Liver Fibrosis Due to NASH
Conditions
Keywords
NASH, noncirrhotic, Monoclonal antibody, LOXL2, Simtuzumab, Nonalcoholic Steatohepatitis, NAFLD, Liver biopsy, MRE, Liver fibrosis, Ishak
Brief summary
The primary objective of this study is to evaluate whether SIM (formerly referred to as GS-6624) is effective at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in participants with NASH. It will consist of 2 phases: * Randomized Double-Blind Phase * Open-Label Phase (optional)
Interventions
BIOLOGICALPlacebo
Placebo to match SIM via subcutaneous injection every week
BIOLOGICALSIM
Subcutaneous injection every week
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults with chronic liver disease due to NASH defined as macrovesicular steatosis involving \> 5% of hepatocytes on a liver biopsy with associated lobular inflammation * Stage 3-4 fibrosis by Ishak score on a liver biopsy * Exclusion of other causes of liver disease including viral hepatitis and alcoholic liver disease * Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x Central Laboratory Upper Limit of Normal (clULN) * Must have serum creatinine \< 2.0 mg/dL * A negative serum pregnancy test is required for females of childbearing potential * All sexually active females of childbearing potential must agree to use a protocol recommended method of contraception during intercourse throughout the study and for 90 days following the last dose of study medication * Lactating females must agree to discontinue nursing before starting study treatment * Males, if not vasectomized, are required to use barrier contraception (condom plus spermicide) during heterosexual intercourse from the screening through the study completion and for 90 days following the last dose of study drug. Key
Exclusion criteria
* Pregnant or breast feeding * Cirrhosis of the liver * Any history of hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding * Weight reduction surgery in the past 5 years * Positive for hepatitis C virus (HCV) RNA * Positive for HBsAg * Alcohol consumption greater than 21oz/week for males or 14oz/week for females * Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at screening. * Clinically significant cardiac disease * History of malignancy, other than non-melanomatous skin cancer, within 5 years prior to screening * Major surgical procedure within 30 days prior to screening or the presence of an open wound * Known hypersensitivity to the investigation product or any of its formulation excipients * History of bleeding diathesis within 6 months of screening * Unavailable for follow-up assessment or concern for individual's compliance with the protocol procedures; * Participation in an investigational trial of a drug or device within 30 days prior to screening * BMI \< 18 kg/m\^2 Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MQC on Liver Biopsy | Baseline to Week 96 | — |
| Event Free Survival (EFS) Using Kaplan-Meier | Baseline up to the time of progression to cirrhosis or last dose date (maximum: 240 weeks in the Blinded Phase), which ever occurred first | The EFS was the primary clinical efficacy endpoint and was assessed by the time to progression to cirrhosis. Participants were considered to have become cirrhotic if they had a post-baseline biopsy consistent with cirrhosis or developed overt signs and symptoms of cirrhosis. All overt signs and symptoms went through an adjudication process and were confirmed before they were considered for the EFS analysis. |
Countries
Belgium, Canada, France, Germany, Italy, Puerto Rico, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Europe and North America. The first participant was screened on 05 December 2012. The last study visit occurred on 29 December 2016.
