Liver Fibrosis Due to NASH
Conditions
Keywords
NASH, cirrhosis, Compensated Liver disease, Monoclonal antibody, LOXL2, Simtuzumab, Nonalcoholic Steatohepatitis, Hepatic venous pressure gradient, HVPG, NAFLD, MRE, Liver biopsy, Liver fibrosis, Ishak
Brief summary
The primary objective of this study is to evaluate the safety and efficacy of SIM (formerly referred to as GS-6624) in adults with compensated cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). It will consist of 2 phases: * Randomized Double-Blind Phase * Open-Label Phase (optional)
Interventions
BIOLOGICALPlacebo
Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks
BIOLOGICALSIM
Intravenous infusion over 30 minutes every 2 weeks
Sponsors
Gilead Sciences
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 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults with cirrhosis of the liver defined as an Ishak fibrosis stage ≥ 5 * Liver biopsy consistent with NASH or cryptogenic cirrhosis * Exclusion of other causes of liver disease including viral hepatitis and alcoholic liver disease * The liver biopsy sample must be determined to be adequate for evaluation by the Central pathologist * Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x the upper limit of the normal range (ULN) * Must have serum creatinine \< 2.0 mg/dL * A negative serum pregnancy test is required for female subjects of childbearing potential * All sexually active female subjects of childbearing potential must agree to use a protocol recommended method of contraception during heterosexual 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 * Male subjects, 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 * Any history of hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding * Weight reduction surgery in the past 5 year * Child-Pugh-Turcotte (CPT) score \>7; Model for End-Stage Liver Disease (MELD) score \> 12 and Body Mass Index (BMI) \<18kg/m2 * 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. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator * 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 subject's compliance with the protocol procedures; * Participation in an investigational trial of a drug or device within 30 days prior to screening * History of solid-organ transplant; poor venous access or requirement for permanent or semi-permanent central vein catheter such as portacath Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) | Baseline to Week 96 | — |
| Event-Free Survival (EFS) Using Kaplan-Meier | Baseline up to the time of clinical event or last dose date (maximum: 240 weeks in Blinded Phase); which ever occurred first | Event free survival (EFS) was the primary clinical efficacy endpoint and was assessed by time to first liver-related event or death, whichever occurs first. Liver-related events included any of the following: * Liver transplantation * Qualification for liver transplantation * Model for End-Stage Liver Disease (MELD) ≥ 15 * Events indicative of hepatic decompensation * Esophageal variceal bleeding * Ascites * Hepatic Encephalopathy * ≥ 2 point increase in Child Pugh-Turcotte (CPT) score * Newly diagnosed varices in a subject without prior varices |
Countries
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 29 October 2012. The last study visit occurred on 03 January 2017.
Pre-assignment details
453 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SIM 200 mg Blinded Phase: Participants received SIM 200 mg administered via intravenous infusion every 2 weeks for up to 240 weeks.
Open-Label Phase: Participants received SIM 700 mg administered via intravenous infusion every 2 weeks for up to an additional 240 weeks. | 87 |
| SIM 700 mg Blinded Phase: Participants received SIM 700 mg administered via intravenous infusion every 2 weeks for up to 240 weeks.
Open-Label Phase: Participants received SIM 700 mg administered via intravenous infusion every 2 weeks for up to an additional 240 weeks. | 86 |
| Placebo Blinded Phase: Participants received placebo to match SIM administered via intravenous infusion every 2 weeks for up to 240 weeks.
