Non-Cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Conditions
Keywords
NASH, Non-Cirrhotic, Steatohepatitis
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Participants will be in the trial for up to 24 weeks, including a screening period lasting up to 8 weeks, a 12-week treatment period, and a 4-week safety follow-up period Participants are not expected to directly benefit from treatment during this trial. Participants will help researchers learn more about and how to develop AZD4831 to treat NASH.
Detailed description
A randomized, double blind, placebo-controlled, parallel-group, multicenter study including a maximum of approximately 90 randomized adult participants with biopsy-proven non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis (NAS ≥ 4, fibrosis stages F1, F2, F3). The study will be conducted at approximately 48 sites across approximately 9 countries. During screening, the participants will be checked for eligibility and enrolled in the study. Following a 8-week screening period, approximately 90 participants will be randomized in a 1:1 ratio to once daily dosing of AZD4831 or placebo. All participants will be treated once daily with AZD4831 or placebo for 12 weeks. The safety, tolerability, and pharmacodynamics will be evaluated at 12 weeks. This is the first clinical study to test AZD4831 in participants with non-cirrhotic NASH with fibrosis.
Interventions
DRUGAZD4831
AZD4831
OTHERPlacebo
Placebo
Sponsors
AstraZeneca
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
1. Participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent. 2. Histological confirmed NASH per Clinical Research Network (CRN) criteria as diagnosed by liver biopsy (within 12 months prior screening, participants without historical biopsy should be willing to undergo a liver biopsy at screening) fulfilling all of the following criteria: * NAS ≥ 4 with a score of ≥ 1 for each component: steatosis, lobular inflammation and ballooning * Presence of fibrosis F1, F2-F3 3. One increased serum ALT measurement (ALT \> ULN) at screening, and historical local serum ALT level (\> ULN \[41 U/L for men and 31 U/L for women\] but \< 300 U/L) on ≥ 1 occasion in the 6 months prior to screening.
Exclusion criteria
1. Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; hemochromatosis; alpha 1 antitrypsin deficiency; Wilson's disease). 2. History of excessive alcohol consumption, defined as an average weekly intake of \> 21 drinks/week for males or \> 14 drinks/week for females. One drink is equivalent to 14 g alcohol. 3. Recent (within 3 months of randomization) use of drugs approved for weight loss (eg, orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those drugs used off-label. 4. High dose vitamin E (\> 400 IU) unless on a stable dose within 6 months of screening. 5. Recent (within 6 months of screening) use of therapies associated with development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines). 6. Recent (within 6 months of screening) use of obeticholic acid or other therapy under investigation for NASH.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative to Baseline Alanine Aminotransferase (ALT) | Measurements on Baseline, Week 2, Week 4, Week 8, Week 12 and Week 16. Change reported from Baseline to Week 12. | ALT at 12 weeks relative to baseline. ALT is measured in Units per litre (U/L) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative to Baseline Pro-C3 | Measurements on Baseline, Week 4 and Week 12 | Pro-C3 at 12 weeks relative to baseline. Pro-C3 is measured in nanograms per milliliter (ng/mL). |
Countries
Argentina, Denmark, Italy, Mexico, Norway, Portugal, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Once-daily dosing of 5mg mitiperstat for 12 weeks | 56 |
| Placebo Once-daily dosing of Placebo for 12 weeks | 56 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 4 | 7 |
Baseline characteristics
| Characteristic | Placebo | Total | Treatment |
|---|---|---|---|
| Age, Continuous | 53.7 Years STANDARD_DEVIATION 9.7 | 52.8 Years STANDARD_DEVIATION 11.5 | 52 Years STANDARD_DEVIATION 13.1 |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized ASIAN | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized HISPANIC OR LATINO | 29 Participants | 58 Participants | 29 Participants |
| Race/Ethnicity, Customized MULTIPLE | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized NOT HISPANIC OR LATINO | 27 Participants | 54 Participants | 27 Participants |
| Race/Ethnicity, Customized NOT REPORTED | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized OTHER | 4 Participants | 10 Participants | 6 Participants |
| Race/Ethnicity, Customized WHITE | 50 Participants | 96 Participants | 46 Participants |
| Sex: Female, Male Female | 27 Participants | 49 Participants | 22 Participants |
| Sex: Female, Male Male | 29 Participants | 63 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 56 |
| other Total, other adverse events | 33 / 56 | 36 / 56 |
| serious Total, serious adverse events | 0 / 56 | 3 / 56 |
Outcome results
Primary
Relative to Baseline Alanine Aminotransferase (ALT)
ALT at 12 weeks relative to baseline. ALT is measured in Units per litre (U/L)
Time frame: Measurements on Baseline, Week 2, Week 4, Week 8, Week 12 and Week 16. Change reported from Baseline to Week 12.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mitiperstat (5mg) | Relative to Baseline Alanine Aminotransferase (ALT) | 0.959 Ratio |
| Placebo | Relative to Baseline Alanine Aminotransferase (ALT) | 0.895 Ratio |
p-value: 0.89395% CI: [-4.1, 20.5]Mixed Models Analysis
Secondary
Relative to Baseline Pro-C3
Pro-C3 at 12 weeks relative to baseline. Pro-C3 is measured in nanograms per milliliter (ng/mL).
Time frame: Measurements on Baseline, Week 4 and Week 12
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mitiperstat (5mg) | Relative to Baseline Pro-C3 | 1.009 Ratio |
| Placebo | Relative to Baseline Pro-C3 | 1.018 Ratio |
p-value: 0.39695% CI: [-7.5, 6.1]Mixed Models Analysis