Pre-assignment details
631 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SIM 75 mg Blinded Phase: Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks. | 71 |
| SIM 125 mg Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks. | 74 |
| Placebo Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks. | 74 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Phase (up to 240 Weeks) | Adverse Event | 3 | 3 | 3 |
| Blinded Phase (up to 240 Weeks) | Death | 0 | 0 | 1 |
| Blinded Phase (up to 240 Weeks) | Investigator's Discretion | 3 | 3 | 2 |
| Blinded Phase (up to 240 Weeks) | Lost to Follow-up | 3 | 3 | 5 |
| Blinded Phase (up to 240 Weeks) | Met protocol-specified reason(s) | 11 | 15 | 16 |
| Blinded Phase (up to 240 Weeks) | Protocol Violation | 2 | 0 | 0 |
| Blinded Phase (up to 240 Weeks) | Randomized but Never Treated | 3 | 0 | 0 |
| Blinded Phase (up to 240 Weeks) | Study Terminated by Sponsor | 40 | 42 | 35 |
| Blinded Phase (up to 240 Weeks) | Withdrew Consent | 9 | 8 | 12 |
| Open-Label Phase (up to 240 Weeks) | Death | 1 | 0 | 0 |
| Open-Label Phase (up to 240 Weeks) | Lost to Follow-up | 1 | 0 | 0 |
| Open-Label Phase (up to 240 Weeks) | Study Terminated by Sponsor | 8 | 15 | 15 |
| Open-Label Phase (up to 240 Weeks) | Withdrew Consent | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | SIM 75 mg | Placebo | SIM 125 mg |
|---|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 8.8 | 54 years STANDARD_DEVIATION 8.8 | 53 years STANDARD_DEVIATION 8.4 | 53 years STANDARD_DEVIATION 9.4 |
| Morphometric Quantitative Collagen (MQC) | 7.0 percentage of liver collagen STANDARD_DEVIATION 4.19 | 7.0 percentage of liver collagen STANDARD_DEVIATION 4.18 | 6.7 percentage of liver collagen STANDARD_DEVIATION 3.78 | 7.2 percentage of liver collagen STANDARD_DEVIATION 4.62 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 34 Participants | 9 Participants | 11 Participants | 14 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 185 Participants | 62 Participants | 63 Participants | 60 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 5 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 206 Participants | 66 Participants | 69 Participants | 71 Participants |
| Region of Enrollment Belgium | 6 Participants | 1 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Canada | 12 Participants | 5 Participants | 1 Participants | 6 Participants |
| Region of Enrollment France | 12 Participants | 4 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Germany | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Italy | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Spain | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 8 Participants | 3 Participants | 5 Participants | 0 Participants |
| Region of Enrollment United States | 163 Participants | 51 Participants | 54 Participants | 58 Participants |
| Sex: Female, Male Female | 138 Participants | 43 Participants | 48 Participants | 47 Participants |
| Sex: Female, Male Male | 81 Participants | 28 Participants | 26 Participants | 27 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 71 | 69 / 74 | 72 / 74 | 29 / 42 |
| serious Total, serious adverse events | 17 / 71 | 17 / 74 | 14 / 74 | 11 / 42 |
Outcome results
Primary
Change From Baseline in MQC on Liver Biopsy
Time frame: Baseline to Week 96
Population: Participants in the Full Analysis Set (all enrolled participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SIM 75 mg | Change From Baseline in MQC on Liver Biopsy | -3.1 percentage of liver collagen | Standard Deviation 4.83 |
| SIM 125 mg | Change From Baseline in MQC on Liver Biopsy | -2.5 percentage of liver collagen | Standard Deviation 5.11 |
| Placebo | Change From Baseline in MQC on Liver Biopsy | -1.9 percentage of liver collagen | Standard Deviation 4.28 |
Comparison: A mixed-effect model for repeated measures (MMRM) with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% confidence interval (CI) for the treatment difference between each treatment arm and placebo in least squares mean (LSMean) change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.95% CI: [-1.3, 1]
Comparison: An MMRM with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% CI for the treatment difference between each treatment arm and placebo in LSMean change from baseline in MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.95% CI: [-1.5, 0.8]
Primary
Event Free Survival (EFS) Using Kaplan-Meier
The EFS was the primary clinical efficacy endpoint and was assessed by the time to progression to cirrhosis. Participants were considered to have become cirrhotic if they had a post-baseline biopsy consistent with cirrhosis or developed overt signs and symptoms of cirrhosis. All overt signs and symptoms went through an adjudication process and were confirmed before they were considered for the EFS analysis.
Time frame: Baseline up to the time of progression to cirrhosis or last dose date (maximum: 240 weeks in the Blinded Phase), which ever occurred first
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SIM 75 mg | Event Free Survival (EFS) Using Kaplan-Meier | NA months |
| SIM 125 mg | Event Free Survival (EFS) Using Kaplan-Meier | NA months |
| Placebo | Event Free Survival (EFS) Using Kaplan-Meier | NA months |
Comparison: Differences in EFS between a given SIM group and placebo were assessed using the log-rank test stratified by the presence or absence of diabetes at baseline.p-value: 0.73Stratified log-rank test
Comparison: Differences in EFS between a given SIM group and placebo were assessed using the log-rank test stratified by the presence or absence of diabetes at baseline.p-value: 0.85Stratified log-rank test