Nonalcoholic Steatohepatitis
Conditions
Brief summary
The primary objective of this study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce associated complications in adults with cirrhosis due to NASH.
Interventions
DRUGSEL
Tablets administered orally once daily
Tablets administered orally once daily
Tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Liver biopsy consistent with NASH and cirrhosis (F4 fibrosis) according to the NASH Clinical Research Network (CRN) classification, in the opinion of the central reader * Has the following laboratory parameters at the screening visit, as determined by the central laboratory: * Alanine aminotransferase (ALT) ≤ 8 x upper limit of normal (ULN) * Creatinine Clearance (CLcr) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation * HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 micromole (μmol) if HbA1c is unable to be resulted) * International normalised ratio (INR) ≤ 1.4, unless due to therapeutic anti-coagulation * Platelet count ≥ 100,000/μL Key
Exclusion criteria
* Prior history of decompensated liver disease including clinical ascites, hepatic encephalopathy (HE), or variceal bleeding * Child-Pugh (CP) score \> 7, as determined at screening, unless due to therapeutic anti-coagulation * Model for End-stage Liver Disease (MELD) score \> 12, as determined at screening, unless due to therapeutic anti-coagulation * Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders, drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitrypsin deficiency, based on medical history and/or centralized review of liver histology. * History of liver transplantation * Current or history of hepatocellular carcinoma (HCC) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH | Week 48 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. |
| Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event | Week 240 | EFS was assessed by the time to the first clinical event, including liver decompensation events, liver transplantation and all-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | Week 48 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). |
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240 | Week 240 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). |
| Percentage of Participants Who Had NASH Resolution at Week 240 | Week 240 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions.As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. |
| Percentage of Participants Who Had NASH Resolution at Week 48 | Week 48 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. |
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240 | Week 240 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, Mexico, New Zealand, Poland, Puerto Rico, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Asia, Australia, New Zealand, Europe and Puerto Rico. The first participant was screened on 30 January 2017. The last study visit occurred on 06 May 2019.
Pre-assignment details
2154 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SEL 18 mg Randomized Phase: SEL 18 mg tablet orally once daily + placebo for up to 240 weeks.
Open-label Phase: Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration, including the treatment duration in the randomized phase, of 240 weeks. | 354 |
| SEL 6 mg Randomized Phase : Selonsertib (SEL) 6 mg tablet orally once daily + placebo for up to 240 weeks.
Open-label (OL) Phase: Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an open-label phase to receive OL SEL 18 mg daily for a total treatment duration, including the treatment duration in the randomized phase, of 240 weeks. | 351 |
| Placebo Randomized Phase: Placebo tablet orally once daily for up to 240 weeks.
Open-label Phase: Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration, including the treatment duration in the randomized phase, of 240 weeks. | 172 |
| Total | 877 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-Label Phase | Death | 0 | 0 | 0 | 2 |
| Open-Label Phase | Investigator's discretion | 0 | 0 | 0 | 2 |
| Open-Label Phase | Study Terminated by Sponsor | 0 | 0 | 0 | 19 |
| Randomized Phase | Adverse Event | 0 | 1 | 0 | 0 |
| Randomized Phase | Entered the Open-Label Phase | 9 | 11 | 3 | 0 |
| Randomized Phase | Investigator's Discretion | 8 | 6 | 2 | 0 |
| Randomized Phase | Lost to Follow-up | 3 | 5 | 1 | 0 |
| Randomized Phase | Randomized but Never Treated | 1 | 3 | 2 | 0 |
| Randomized Phase | Study Terminated by Sponsor | 326 | 317 | 161 | 0 |
| Randomized Phase | Withdrew consent | 8 | 11 | 5 | 0 |
Baseline characteristics
| Characteristic | SEL 18 mg | Total | Placebo | SEL 6 mg |
|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 8.5 | 58 years STANDARD_DEVIATION 8.6 | 60 years STANDARD_DEVIATION 8.4 | 57 years STANDARD_DEVIATION 8.7 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 49 Participants | 122 Participants | 22 Participants | 51 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 300 Participants | 746 Participants | 149 Participants | 297 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 5 Participants | 9 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 3 Participants | 6 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 73 Participants | 165 Participants | 33 Participants | 59 Participants |
| Race/Ethnicity, Customized Race Black | 5 Participants | 10 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 4 Participants | 5 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 7 Participants | 14 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 261 Participants | 676 Participants | 136 Participants | 279 Participants |
| Sex: Female, Male Female | 216 Participants | 547 Participants | 101 Participants | 230 Participants |
| Sex: Female, Male Male | 138 Participants | 330 Participants | 71 Participants | 121 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 | 0 / 354 | 0 / 351 | 0 / 172 | 2 / 23 |
| other Total, other adverse events | 251 / 354 | 276 / 351 | 135 / 172 | 17 / 23 |
| serious Total, serious adverse events | 60 / 354 | 53 / 351 | 22 / 172 | 7 / 23 |
Outcome results
Primary
Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event
EFS was assessed by the time to the first clinical event, including liver decompensation events, liver transplantation and all-cause mortality.
Time frame: Week 240
Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
Primary
Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.
Time frame: Week 48
Population: The Full Analysis Set included all participants who were randomized into the study and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEL 18 mg | Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH | 14.4 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH | 12.8 percentage of participants |
| Placebo | Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH | 12.8 percentage of participants |
p-value: 0.557295% CI: [-4.4, 8.2]Mantel Haenszel
p-value: 0.927295% CI: [-6, 6.5]Mantel Haenszel
Secondary
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).
Time frame: Week 240
Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
Secondary
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEL 18 mg | Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | 18.9 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | 16.8 percentage of participants |
| Placebo | Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | 15.7 percentage of participants |
p-value: 0.28595% CI: [-3.1, 10.6]Mantel Haenszel
p-value: 0.673195% CI: [-5.3, 8.2]Mantel Haenszel
Secondary
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.
Time frame: Week 240
Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
Secondary
Percentage of Participants Who Had NASH Resolution at Week 240
NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions.As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1.
Time frame: Week 240
Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.
Secondary
Percentage of Participants Who Had NASH Resolution at Week 48
NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1.
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEL 18 mg | Percentage of Participants Who Had NASH Resolution at Week 48 | 2.3 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Had NASH Resolution at Week 48 | 3.7 percentage of participants |
| Placebo | Percentage of Participants Who Had NASH Resolution at Week 48 | 4.1 percentage of participants |
p-value: 0.36595% CI: [-5.5, 2]Mantel Haenszel
p-value: 0.855795% CI: [-4.3, 3.6]Mantel Haenszel