Nonalcoholic Steatohepatitis (NASH)
Conditions
Keywords
Nonalcoholic Steatohepatitis, NASH, Nonalcoholic Fatty Liver Disease
Brief summary
This phase 2, double blind, placebo-controlled, randomized study is to assess the safety and efficacy of miricorilant (CORT118335) in patients with presumed Nonalcoholic Steatohepatitis (NASH).
Detailed description
This is a randomized, double-blind, placebo-controlled study that assessed the safety efficacy and pharmacokinetics (PK) of miricorilant in patients with presumed Nonalcoholic Steatohepatitis (NASH). Patients who meet the criteria for Study CORT118335-860 were randomized on Day 1 to receive 900 mg miricorilant, 600 mg miricorilant, or placebo for 12 weeks. Due to observations related to safety, the study was terminated prior to completion and study objectives, endpoints, and procedures were modified as specified in the protocol.
Interventions
DRUGMiricorilant
Tablets taken orally
DRUGPlacebo
Placebo tablets
Sponsors
Corcept Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of NASH based on a biopsy obtained within the last year OR * Have a diagnosis of presumed NASH based on blood tests and scans
Exclusion criteria
* Have participated in another clinical trial within the last year and received active treatment for NASH * Have participated in another clinical trial for any other indication within the last 3 months * Are pregnant or lactating women * Have a BMI \<18 kg/m\^2 * Have had liver transplantation or plan to have liver transplantation during the study * Have type 1 diabetes or poorly controlled type 2 diabetes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Liver Fat Content Assessed by Magnetic Resonance Imaging-Proton Density Fat Fraction | Baseline and up to ~Day 95 | The change from baseline in liver fat content (LFC) by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) for each miricorilant dose level (600 mg, 900 mg) versus placebo was assessed. MRI-PDFF was performed to determine the degree of LFC reduction. The relative change is defined for each participant as %: (\[Post-Baseline LFC-Baseline LFC\]/Baseline LFC) × 100. Due to observations related to safety, the study was terminated. If the participant had at least 6 weeks of treatment, the assessment was completed at the early termination visit. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Baseline and up to ~Day 95 | The number of participants (defined as responders) with a ≥30% reduction in LFC from baseline by treatment group as assessed by MRI-PDFF. The number of participants with a reduction in LFC from baseline of \<30% were defined as non-responders. MRI-PDFF was performed at screening and up to 33 days after last dose of study drug. Due to observations related to safety, the study was terminated. If the participant had at least 6 weeks of treatment, the assessment was completed at the early termination visit. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
| Change From Baseline in Aspartate Aminotransferase | Baseline and Week 6 | The change in aspartate aminotransferase (AST) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
| Change From Baseline in Alanine Aminotransferase | Baseline and Week 6 | The change in serum alanine aminotransferase (ALT) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
| Change From Baseline in Propeptide of Type III Collagen | Baseline and Week 6 | The change in serum propeptide of Type III collagen (pro-C3) from baseline at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
| Change From Baseline in Enhanced Liver Fibrosis Score | Baseline and Week 6 | The change in enhanced liver fibrosis (ELF) from baseline for each treatment group at the Week 6 visit is summarized. The ELF score combines 3 serum biomarkers (hyaluronic acid, tissue inhibitor of metalloproteinases-1 \[TIMP-1\] and type III procollagen \[PIIINP\]) which have been shown to correlate with the degree of liver fibrosis assessed by liver biopsy. Each of these markers is measured by an immunoassay and an ELF score is generated \[ELF=2.278+0.851 ln(HA)+0.751 ln(PIIINP)+0.394 ln(TIMP-1)\], from which a level of fibrosis severity can be determined; higher ELF scores are associated with worsening liver fibrosis. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
| Change From Baseline in Gamma-glutamyl Transferase | Baseline and Week 6 | The change in gamma-glutamyl transferase (GGT) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups. |
Other
| Measure | Time frame |
|---|---|
| Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Baseline and up to ~Day 95 |
| Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Baseline and up to ~Day 95 |
Countries
United States
Participant flow
Pre-assignment details
Twelve adult patients with presumed NASH were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Miricorilant- 900 mg Participants received 900 mg miricorilant (6 miricorilant tablets of 150 mg) orally once daily. | 3 |
| Miricorilant- 600 mg Participants received 600 mg miricorilant (4 miricorilant tablets of 150 mg and 2 placebo tablets) orally once daily. | 5 |
| Placebo Participants received 6 placebo tablets orally once daily. | 4 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 0 |
| Overall Study | Sponsor request | 0 | 3 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Miricorilant- 600 mg | Miricorilant- 900 mg |
