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 progression to cirrhosis and associated complications in adults with NASH and bridging (F3) fibrosis.
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 bridging (F3 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: * 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 * Hemoglobin A1c (HbA1c) ≤ 9.5% (or serum fructosamine ≤ 381 μmol if HbA1c is unable to be resulted) * Total bilirubin ≤ 1.3 x ULN (unless an alternate etiology such as Gilbert's syndrome or hemolytic anemia is present) Key
Exclusion criteria
* Prior history of decompensated liver disease including clinical ascites, hepatic encephalopathy (HE), or variceal bleeding * Child-Pugh (CP) score \> 6, 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-antitryspin 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 Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH 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). 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 progression to cirrhosis on liver biopsy, 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 Progression to Cirrhosis at Week 48 | Week 48 | Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from \< 4 at baseline to 4 at Week 48. |
| Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240 | Week 240 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN. |
| Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48 | Week 48 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN. |
| 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
Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, 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, Europe, Australia, South America, Puerto Rico, and New Zealand. The first participant was screened on 13 February 2017. The last study visit occurred on 19 June 2019.
Pre-assignment details
2250 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SEL 18 mg Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks
Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis 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 of 240 weeks inclusive of the randomized phase. | 322 |
| SEL 6 mg Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks
OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis 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 of 240 weeks inclusive of the randomized phase. | 321 |
| Placebo Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks
OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis 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 of 240 weeks inclusive of the randomized phase. | 159 |
| Total | 802 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-label Phase | Investigator's Discretion | 0 | 0 | 0 | 4 |
| Open-label Phase | Study Terminated by Sponsor | 0 | 0 | 0 | 89 |
| Open-label Phase | Withdrew Consent | 0 | 0 | 0 | 6 |
| Randomized Phase | Adverse Event | 0 | 1 | 0 | 0 |
| Randomized Phase | Entered the Open-Label Phase | 36 | 45 | 18 | 0 |
| Randomized Phase | Investigator's Discretion | 6 | 6 | 3 | 0 |
| Randomized Phase | Lost to Follow-up | 5 | 1 | 1 | 0 |
| Randomized Phase | Randomized but Never Treated | 2 | 2 | 2 | 0 |
| Randomized Phase | Study Terminated by Sponsor | 259 | 260 | 128 | 0 |
| Randomized Phase | Withdrew Consent | 16 | 8 | 9 | 0 |
Baseline characteristics
| Characteristic | SEL 18 mg | SEL 6 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9.1 | 57 years STANDARD_DEVIATION 9.2 | 57 years STANDARD_DEVIATION 9 | 57 years STANDARD_DEVIATION 9.1 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 52 Participants | 48 Participants | 22 Participants | 122 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 269 Participants | 269 Participants | 137 Participants | 675 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 5 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Asian | 88 Participants | 84 Participants | 41 Participants | 213 Participants |
| Race/Ethnicity, Customized Race Black | 8 Participants | 5 Participants | 2 Participants | 15 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 219 Participants | 227 Participants | 113 Participants | 559 Participants |
| Region of Enrollment Argentina | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Region of Enrollment Australia | 9 Participants | 12 Participants | 3 Participants | 24 Participants |
| Region of Enrollment Austria | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Belgium | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Region of Enrollment Brazil | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Region of Enrollment Canada | 16 Participants | 14 Participants | 8 Participants | 38 Participants |
| Region of Enrollment France | 14 Participants | 10 Participants | 5 Participants | 29 Participants |
| Region of Enrollment Germany | 4 Participants | 3 Participants | 4 Participants | 11 Participants |
| Region of Enrollment Hong Kong | 10 Participants | 8 Participants | 6 Participants | 24 Participants |
| Region of Enrollment India | 7 Participants | 4 Participants | 4 Participants | 15 Participants |
| Region of Enrollment Israel | 2 Participants | 4 Participants | 3 Participants | 9 Participants |
| Region of Enrollment Italy | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Japan | 38 Participants | 23 Participants | 19 Participants | 80 Participants |
| Region of Enrollment Malaysia | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Mexico | 5 Participants | 2 Participants | 1 Participants | 8 Participants |
| Region of Enrollment Netherlands | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment New Zealand | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Poland | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Portugal | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Puerto Rico | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Singapore | 4 Participants | 5 Participants | 2 Participants | 11 Participants |
| Region of Enrollment South Korea | 8 Participants | 13 Participants | 7 Participants | 28 Participants |
| Region of Enrollment Spain | 9 Participants | 10 Participants | 4 Participants | 23 Participants |
| Region of Enrollment Switzerland | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Taiwan | 7 Participants | 14 Participants | 0 Participants | 21 Participants |
| Region of Enrollment United Kingdom | 8 Participants | 5 Participants | 7 Participants | 20 Participants |
| Region of Enrollment United States | 161 Participants | 172 Participants | 80 Participants | 413 Participants |
| Sex: Female, Male Female | 181 Participants | 196 Participants | 76 Participants | 453 Participants |
| Sex: Female, Male Male | 141 Participants | 125 Participants | 83 Participants | 349 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 / 322 | 0 / 321 | 0 / 159 | 0 / 99 |
| other Total, other adverse events | 248 / 322 | 254 / 321 | 130 / 159 | 48 / 99 |
| serious Total, serious adverse events | 47 / 322 | 36 / 321 | 17 / 159 | 6 / 99 |
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 progression to cirrhosis on liver biopsy, 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 Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH 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). 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 Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48 | 9.6 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48 | 12.1 percentage of participants |
| Placebo | Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48 | 13.2 percentage of participants |
p-value: 0.494195% CI: [-8.3, 4]Mantel Haenszel
p-value: 0.932195% CI: [-6.6, 6]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 | 12.7 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | 13.7 percentage of participants |
| Placebo | Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | 16.4 percentage of participants |
p-value: 0.563695% CI: [-8.7, 4.8]Mantel Haenszel
p-value: 0.591595% CI: [-8.6, 4.9]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 Without Worsening of Fibrosis at Week 240
NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN.
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 Without Worsening of Fibrosis at Week 48
NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN.
Time frame: Week 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEL 18 mg | Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48 | 5.0 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48 | 4.4 percentage of participants |
| Placebo | Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48 | 8.9 percentage of participants |
p-value: 0.245595% CI: [-8.5, 2.2]Mantel Haenszel
p-value: 0.137195% CI: [-9.3, 1.3]Mantel Haenszel
Secondary
Percentage of Participants Who Had Progression to Cirrhosis at Week 48
Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from \< 4 at baseline to 4 at Week 48.
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 Progression to Cirrhosis at Week 48 | 13.0 percentage of participants |
| SEL 6 mg | Percentage of Participants Who Had Progression to Cirrhosis at Week 48 | 15.6 percentage of participants |
| Placebo | Percentage of Participants Who Had Progression to Cirrhosis at Week 48 | 15.7 percentage of participants |
p-value: 0.259395% CI: [-10.8, 2.9]Mantel Haenszel
p-value: 0.80895% CI: [-7.9, 6.1]Mantel Haenszel