Nonalcoholic Steatohepatitis
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).
Interventions
DRUGSemaglutide
Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly
DRUGFirsocostat
Tablets administered orally once daily
DRUGCilofexor
Tablets administered orally once daily
Sponsors
Novo Nordisk A/S
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Historical liver biopsy consistent with NASH with stage 2-3 fibrosis according to NASH Clinical Research Network (CRN) classification OR clinical diagnosis of nonalcoholic fatty liver disease and screening FibroTest, magnetic resonance imaging - proton density fat fraction (MRI-PDFF), and FibroScan * Screening laboratory parameters, as determined by central laboratory: * Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN) * Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation * HbA1c ≤ 9.5% * International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy * Platelet count ≥ 100,000/μL * Total bilirubin \< 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present * Calcitonin ≤ 100 ng/L * Body Mass Index (BMI) \> 23 kg/m\^2 and body weight of \> 60 kg Key
Exclusion criteria
* Any historical liver biopsy consistent with cirrhosis * Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding * Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment * History of liver transplantation * History of hepatocellular carcinoma * History of pancreatitis (acute or chronic) * Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma * Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the period from 90 days prior to the date of the Screening Visit * Individuals on antidiabetic medications must be on a stable dose for at least 90 days prior to the date of the Screening Visit and in the period between the date of the Screening Visit and Enrollment (Day -14) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | First dose date up to Week 24 plus 30 days | Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | First dose date up to 24 weeks plus 30 days | Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States. The first participant was screened on 29 July 2019. The last study visit occurred on 13 July 2020.
Pre-assignment details
209 participants were screened. 109 participants were enrolled. 1 participant was enrolled but was not randomized and was not included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Semaglutide Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks. | 21 |
| Semaglutide + Firsocostat 20 mg Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily with or without food for 24 weeks. | 22 |
| Semaglutide + Cilofexor 30 mg Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks. | 22 |
| Semaglutide + Cilofexor 100 mg Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 100 mg tablet orally once daily with or without food for 24 weeks. | 22 |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks. | 21 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 | 0 | 1 |
| Overall Study | Investigator's Discretion | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrew Consent | 1 | 1 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Semaglutide + Cilofexor 100 mg | Semaglutide + Cilofexor 30 mg | Semaglutide + Firsocostat 20 mg | Semaglutide |
|---|---|---|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 11.1 | 53 years STANDARD_DEVIATION 11.4 | 54 years STANDARD_DEVIATION 10.8 | 51 years STANDARD_DEVIATION 10.9 | 52 years STANDARD_DEVIATION 12.6 | 55 years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 43 Participants | 11 Participants | 7 Participants | 5 Participants | 12 Participants | 8 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 65 Participants | 10 Participants | 15 Participants | 17 Participants | 10 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 92 Participants | 19 Participants | 19 Participants | 18 Participants | 19 Participants | 17 Participants |
| Sex: Female, Male Female | 74 Participants | 15 Participants | 13 Participants | 16 Participants | 15 Participants | 15 Participants |
| Sex: Female, Male Male | 34 Participants | 6 Participants | 9 Participants | 6 Participants | 7 Participants | 6 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 / 21 | 0 / 22 | 0 / 22 | 0 / 22 | 0 / 21 |
| other Total, other adverse events | 16 / 21 | 17 / 22 | 18 / 22 | 13 / 22 | 17 / 21 |
| serious Total, serious adverse events | 1 / 21 | 0 / 22 | 0 / 22 | 1 / 22 | 0 / 21 |
Outcome results
Primary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: First dose date up to Week 24 plus 30 days
Population: The Safety Analysis Set included participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Semaglutide | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 81.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 86.4 percentage of participants |
| Semaglutide + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 81.8 percentage of participants |
| Semaglutide + Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 72.7 percentage of participants |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 90.5 percentage of participants |
Primary
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.
Time frame: First dose date up to 24 weeks plus 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Semaglutide | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 1 | 61.9 percentage of participants |
| Semaglutide | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 2 | 23.8 percentage of participants |
| Semaglutide | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 3 | 0.0 percentage of participants |
| Semaglutide | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 1 | 63.6 percentage of participants |
| Semaglutide + Firsocostat 20 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 2 | 22.7 percentage of participants |
| Semaglutide + Firsocostat 20 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 3 | 4.5 percentage of participants |
| Semaglutide + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0.0 percentage of participants |
| Semaglutide + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 2 | 31.8 percentage of participants |
| Semaglutide + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 3 | 0.0 percentage of participants |
| Semaglutide + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 1 | 36.4 percentage of participants |
| Semaglutide + Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 1 | 50.0 percentage of participants |
| Semaglutide + Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 2 | 18.2 percentage of participants |
| Semaglutide + Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 4 | 9.1 percentage of participants |
| Semaglutide + Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 3 | 0.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 3 | 0.0 percentage of participants |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 2 | 9.5 percentage of participants |
| Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Grade 1 | 66.7 percentage of participants |