NASH - Nonalcoholic Steatohepatitis
Conditions
Keywords
Nonalcoholic steatohepatitis (NASH), FXR agonist, Nonalcoholic Fatty Liver Disease (NAFLD), THR-β agonist
Brief summary
This is a Phase 2a Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as well as in Combination with TERN-101 in Noncirrhotic Adults with Presumed Non-Alcoholic Steatohepatitis (NASH)
Interventions
Sponsors
Terns, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female, 18 to 75 years of age * Overweight or obese with a body mass index (BMI) ≥ 25 kg/m2 * Presumed NASH diagnosed by prior biopsy and/or imaging criteria * Written informed consent Key
Exclusion criteria
* History or clinical evidence of chronic liver diseases other than NAFLD * History or known clinical evidence of cirrhosis, esophageal varices, hepatic decompensation or other severe liver impairment, * History of liver transplant, or current placement on a liver transplant list * Current diagnosis or history of pituitary or thyroid disorders - except for patients with primary hypothyroidism on a stable dose of thyroid hormone replacement therapy. * Abnormal TSH or free T4 levels * Weight loss of \> 5% total body weight within 3 months prior to Screening * Uncontrolled diabetes * Uncontrolled hyperlipidemia * Unstable cardiovascular disease * Excessive alcohol consumption Other protocol-defined I/E criteria that apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo. | 12 weeks | Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) is a non-invasive imaging technique that measures fat content in tissue, particularly in the liver. Relative change from baseline is calculated for each subject as 100 x \[(Week 12 Value - Baseline Value)/Baseline Value\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo | 12 weeks | Corrected T1 (cT1) is a quantitative MRI relaxation parameter that measures liver inflammation and fibrosis. Change from baseline is calculated for each subject as (Week 12 Value - Baseline Value). |
| Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | 12 weeks | Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) is a non-invasive imaging technique that measures fat content in tissue, particularly in the liver. Relative change from baseline is calculated for each subject as 100 x \[(Week 12 Value - Baseline Value)/Baseline Value\]. |
| Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | 12 weeks | Corrected T1 (cT1) is a quantitative MRI relaxation parameter that measures liver inflammation and fibrosis. Change from baseline is calculated for each subject as (Week 12 Value - Baseline Value). |
| Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 16 weeks | This outcome measures the number and percentage of participants with any Treatment Emergent Adverse Event (TEAE) for All Treatment Groups (0% Threshold). TEAEs by System Organ Class and Preferred Term meeting the 5% Threshold are reported in the Other Adverse Events section. |
Countries
United States
Participant flow
Pre-assignment details
A total of 591 patients were screened with 429 patients failing screening.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: TERN-501 1 mg Orally administered.
TERN-501: Investigational drug | 23 |
| Arm 2: TERN-501 3 mg Orally administered.
TERN-501: Investigational drug | 23 |
| Arm 3: TERN-501 6 mg Orally administered.
TERN-501: Investigational drug | 22 |
| Arm 4: TERN-501 3 mg + TERN-101 10 mg Orally administered.
TERN-501: Investigational drug
TERN-101: Investigational drug | 23 |
| Arm 5: TERN-501 6 mg + TERN-101 10 mg Orally administered.
TERN-501: Investigational drug
TERN-101: Investigational drug | 23 |
| Arm 6:TERN-101 10 mg Orally administered.
TERN-101: Investigational drug | 24 |
| Arm 7: Matching Placebo Orally administered.
Placebo: Matching placebo | 24 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Sponsor Discretion | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: TERN-501 1 mg | Arm 2: TERN-501 3 mg | Arm 3: TERN-501 6 mg | Arm 4: TERN-501 3 mg + TERN-101 10 mg | Arm 5: TERN-501 6 mg + TERN-101 10 mg | Arm 6:TERN-101 10 mg | Arm 7: Matching Placebo | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 3 Participants | 7 Participants | 3 Participants | 4 Participants | 3 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 18 Participants | 19 Participants | 16 Participants | 20 Participants | 20 Participants | 21 Participants | 132 Participants |
| Age, Continuous | 56.0 years | 55.0 years | 53.0 years | 59.0 years | 56.0 years | 56.5 years | 53.5 years | 55.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 13 Participants | 15 Participants | 11 Participants | 14 Participants | 10 Participants | 19 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 10 Participants | 7 Participants | 12 Participants | 9 Participants | 14 Participants | 5 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 12 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other (Puerto Rican) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 22 Participants | 18 Participants | 20 Participants | 18 Participants | 19 Participants | 22 Participants | 139 Participants |
| Sex: Female, Male Female | 11 Participants | 13 Participants | 16 Participants | 11 Participants | 11 Participants | 12 Participants | 15 Participants | 89 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 6 Participants | 12 Participants | 12 Participants | 12 Participants | 9 Participants | 73 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 | 0 / 22 | 0 / 23 | 0 / 23 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 2 / 23 | 8 / 23 | 5 / 22 | 10 / 23 | 6 / 23 | 5 / 24 | 5 / 24 |
| serious Total, serious adverse events | 1 / 23 | 0 / 23 | 0 / 22 | 0 / 23 | 0 / 23 | 2 / 24 | 0 / 24 |
Outcome results
Primary
Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo.
Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) is a non-invasive imaging technique that measures fat content in tissue, particularly in the liver. Relative change from baseline is calculated for each subject as 100 x \[(Week 12 Value - Baseline Value)/Baseline Value\].
