NASH - Nonalcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis
Conditions
Keywords
NASH
Brief summary
This is a randomized, double-blinded study of three doses of MSDC-0602K or placebo given orally once daily to subjects with biopsy proven NASH with fibrosis and no cirrhosis.
Detailed description
This is a randomized, double-blinded study of three doses of MSDC-0602K or placebo given orally once daily to subjects with biopsy proven NASH with fibrosis and no cirrhosis. Visits to the clinic will be at baseline, 1, 2, 3, 6, 9, and 12 months, with one 2- week follow-up visit. Safety will be assessed by monitoring of vital signs, 12 lead electrocardiogram (ECG), physical examinations, safety labs, and adverse events (AEs).
Interventions
DRUGMSDC-0602K
MSDC-0602K capsules
DRUGPlacebo
Placebo capsules
Sponsors
Chiltern International Inc.
Cirius Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Selected Inclusion Criteria: * Adult subjects 18 years of age or greater * Histological evidence of NASH, based on biopsy, with a NAS (NASH CRN scoring) ≥ 4 with a score of at least 1 in each component of NAS. * Histological evidence of liver fibrosis defined as NASH CRN System fibrosis score F1 to F3. * Subjects with type 2 diabetes mellitus (DM) must be under stable and reasonable control. * Male and female subjects who are taking Vitamin E should be on a stable dose of Vitamin E (if ≥ 400 IU) for a period of at least 3 months prior to randomization. * Females should be either postmenopausal (at least 12 months since last menses) or surgically sterilized (bilateral tubal ligation or hysterectomy). Males with female partners of child-bearing potential must agree to use adequate contraceptive methods (including a condom, plus one other form of contraception) if engaging in sexual intercourse. * Willing and able to sign an informed consent document indicating understanding the purpose of and procedures required for the study and willingness to participate in the study. Selected
Exclusion criteria
* Known history of HIV. * Prior liver transplantation. * Other well-documented causes of active chronic liver disease. * History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding. * History of alcohol abuse or drug abuse within 6 months of Screening. * Type 1 diabetes mellitus. * Current or history of recent (≤ 6 months) use of ursodeoxycholic acid. * Use of concomitant medications with a known significant metabolism by CYP2C8 or CPY2C9. * History of diabetic ketoacidosis or hyperosmolar non-ketotic coma within 6 months prior to randomization. * History of heart failure (including CHF) or previous cardiovascular event (myocardial infarct, by-pass surgery, or PTCA) within the past 6 months prior to randomization. * Blood pressure greater than 160/100 mmHg. * Participation in an investigational study or received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to study drug administration. * Malignancy, including leukemia and lymphoma (excluding basal cell and squamous skin cell cancers and localized prostrate cancer) treated within the last 2 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Hepatic Histological Improvement in NAS | 12 months (360 days) | * A decrease of at least 2 points in NAS at 12 months. * At least a 1 point reduction in either ballooning or inflammation from baseline to 12 months. * no increase in CRN fibrosis score (i.e., an increase of 1 stage or more) from baseline to 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months. | 12 months (360 days) | * Decrease in fibrosis CRN staging score of \>= 1 full stage from baseline to 12 months * No increase in ballooning CRN score from baseline to 12 months * No increase in inflammation CRN score from baseline to 12-months |
| Mean Change From Baseline in NAFLD Activity Score (NAS) | 12 months (360 days) | NAS is the sum of the scores of steatosis, inflammation, and ballooning. It has a range of 0 to 8 with higher scores indicating worse disease severity. |
| Mean Change From Baseline in CRN Steatosis Score | 12 months (360 days) | Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis. |
| Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months. | 12 months (360 days) | * CRN ballooning score of 0 at 12-months * CRN inflammation score of 0 or 1 at 12-months * No increase in CRN fibrosis score from baseline to 12-months |
| Mean Change From Baseline in CRN Ballooning Score | 12 months (360 days) | Hepatocellular ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe hepatocellular ballooning. |
| Mean Change From Baseline in CRN Fibrosis Staging Score | 12 months (360 days) | Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis. |
| Mean Change From Baseline in CRN Inflammation Score | 12 months (360 days) | Inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe inflammation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo capsule taken once daily for 360 days
Placebo: Placebo capsules | 94 |
| MSDC-0602K 62.5 mg MSDC-0602K 62.5 mg taken once daily for 360 days
MSDC-0602K: MSDC-0602K capsules | 99 |