|---|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 16.68 | 43.3 years STANDARD_DEVIATION 15.15 | 54.2 years STANDARD_DEVIATION 19.87 | 55.7 years STANDARD_DEVIATION 14.74 |
| Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) & Gamma Glutamyl Transferase (GGT) ALT | 44.9 Units/Liter (U/L) STANDARD_DEVIATION 16.86 | 54.0 Units/Liter (U/L) STANDARD_DEVIATION 12.11 | 33.2 Units/Liter (U/L) STANDARD_DEVIATION 15.94 | 52.3 Units/Liter (U/L) STANDARD_DEVIATION 15.63 |
| Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) & Gamma Glutamyl Transferase (GGT) AST | 29.9 Units/Liter (U/L) STANDARD_DEVIATION 9.68 | 31 Units/Liter (U/L) STANDARD_DEVIATION 4.08 | 25.6 Units/Liter (U/L) STANDARD_DEVIATION 12.76 | 35.7 Units/Liter (U/L) STANDARD_DEVIATION 8.14 |
| Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) & Gamma Glutamyl Transferase (GGT) GGT | 43.8 Units/Liter (U/L) STANDARD_DEVIATION 32.2 | 59.0 Units/Liter (U/L) STANDARD_DEVIATION 50.29 | 26.2 Units/Liter (U/L) STANDARD_DEVIATION 9.2 | 52.7 Units/Liter (U/L) STANDARD_DEVIATION 19.63 |
| Enhanced Liver Fibrosis Score | 9.438 ELF score STANDARD_DEVIATION 0.69 | 9.330 ELF score STANDARD_DEVIATION 0.805 | 9.358 ELF score STANDARD_DEVIATION 0.486 | 9.713 ELF score STANDARD_DEVIATION 1.011 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 4 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Liver Fat Content (LFC) Assessed by MRI-PDFF | 19.33 Percentage of liver fat content STANDARD_DEVIATION 7.526 | 19.93 Percentage of liver fat content STANDARD_DEVIATION 8.75 | 15.70 Percentage of liver fat content STANDARD_DEVIATION 6.536 | 24.57 Percentage of liver fat content STANDARD_DEVIATION 6.038 |
| Propeptide of Type III Collagen (Pro-C3) | 13.28 micrograms/liter (μg/L) STANDARD_DEVIATION 4.159 | 13.73 micrograms/liter (μg/L) STANDARD_DEVIATION 4.727 | 11.20 micrograms/liter (μg/L) STANDARD_DEVIATION 2.189 | 16.13 micrograms/liter (μg/L) STANDARD_DEVIATION 5.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 3 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 12 participants | 4 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 1 / 4 |
| serious Total, serious adverse events | 2 / 3 | 0 / 5 | 0 / 4 |
Outcome results
Primary
Relative Change From Baseline in Liver Fat Content Assessed by Magnetic Resonance Imaging-Proton Density Fat Fraction
The change from baseline in liver fat content (LFC) by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) for each miricorilant dose level (600 mg, 900 mg) versus placebo was assessed. MRI-PDFF was performed to determine the degree of LFC reduction. The relative change is defined for each participant as %: (\[Post-Baseline LFC-Baseline LFC\]/Baseline LFC) × 100. Due to observations related to safety, the study was terminated. If the participant had at least 6 weeks of treatment, the assessment was completed at the early termination visit. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and up to ~Day 95
Population: The analysis population included all participants who were randomized to the study and had a post-baseline LFC assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Relative Change From Baseline in Liver Fat Content Assessed by Magnetic Resonance Imaging-Proton Density Fat Fraction | -50.28 Percent change | Standard Deviation 13.723 |
| Miricorilant- 600 mg | Relative Change From Baseline in Liver Fat Content Assessed by Magnetic Resonance Imaging-Proton Density Fat Fraction | -22.94 Percent change | Standard Deviation 71.943 |
| Placebo | Relative Change From Baseline in Liver Fat Content Assessed by Magnetic Resonance Imaging-Proton Density Fat Fraction | 4.63 Percent change | Standard Deviation 5.232 |
Secondary
Change From Baseline in Alanine Aminotransferase
The change in serum alanine aminotransferase (ALT) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and Week 6
Population: The analysis population included all participants who were randomized to the study and had a post-baseline ALT assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Change From Baseline in Alanine Aminotransferase | 810.0 U/L | — |
| Miricorilant- 600 mg | Change From Baseline in Alanine Aminotransferase | 826.0 U/L | — |
| Placebo | Change From Baseline in Alanine Aminotransferase | -16 U/L | Standard Deviation 2.83 |
Secondary
Change From Baseline in Aspartate Aminotransferase
The change in aspartate aminotransferase (AST) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and Week 6
Population: The analysis population included all participants who were randomized to the study and had a post-baseline AST assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Change From Baseline in Aspartate Aminotransferase | 346.0 units per liter (U/L) | — |
| Miricorilant- 600 mg | Change From Baseline in Aspartate Aminotransferase | 321.0 units per liter (U/L) | — |
| Placebo | Change From Baseline in Aspartate Aminotransferase | -9.5 units per liter (U/L) | Standard Deviation 3.54 |
Secondary
Change From Baseline in Enhanced Liver Fibrosis Score
The change in enhanced liver fibrosis (ELF) from baseline for each treatment group at the Week 6 visit is summarized. The ELF score combines 3 serum biomarkers (hyaluronic acid, tissue inhibitor of metalloproteinases-1 \[TIMP-1\] and type III procollagen \[PIIINP\]) which have been shown to correlate with the degree of liver fibrosis assessed by liver biopsy. Each of these markers is measured by an immunoassay and an ELF score is generated \[ELF=2.278+0.851 ln(HA)+0.751 ln(PIIINP)+0.394 ln(TIMP-1)\], from which a level of fibrosis severity can be determined; higher ELF scores are associated with worsening liver fibrosis. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and Week 6
