5 Participants |
| Placebo QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (Ishak Score) After 12 Weeks of Treatment | 0 Participants |
Secondary
The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (METAVIR Score) After 12 Weeks of Treatment
The number of participants with ≥ 2 stage improvement in liver fibrosis is used to asses the effects of treatment compared to placebo. The METAVIR system is used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C virus (HCV). It assesses liver biopsies for activity grade (A0-A3) and fibrosis stage (Stage 1 - 4). Participants without a measurement at Week 12 are considered non-responders. Activity Grade: A0 = no activity; A1 = mild activity; A2 = moderate activity; A3 = severe activity Fibrosis stage: 1 = portal fibrosis without septa ; 2 = portal fibrosis with few septa; 3 = numerous septa without cirrhosis; 4 = cirrhosis
Time frame: Week 12
Population: Modified Intent to Treat Analysis Set: All participants who are randomized to a treatment and receive at least 1 dose of study medication analyzed as per randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BMS-986263 45 mg QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (METAVIR Score) After 12 Weeks of Treatment | 0 Participants |
| BMS-986263 90 mg QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (METAVIR Score) After 12 Weeks of Treatment | 2 Participants |
| Placebo QW (Once Weekly) | The Number of Participants With ≥ 2 Stage Improvement in Liver Fibrosis (METAVIR Score) After 12 Weeks of Treatment | 0 Participants |