Open-Label Phase: Open-Label Phase: Participants received SIM 700 mg administered via intravenous infusion every 2 weeks for up to an additional 240 weeks. | 85 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Phase (Up to 240 Weeks) | Adverse Event | 5 | 2 | 7 |
| Blinded Phase (Up to 240 Weeks) | Death | 0 | 2 | 0 |
| Blinded Phase (Up to 240 Weeks) | Investigator's Discretion | 5 | 0 | 2 |
| Blinded Phase (Up to 240 Weeks) | Lost to Follow-up | 4 | 3 | 1 |
| Blinded Phase (Up to 240 Weeks) | Met Protocol-Specified Reason(s) | 15 | 17 | 8 |
| Blinded Phase (Up to 240 Weeks) | Missing | 1 | 0 | 0 |
| Blinded Phase (Up to 240 Weeks) | Randomized but Never Treated | 0 | 0 | 1 |
| Blinded Phase (Up to 240 Weeks) | Study Terminated by Sponsor | 43 | 55 | 61 |
| Blinded Phase (Up to 240 Weeks) | Withdrew Consent | 14 | 7 | 6 |
| Open-Label Phase (Up to 240 Weeks) | Adverse Event | 5 | 1 | 1 |
| Open-Label Phase (Up to 240 Weeks) | Investigator's Discretion | 1 | 0 | 1 |
| Open-Label Phase (Up to 240 Weeks) | Progressive Disease | 1 | 0 | 0 |
| Open-Label Phase (Up to 240 Weeks) | Study Terminated by Sponsor | 8 | 16 | 6 |
Baseline characteristics
| Characteristic | SIM 700 mg | Placebo | SIM 200 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 7.3 | 56 years STANDARD_DEVIATION 7.8 | 56 years STANDARD_DEVIATION 7.2 | 55 years STANDARD_DEVIATION 7.4 |
| Hepatic Venous Pressure Gradient (HVPG) | 12.8 mmHg STANDARD_DEVIATION 5.37 | 13.0 mmHg STANDARD_DEVIATION 5.25 | 12.9 mmHg STANDARD_DEVIATION 5.1 | 12.9 mmHg STANDARD_DEVIATION 5.22 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 17 Participants | 10 Participants | 12 Participants | 39 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 69 Participants | 75 Participants | 75 Participants | 219 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Black | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Other | 7 Participants | 1 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized Race White | 75 Participants | 83 Participants | 80 Participants | 238 Participants |
| Region of Enrollment Canada | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
| Region of Enrollment France | 4 Participants | 3 Participants | 6 Participants | 13 Participants |
| Region of Enrollment Germany | 4 Participants | 3 Participants | 1 Participants | 8 Participants |
| Region of Enrollment Italy | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Spain | 5 Participants | 0 Participants | 3 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
| Region of Enrollment United States | 68 Participants | 76 Participants | 67 Participants | 211 Participants |
| Sex: Female, Male Female | 54 Participants | 56 Participants | 53 Participants | 163 Participants |
| Sex: Female, Male Male | 32 Participants | 29 Participants | 34 Participants | 95 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 | 85 / 87 | 81 / 86 | 83 / 85 | 32 / 40 |
| serious Total, serious adverse events | 37 / 87 | 36 / 86 | 25 / 85 | 17 / 40 |
Outcome results
Primary
Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)
Time frame: Baseline to Week 96
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SIM 200 mg | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) | -0.1 mmHg | Standard Deviation 3.76 |
| SIM 700 mg | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) | 0.0 mmHg | Standard Deviation 4.23 |
| Placebo | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) | -0.1 mmHg | Standard Deviation 4.01 |
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 HVPG at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in HVPG at Week 96 contributed to the overall model.95% CI: [-1.2, 1.5]
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 HVPG at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in HVPG at Week 96 contributed to the overall model.95% CI: [-1.2, 1.4]
Primary
Event-Free Survival (EFS) Using Kaplan-Meier
Event free survival (EFS) was the primary clinical efficacy endpoint and was assessed by time to first liver-related event or death, whichever occurs first. Liver-related events included any of the following: * Liver transplantation * Qualification for liver transplantation * Model for End-Stage Liver Disease (MELD) ≥ 15 * Events indicative of hepatic decompensation * Esophageal variceal bleeding * Ascites * Hepatic Encephalopathy * ≥ 2 point increase in Child Pugh-Turcotte (CPT) score * Newly diagnosed varices in a subject without prior varices
Time frame: Baseline up to the time of clinical event or last dose date (maximum: 240 weeks in Blinded Phase); which ever occurred first
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SIM 200 mg | Event-Free Survival (EFS) Using Kaplan-Meier | NA months |
| SIM 700 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 HVPG category (\< 10 mmHg vs ≥ 10 mmHg) and presence or absence of diabetes at baseline.p-value: 0.41Stratified log-rank test
Comparison: Differences in EFS between a given SIM group and placebo were assessed using the log-rank test stratified by HVPG category (\< 10 mmHg vs ≥ 10 mmHg) and presence or absence of diabetes at baseline.p-value: 0.065Stratified log-rank test