Non-Alcoholic Steatohepatitis (NASH)
Conditions
Keywords
GS-4997, Non-alcoholic fatty liver disease (NAFLD), Fibrosis, Simtuzumab (SIM), Apoptosis signal-regulating kinase 1, ASK1 inhibitor
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of GS-4997 (selonsertib \[SEL\]) alone or in combination with simtuzumab (SIM) in adults with nonalcoholic steatohepatitis (NASH) and fibrosis stages F2-F3. Participants will be randomized in a 2:2:1:1:1 ratio to 1 of 5 study treatment arms.
Interventions
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Males and non-pregnant, non-lactating females * Evidence of NASH with fibrosis on biopsy Key
Exclusion criteria
* Cirrhosis of the liver (e.g. Brunt/Kleiner score of F4) * Other causes of liver disease including viral hepatitis and alcoholic liver disease * Any history of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding * History of liver transplantation * Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1 oz/30 mL of alcohol is present in 1 12 oz/360 mL beer, 1 4 oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40% proof alcohol) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Baseline up to last dose plus 30 days (up to Week 28) | Treatment-emergent events began on or after the first dosing date up to 30 days after the last dosing date or led to premature discontinuation of study drug. The severity of laboratory abnormalities was assessed as Grade 0, 1 (mild), 2 (moderate), 3 (severe), or 4 (potentially life threatening) using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. |
| Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Baseline up to follow up visit (Week 28) | — |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States and Canada. The first participant was screened on 08 June 2015.The last study visit occurred on 11 October 2016.
Pre-assignment details
242 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SEL 6 mg Selonsertib (SEL) 6 mg tablet once daily for 24 weeks. | 20 |
| SEL 18 mg SEL 18 mg tablet once daily for 24 weeks. | 22 |
| SEL 6 mg+SIM 125 mg SEL 6 mg tablet once daily plus simtuzumab (SIM) 125 mg/mL administered subcutaneously once weekly for 24 weeks. | 10 |
| SEL 18 mg+SIM 125 mg SEL 18 mg tablet once daily plus SIM 125 mg/mL administered subcutaneously once weekly for 24 weeks. | 10 |
| SIM 125 mg SIM 125 mg/mL administered subcutaneously once weekly for 24 weeks. | 10 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrew Consent | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | SEL 6 mg | SEL 18 mg | SEL 6 mg+SIM 125 mg | SEL 18 mg+SIM 125 mg | SIM 125 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 11.5 | 56 years STANDARD_DEVIATION 9 | 52 years STANDARD_DEVIATION 9.7 | 51 years STANDARD_DEVIATION 11.1 | 57 years STANDARD_DEVIATION 7.7 | 54 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 5 Participants | 2 Participants | 1 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 15 Participants | 5 Participants | 8 Participants | 9 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 17 Participants | 19 Participants | 10 Participants | 9 Participants | 10 Participants | 65 Participants |
| Region of Enrollment Canada | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 17 Participants | 21 Participants | 10 Participants | 9 Participants | 9 Participants | 66 Participants |
| Sex: Female, Male Female | 13 Participants | 15 Participants | 9 Participants | 7 Participants | 6 Participants | 50 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 1 Participants | 3 Participants | 4 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 22 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 17 / 20 | 14 / 22 | 9 / 10 | 9 / 10 | 7 / 10 |
| serious Total, serious adverse events | 2 / 20 | 2 / 22 | 0 / 10 | 1 / 10 | 0 / 10 |
Outcome results
Primary
Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality
Treatment-emergent events began on or after the first dosing date up to 30 days after the last dosing date or led to premature discontinuation of study drug. The severity of laboratory abnormalities was assessed as Grade 0, 1 (mild), 2 (moderate), 3 (severe), or 4 (potentially life threatening) using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
Time frame: Baseline up to last dose plus 30 days (up to Week 28)
Population: Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SEL 6 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | TEAEs | 17 Participants |
| SEL 6 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Any Grade ≥ 1 Laboratory Abnormality | 17 Participants |
| SEL 6 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | SAEs | 2 Participants |
| SEL 18 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | SAEs | 2 Participants |
| SEL 18 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | TEAEs | 15 Participants |
| SEL 18 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Any Grade ≥ 1 Laboratory Abnormality | 21 Participants |
| SEL 6 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | SAEs | 0 Participants |
| SEL 6 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | TEAEs | 9 Participants |
| SEL 6 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Any Grade ≥ 1 Laboratory Abnormality | 9 Participants |
| SEL 18 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | TEAEs | 9 Participants |
| SEL 18 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Any Grade ≥ 1 Laboratory Abnormality | 10 Participants |
| SEL 18 mg+SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | SAEs | 1 Participants |
| SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | SAEs | 0 Participants |
| SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | TEAEs | 7 Participants |
| SIM 125 mg | Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Any Grade ≥ 1 Laboratory Abnormality | Any Grade ≥ 1 Laboratory Abnormality | 8 Participants |
Primary
Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events
Time frame: Baseline up to follow up visit (Week 28)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SEL 6 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study Drug | 1 Participants |
| SEL 6 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study | 1 Participants |
| SEL 18 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study Drug | 2 Participants |
| SEL 18 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study | 1 Participants |
| SEL 6 mg+SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study Drug | 0 Participants |
| SEL 6 mg+SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study | 0 Participants |
| SEL 18 mg+SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study | 0 Participants |
| SEL 18 mg+SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study Drug | 0 Participants |
| SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study Drug | 0 Participants |
| SIM 125 mg | Number of Participants Who Prematurely Discontinued Study Drug or Study Due to Adverse Events | Discontinued Study | 0 Participants |