Nonalcoholic Steatohepatitis
Conditions
Brief summary
The goal of this clinical study is to understand whether the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR), cause fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with cirrhosis due to NASH.
Interventions
Administered as subcutaneous (SC) injection
DRUGCilofexor (CILO)/Firsocostat (FIR)
Tablets administered orally
DRUGPTM SEMA
Administered as SC injection
DRUGPTM CILO/FIR
Tablets administered orally
Sponsors
Novo Nordisk A/S
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Liver biopsy consistent with cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH) in the opinion of the central reader. In individuals who have never had a liver biopsy, a screening liver biopsy may be performed. * Screening laboratory parameters as determined by the study central laboratory: * Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m\^2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation. * Hemoglobin A1c (HbA1c) ≤ 10% * International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation * Platelet count ≥ 125,000/µL * Alanine aminotransferase (ALT) \< 5 x upper limit of normal (ULN) * Serum albumin ≥ 3.5 g/dL * Serum alkaline phosphatase (ALP) ≤ 2 x ULN * Body mass index (BMI) ≥ 23 kg/m\^2 at screening. Key
Exclusion criteria
* Prior history of decompensated liver disease, including ascites, hepatic encephalopathy (HE), or variceal bleeding. * Child-Pugh (CP) score \> 6 at screening, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation. * Model for End-stage Liver Disease (MELD) score \> 12 at screening, unless due to an alternative etiology such as therapeutic anticoagulation. * Other causes of liver disease based on medical history and/or central reader review of liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency. * Chronic hepatitis B virus (HBV) infection (HBsAg positive), or Chronic hepatitis C virus (HCV) infection (HCV antibody and HCV ribonucleic acid (RNA) positive). Individuals cured of HCV infection less than 2 years prior to the screening visit are not eligible. * History of liver transplantation. * Current or prior history of hepatocellular carcinoma (HCC). * Men who habitually drink greater than 21 units/week of alcohol or women who habitually drink greater than 14 units/week of alcohol (1 unit is equivalent to 12 ounce (oz)/360 mL of beer, a 4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor). * For individuals on vitamin E regimen ≥ 800 IU/day, or pioglitazone, dose must be stable, in the opinion of the investigator for at least 180 days prior to the historical or screening liver biopsy. * For individuals on medications for diabetes, dose must be stable, in the opinion of the investigator, for at least 90 days prior to the historical or screening liver biopsy. * History of type 1 diabetes. * Treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the period from 90 days prior to the screening visit and for individuals with a qualifying historical liver biopsy, for 90 days prior to the date of the historical liver biopsy. * For individuals who have not completed a series of an authorized coronavirus disease 2019 (COVID-19) vaccination regimen prior to screening, a positive result for COVID-19 on severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) test. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups | Week 72 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved ≥1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone | Week 72 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. |
| Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups | Week 72 | NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Worsening in fibrosis was defined as a change in fibrosis worsening stage as per NASH CRN criteria. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. |
| Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups | Week 72 | NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Worsening in fibrosis was defined as a change in fibrosis worsening stage as per NASH CRN criteria. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off. |
Countries
Australia, Canada, France, Japan, Puerto Rico, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Canada, France, Japan, Australia and Spain.