Population: The analysis population included all participants who were randomized to the study and had a post-baseline liver fibrosis assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Change From Baseline in Enhanced Liver Fibrosis Score | 1.050 ELF score | — |
| Placebo | Change From Baseline in Enhanced Liver Fibrosis Score | 0.225 ELF score | Standard Deviation 0.459 |
Secondary
Change From Baseline in Gamma-glutamyl Transferase
The change in gamma-glutamyl transferase (GGT) from baseline for each treatment group at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and Week 6
Population: The analysis population included all participants who were randomized to the study and had a post-baseline GGT assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Change From Baseline in Gamma-glutamyl Transferase | 29.0 U/L | — |
| Miricorilant- 600 mg | Change From Baseline in Gamma-glutamyl Transferase | 82.0 U/L | — |
| Placebo | Change From Baseline in Gamma-glutamyl Transferase | -26.0 U/L | Standard Deviation 31.11 |
Secondary
Change From Baseline in Propeptide of Type III Collagen
The change in serum propeptide of Type III collagen (pro-C3) from baseline at the Week 6 visit is summarized. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and Week 6
Population: The analysis population included all participants who were randomized to the study and had a post-baseline pro-C3 assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miricorilant- 900 mg | Change From Baseline in Propeptide of Type III Collagen | 4.0 μg/L | — |
| Placebo | Change From Baseline in Propeptide of Type III Collagen | -1.65 μg/L | Standard Deviation 2.475 |
Secondary
Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF
The number of participants (defined as responders) with a ≥30% reduction in LFC from baseline by treatment group as assessed by MRI-PDFF. The number of participants with a reduction in LFC from baseline of \<30% were defined as non-responders. MRI-PDFF was performed at screening and up to 33 days after last dose of study drug. Due to observations related to safety, the study was terminated. If the participant had at least 6 weeks of treatment, the assessment was completed at the early termination visit. Due to the small sample size, no formal tests were performed to assess statistical differences between treatment groups.
Time frame: Baseline and up to ~Day 95
Population: The analysis population included all participants who were randomized to the study and had a post-baseline LFC assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Miricorilant- 900 mg | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Responders with a reduction in LFC from baseline of ≥30% | 3 Participants |
| Miricorilant- 900 mg | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Non-responders with a reduction in LFC from baseline of <30% | 0 Participants |
| Miricorilant- 600 mg | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Responders with a reduction in LFC from baseline of ≥30% | 1 Participants |
| Miricorilant- 600 mg | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Non-responders with a reduction in LFC from baseline of <30% | 1 Participants |
| Placebo | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Responders with a reduction in LFC from baseline of ≥30% | 0 Participants |
| Placebo | Number of Participants Achieving a Relative Reduction From Baseline in LFC of ≥30% by MRI-PDFF | Non-responders with a reduction in LFC from baseline of <30% | 2 Participants |
Other Pre-specified
Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo
Time frame: Baseline and up to ~Day 95
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Miricorilant- 900 mg | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Responders | 1 Participants |
| Miricorilant- 900 mg | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Non-Responders | 2 Participants |
| Miricorilant- 600 mg | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Responders | 1 Participants |
| Miricorilant- 600 mg | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Non-Responders | 1 Participants |
| Placebo | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Responders | 0 Participants |
| Placebo | Number of Participants With a Relative Reduction in Liver Fat Content ≥50% by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) for Miricorilant Versus Placebo | Non-Responders | 2 Participants |
Other Pre-specified
Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo
Time frame: Baseline and up to ~Day 95
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Miricorilant- 900 mg | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Responders | 0 Participants |
| Miricorilant- 900 mg | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Non-Responders | 3 Participants |
| Miricorilant- 600 mg | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Responders | 1 Participants |
| Miricorilant- 600 mg | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Non-Responders | 1 Participants |
| Placebo | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Responders | 0 Participants |
| Placebo | Number of Participants With Complete Resolution in Liver Fat by MRI-PDFF for Miricorilant Versus Placebo | Non-Responders | 2 Participants |