Time frame: 12 weeks
Population: Efficacy Analysis Set: All patients who were randomized and received at least 1 dose of the study. Primary analyses were based on observed data, i.e. no imputation was performed for missing data at Week 12. Therefore, the number of patients analyzed at Week 12 may not be the same as the number of patients treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: TERN-501 1 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo. | -15.39 Percent change from baseline | Standard Error 5.186 |
| Arm 2: TERN-501 3 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo. | -27.48 Percent change from baseline | Standard Error 5.74 |
| Arm 3: TERN-501 6 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo. | -44.81 Percent change from baseline | Standard Error 5.856 |
| Arm 7: Matching Placebo | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo. | -4.01 Percent change from baseline | Standard Error 5.416 |
Comparison: Arm 1 compared to Placebop-value: 0.130395% CI: [-26.178, 3.406]ANCOVA
Comparison: Arm 2 compared to Placebop-value: 0.003695% CI: [-39.14, -7.799]ANCOVA
Comparison: Arm 3 compared to Placebop-value: <0.000195% CI: [-56.545, -25.064]ANCOVA
Secondary
Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo
Corrected T1 (cT1) is a quantitative MRI relaxation parameter that measures liver inflammation and fibrosis. Change from baseline is calculated for each subject as (Week 12 Value - Baseline Value).
Time frame: 12 weeks
Population: Efficacy Analysis Set: All randomized patients who received at least 1 dose of study drug. Primary analyses were based on observed data, i.e. no imputation was performed for missing data at Week 12. Therefore, the number of patients analyzed at Week 12 may not be the same as the number of patients treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: TERN-501 1 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo | -28.2 msec | Standard Error 14.62 |
| Arm 2: TERN-501 3 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo | -25.6 msec | Standard Error 15.71 |
| Arm 3: TERN-501 6 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo | -72.0 msec | Standard Error 16.12 |
| Arm 7: Matching Placebo | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501 Monotherapy (Arms 1, 2 and 3) Compared to Placebo | 3.6 msec | Standard Error 14.92 |
Comparison: Arm 1 compared to Placebop-value: 0.128995% CI: [-73.17, 9.39]ANCOVA
Comparison: Arm 2 compared to Placebop-value: 0.17995% CI: [-72.08, 13.58]ANCOVA
Comparison: Arm 3 compared to Placebop-value: 0.000895% CI: [-119.08, -32.23]ANCOVA
Secondary
Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo
Corrected T1 (cT1) is a quantitative MRI relaxation parameter that measures liver inflammation and fibrosis. Change from baseline is calculated for each subject as (Week 12 Value - Baseline Value).
Time frame: 12 weeks
Population: Efficacy Analysis Set: All randomized patients who received at least 1 dose of study drug. Primary analyses were based on observed data, i.e. no imputation was performed for missing data at Week 12. Therefore, the number of patients analyzed at Week 12 may not be the same as the number of patients treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: TERN-501 1 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | -59.0 msec | Standard Error 16.25 |
| Arm 2: TERN-501 3 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | -65.5 msec | Standard Error 14.99 |
| Arm 3: TERN-501 6 mg | Change From Baseline in cT1 Relaxation Time at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | 3.6 msec | Standard Error 14.92 |
Comparison: Arm 4 compared to Placebop-value: 0.005395% CI: [-106.33, -18.96]ANCOVA
Comparison: Arm 5 compared to Placebop-value: 0.001495% CI: [-110.97, -27.39]ANCOVA
Secondary
Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%)
This outcome measures the number and percentage of participants with any Treatment Emergent Adverse Event (TEAE) for All Treatment Groups (0% Threshold). TEAEs by System Organ Class and Preferred Term meeting the 5% Threshold are reported in the Other Adverse Events section.
Time frame: 16 weeks
Population: All 162 patients who were randomized and received at least 1 dose of study drug were included in the Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: TERN-501 1 mg | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 11 Participants |
| Arm 2: TERN-501 3 mg | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 13 Participants |
| Arm 3: TERN-501 6 mg | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 11 Participants |
| Arm 7: Matching Placebo | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 14 Participants |
| Arm 5: TERN-501 6 mg + TERN-101 10 mg | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 12 Participants |
| Arm 6:TERN-101 10 mg | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 10 Participants |
| Arm 7: Matching Placebo | Number and Percentage of Participants With Any Treatment Emergent Adverse Event for All Treatment Groups (Threshold of 0%) | 11 Participants |
Secondary
Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo
Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) is a non-invasive imaging technique that measures fat content in tissue, particularly in the liver. Relative change from baseline is calculated for each subject as 100 x \[(Week 12 Value - Baseline Value)/Baseline Value\].
Time frame: 12 weeks
Population: Efficacy Analysis Set: All randomized patients who received at least 1 dose of study drug. Primary analyses were based on observed data, i.e. no imputation was performed for missing data at Week 12. Therefore, the number of patients analyzed at Week 12 may not be the same as the number of patients treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: TERN-501 1 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | -20.75 Percent change from baseline | Standard Error 5.713 |
| Arm 2: TERN-501 3 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | -47.74 Percent change from baseline | Standard Error 5.412 |
| Arm 3: TERN-501 6 mg | Relative Change From Baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 Combination (Arms 4 and 5) Compared to Placebo | -4.01 Percent change from baseline | Standard Error 5.416 |
Comparison: Arm 4 compared to Placebop-value: 0.035895% CI: [-32.352, -1.128]ANCOVA
Comparison: Arm 5 compared to Placebop-value: <0.000195% CI: [-58.858, -28.612]ANCOVA