| MSDC-0602K 125 mg MSDC-0602K 125 mg taken once daily for 360 days
MSDC-0602K: MSDC-0602K capsules | 98 |
| MSDC-0602K 250 mg MSDC-0602K 250 mg taken once daily for 360 days
MSDC-0602K: MSDC-0602K capsules | 101 |
| Total | 392 |
Baseline characteristics
| Characteristic | Placebo | MSDC-0602K 62.5 mg | MSDC-0602K 125 mg | MSDC-0602K 250 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.6 years STANDARD_DEVIATION 11.2 | 56.9 years STANDARD_DEVIATION 10.3 | 56.0 years STANDARD_DEVIATION 10.9 | 56.8 years STANDARD_DEVIATION 10.4 | 56.1 years STANDARD_DEVIATION 10.64 |
| Age, Customized Age at Enrollment < 55 years | 43 Participants | 35 Participants | 42 Participants | 37 Participants | 157 Participants |
| Age, Customized Age at Enrollment >= 55 years | 51 Participants | 64 Participants | 56 Participants | 64 Participants | 235 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 32 Participants | 29 Participants | 33 Participants | 119 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 67 Participants | 69 Participants | 68 Participants | 273 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian Or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Black Or African American | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 14 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian Or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 85 Participants | 93 Participants | 91 Participants | 91 Participants | 360 Participants |
| Sex: Female, Male Female | 51 Participants | 56 Participants | 63 Participants | 58 Participants | 228 Participants |
| Sex: Female, Male Male | 43 Participants | 43 Participants | 35 Participants | 43 Participants | 164 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 | 1 / 94 | 0 / 99 | 1 / 98 | 0 / 101 |
| other Total, other adverse events | 75 / 94 | 78 / 99 | 76 / 98 | 77 / 101 |
| serious Total, serious adverse events | 9 / 94 | 5 / 99 | 13 / 98 | 7 / 101 |
Outcome results
Primary
Number of Participants With Hepatic Histological Improvement in NAS
* A decrease of at least 2 points in NAS at 12 months. * At least a 1 point reduction in either ballooning or inflammation from baseline to 12 months. * no increase in CRN fibrosis score (i.e., an increase of 1 stage or more) from baseline to 12 months.
Time frame: 12 months (360 days)
Population: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Hepatic Histological Improvement in NAS | 22 Participants |
| MSDC-0602K 62.5 mg | Number of Participants With Hepatic Histological Improvement in NAS | 25 Participants |
| MSDC-0602K 125 mg | Number of Participants With Hepatic Histological Improvement in NAS | 27 Participants |
| MSDC-0602K 250 mg | Number of Participants With Hepatic Histological Improvement in NAS | 34 Participants |
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.74795% CI: [0.44, 1.81]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.57595% CI: [0.6, 2.48]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.15895% CI: [0.83, 3.27]Regression, Logistic
Secondary
Mean Change From Baseline in CRN Ballooning Score
Hepatocellular ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe hepatocellular ballooning.
Time frame: 12 months (360 days)
Population: Analysis Population Description: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in CRN Ballooning Score | -0.2 Scores on a scale | Standard Deviation 0.98 |
| MSDC-0602K 62.5 mg | Mean Change From Baseline in CRN Ballooning Score | -0.4 Scores on a scale | Standard Deviation 0.94 |
| MSDC-0602K 125 mg | Mean Change From Baseline in CRN Ballooning Score | -0.4 Scores on a scale | Standard Deviation 0.94 |
| MSDC-0602K 250 mg | Mean Change From Baseline in CRN Ballooning Score | -0.4 Scores on a scale | Standard Deviation 0.91 |
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.41695% CI: [-0.4, 0.2]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.05695% CI: [-0.5, 0]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.2295% CI: [-0.4, 0.1]ANCOVA
Secondary
Mean Change From Baseline in CRN Fibrosis Staging Score
Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis.
Time frame: 12 months (360 days)
Population: Analysis Population Description: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in CRN Fibrosis Staging Score | 0.0 Scores on a scale | Standard Deviation 1.1 |
| MSDC-0602K 62.5 mg | Mean Change From Baseline in CRN Fibrosis Staging Score | 0.1 Scores on a scale | Standard Deviation 1.07 |
| MSDC-0602K 125 mg | Mean Change From Baseline in CRN Fibrosis Staging Score | -0.1 Scores on a scale | Standard Deviation 1.16 |
| MSDC-0602K 250 mg | Mean Change From Baseline in CRN Fibrosis Staging Score | -0.1 Scores on a scale | Standard Deviation 1.27 |
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.92895% CI: [-0.3, 0.3]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.24495% CI: [-0.5, 0.1]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.22895% CI: [-0.5, 0.1]ANCOVA
Secondary
Mean Change From Baseline in CRN Inflammation Score
Inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe inflammation.