Pre-assignment details
1595 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SEMA + CILO/FIR FDC Participants received semaglutide (SEMA) 3.0 mg/mL subcutaneous (SC) injection once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet orally, once daily up to 72 weeks. | 124 |
| SEMA + PTM CILO/FIR Participants received SEMA 3.0 mg/mL SC injection, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet orally, once daily up to 72 weeks. | 122 |
| PTM SEMA + CILO/FIR FDC Participants received PTM SEMA SC injection, once weekly and CILO/FIR 30 mg/20 mg FDC tablet orally, once daily up to 72 weeks. | 123 |
| PTM SEMA + PTM CILO/FIR Participants received PTM SEMA SC injection, once weekly and PTM CILO/FIR FDC tablet orally, once daily up to 72 weeks. | 84 |
| Total | 453 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 8 | 6 | 3 |
| Overall Study | Death | 0 | 1 | 1 | 0 |
| Overall Study | Investigator's Discretion | 3 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 | 6 | 7 |
| Overall Study | Protocol Violation | 3 | 1 | 1 | 2 |
| Overall Study | Randomized but Never Treated | 1 | 2 | 0 | 1 |
| Overall Study | Site Terminated by Sponsor | 1 | 1 | 0 | 0 |
| Overall Study | Withdrew Consent | 5 | 5 | 17 | 7 |
Baseline characteristics
| Characteristic | SEMA + CILO/FIR FDC | SEMA + PTM CILO/FIR | PTM SEMA + CILO/FIR FDC | PTM SEMA + PTM CILO/FIR | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 52 Participants | 49 Participants | 56 Participants | 40 Participants | 197 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 73 Participants | 67 Participants | 44 Participants | 256 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 10.4 | 61 years STANDARD_DEVIATION 9.2 | 62 years STANDARD_DEVIATION 9.5 | 63 years STANDARD_DEVIATION 9.1 | 62 years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 23 Participants | 30 Participants | 19 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 95 Participants | 99 Participants | 90 Participants | 62 Participants | 346 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 9 Participants | 15 Participants | 3 Participants | 38 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 5 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) White | 100 Participants | 108 Participants | 98 Participants | 66 Participants | 372 Participants |
| Region of Enrollment Australia | 6 Participants | 2 Participants | 6 Participants | 2 Participants | 16 Participants |
| Region of Enrollment Canada | 7 Participants | 7 Participants | 12 Participants | 6 Participants | 32 Participants |
| Region of Enrollment France | 5 Participants | 5 Participants | 9 Participants | 10 Participants | 29 Participants |
| Region of Enrollment Japan | 4 Participants | 6 Participants | 6 Participants | 1 Participants | 17 Participants |
| Region of Enrollment Spain | 7 Participants | 3 Participants | 2 Participants | 2 Participants | 14 Participants |
| Region of Enrollment United States | 95 Participants | 99 Participants | 88 Participants | 63 Participants | 345 Participants |
| Sex: Female, Male Female | 83 Participants | 85 Participants | 74 Participants | 50 Participants | 292 Participants |
| Sex: Female, Male Male | 41 Participants | 37 Participants | 49 Participants | 34 Participants | 161 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 / 125 | 1 / 124 | 1 / 123 | 0 / 85 |
| other Total, other adverse events | 101 / 124 | 97 / 122 | 85 / 123 | 60 / 84 |
| serious Total, serious adverse events | 17 / 124 | 13 / 122 | 18 / 123 | 11 / 84 |
Outcome results
Primary
Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off.
Time frame: Week 72
Population: Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + PTM CILO/FIR were analyzed. The Full Analysis Set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEMA + CILO/FIR FDC | Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups | 13.7 percentage of participants |
| PTM SEMA + PTM CILO/FIR | Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups | 8.3 percentage of participants |
p-value: 0.228995% CI: [-3.6, 14.9]Stratified Mantel-Haenszel test
Secondary
Percentage of Participants Who Achieved ≥1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off.
Time frame: Week 72
Population: Participants in the Full Analysis Set in SEMA + CILO/FIR and SEMA + PTM CILO/FIR were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEMA + CILO/FIR FDC | Percentage of Participants Who Achieved ≥1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone | 13.7 percentage of participants |
| PTM SEMA + PTM CILO/FIR | Percentage of Participants Who Achieved ≥1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone | 15.6 percentage of participants |
p-value: 0.695995% CI: [-11.1, 7.4]Stratified Mantel-Haenszel test
Secondary
Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups
NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Worsening in fibrosis was defined as a change in fibrosis worsening stage as per NASH CRN criteria. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off.
Time frame: Week 72
Population: Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + PTM CILO/FIR with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEMA + CILO/FIR FDC | Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups | 57.3 percentage of participants |
| PTM SEMA + PTM CILO/FIR | Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups | 22.4 percentage of participants |
p-value: <0.000195% CI: [18.8, 52.6]Stratified Mantel-Haenszel test
Secondary
Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups
NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. Worsening in fibrosis was defined as a change in fibrosis worsening stage as per NASH CRN criteria. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off.
Time frame: Week 72
Population: Participants in the Full Analysis Set in SEMA + CILO/FIR FDC and PTM SEMA + CILO/FIR FDC with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SEMA + CILO/FIR FDC | Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups | 57.3 percentage of participants |
| PTM SEMA + PTM CILO/FIR | Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups | 31.8 percentage of participants |
p-value: 0.000695% CI: [11.3, 40.9]Stratified Mantel-Haenszel test