Time frame: 12 months (360 days)
Population: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in CRN Inflammation Score | -0.1 Scores on a scale | Standard Deviation 0.7 |
| MSDC-0602K 62.5 mg | Mean Change From Baseline in CRN Inflammation Score | -0.1 Scores on a scale | Standard Deviation 0.71 |
| MSDC-0602K 125 mg | Mean Change From Baseline in CRN Inflammation Score | -0.2 Scores on a scale | Standard Deviation 0.56 |
| MSDC-0602K 250 mg | Mean Change From Baseline in CRN Inflammation Score | -0.1 Scores on a scale | Standard Deviation 0.66 |
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.48895% CI: [-0.1, 0.2]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.29195% CI: [-0.3, 0.1]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.59595% CI: [-0.2, 0.1]ANCOVA
Secondary
Mean Change From Baseline in CRN Steatosis Score
Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis.
Time frame: 12 months (360 days)
Population: Analysis Population Description: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in CRN Steatosis Score | -0.4 Scores on a scale | Standard Deviation 0.8 |
| MSDC-0602K 62.5 mg | Mean Change From Baseline in CRN Steatosis Score | -0.6 Scores on a scale | Standard Deviation 0.88 |
| MSDC-0602K 125 mg | Mean Change From Baseline in CRN Steatosis Score | -0.5 Scores on a scale | Standard Deviation 0.93 |
| MSDC-0602K 250 mg | Mean Change From Baseline in CRN Steatosis Score | -0.7 Scores on a scale | Standard Deviation 0.94 |
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.22495% CI: [-0.4, 0.1]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.09695% CI: [-0.4, 0]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.00795% CI: [-0.6, -0.1]ANCOVA
Secondary
Mean Change From Baseline in NAFLD Activity Score (NAS)
NAS is the sum of the scores of steatosis, inflammation, and ballooning. It has a range of 0 to 8 with higher scores indicating worse disease severity.
Time frame: 12 months (360 days)
Population: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in NAFLD Activity Score (NAS) | -0.6 Scores on a scale | Standard Deviation 1.8 |
| MSDC-0602K 62.5 mg | Mean Change From Baseline in NAFLD Activity Score (NAS) | -1.0 Scores on a scale | Standard Deviation 1.66 |
| MSDC-0602K 125 mg | Mean Change From Baseline in NAFLD Activity Score (NAS) | -1.1 Scores on a scale | Standard Deviation 1.74 |
| MSDC-0602K 250 mg | Mean Change From Baseline in NAFLD Activity Score (NAS) | -1.2 Scores on a scale | Standard Deviation 1.83 |
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.39295% CI: [-0.7, 0.3]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.02395% CI: [-1.1, -0.1]ANCOVA
Comparison: The null hypothesis is that there is no difference in changes between the MSDC-0602K dose and placebo.p-value: 0.02895% CI: [-1, -0.1]ANCOVA
Secondary
Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months.
* Decrease in fibrosis CRN staging score of \>= 1 full stage from baseline to 12 months * No increase in ballooning CRN score from baseline to 12 months * No increase in inflammation CRN score from baseline to 12-months
Time frame: 12 months (360 days)
Population: Analysis Population Description: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months. | 16 Participants |
| MSDC-0602K 62.5 mg | Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months. | 20 Participants |
| MSDC-0602K 125 mg | Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months. | 23 Participants |
| MSDC-0602K 250 mg | Number of Subjects With Improvement of Fibrosis (CRN Staging Score) by at Least 1 Stage With no Worsening of NASH at 12 Months. | 25 Participants |
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.65795% CI: [0.55, 2.55]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.33295% CI: [0.69, 3.06]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.2795% CI: [0.72, 3.16]Regression, Logistic
Secondary
Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months.
* CRN ballooning score of 0 at 12-months * CRN inflammation score of 0 or 1 at 12-months * No increase in CRN fibrosis score from baseline to 12-months
Time frame: 12 months (360 days)
Population: Analysis Population Description: Subjects in the Modified Intent-to-Treat Set with available baseline biopsy and 12-month biopsy taken within 14 days of study drug discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months. | 15 Participants |
| MSDC-0602K 62.5 mg | Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months. | 17 Participants |
| MSDC-0602K 125 mg | Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months. | 23 Participants |
| MSDC-0602K 250 mg | Number of Subjects With Resolution of NASH With no Worsening of Fibrosis at 12 Months. | 27 Participants |
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.82895% CI: [0.49, 2.42]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.29995% CI: [0.7, 3.21]Regression, Logistic
Comparison: The null hypothesis is that there is no difference in response rates between the MSDC-0602K dose and placebo.p-value: 0.11695% CI: [0.86, 3.82]Regression, Logistic