A Study to Evaluate Safety and Pharmacodynamic Efficacy of 0382 in Obese Subjects With NAFLD/NASH.

Study Overview
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Brief Summary
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A Phase 2 study with 4 treatment groups of two differing doses and matched placebos designed to evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in obese subjects with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The subjects will have biopsy-confirmed NAFLD/NASH with liver fibrosis stage F1, F2 or F3. Approximately 72 subjects will be randomized

Detailed Description
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This is a randomized, double-blind, placebo-controlled, study to evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in obese subjects with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The subjects will have biopsy-confirmed NAFLD/NASH with liver fibrosis stage F1, F2 or F3. Approximately 72 subjects will be randomized across multiple study sites.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Pharmacodynamic Effects of MEDI0382 in Obese Subjects With Non-Alcoholic Fatty Liver Disease (NAFLD)/ Non-Alcoholic Steatohepatitis (NASH)

Conditions
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Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: MEDI0382 high dose
* Drug: Placebo for MEDI0382 high dose
* Drug: MEDI0382 low dose
* Drug: Placebo for MEDI0382 low dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent (with the exception of consent for future genetic and non genetic research) prior to performing any study-specific procedures, including screening evaluations. Subjects aged ≥ 18 years at the time of consent. Body mass index ≥ 30 kg/m2 at screening. HbA1c ≤ 9.5% (inclusive) at screening if T2DM present, managed by either diet and/or a stable dose of metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, sulphonylureas or acarbose (ie, no major dose adjustments in prior 3 months to screening). Definitive NAFLD / NASH with NASH activity score (NAS) ≥ 4 with ≥ 1 in each component (i.e. steatosis, lobular inflammation and ballooning), as diagnosed by liver biopsy within 6 months of screening with liver fibrosis stage F1, F2 or F3. The number of subjects with F1 will be capped at 25% in the study. Evidence of hepatic steatosis or liver fat (≥ 10%) by MRI. Women of childbearing potential: Who are sexually active with a non-sterilized male partner must have used at least one highly effective method of contraception from screening, and must agree to continue using such precautions through to the end of the study. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Must have a negative urine pregnancy test within 72 hours prior to the first dose of investigational product; and not be breastfeeding. Exclusion Criteria: History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product, put the subject at risk, influence the subject's ability to participate or affect the interpretation of the results of the study. 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) including positive results for hepatitis B surface antigen (HBsAg) or hepatitis C antibody tests (anti-HCV). History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy or variceal bleeding. Prior or planned liver transplantation. Alcohol consumption > 21 units of alcohol per week for men and > 14 units per week for women on average over a two-year time frame prior to baseline biopsy. Evidence of alcohol dependence as assessed by the Alcohol Use Disorder Identification Test (AUDIT) questionnaire at screening A history of type 1 diabetes mellitus (T1DM), a history of diabetic ketoacidosis or current use of insulin-based therapies. Clinically significant inflammatory bowel disease or other severe disease or surgery affecting the upper GI tract (including bariatric surgery) which may affect gastric emptying or could affect the interpretation of safety and tolerability data Physician-diagnosed diabetic subjects with clinically significant gastroparesis (as judged by the investigator) or those treated for gastroparesis within 6 months prior to screening History of > 5 kg weight loss in the last 6 months prior to screening or recent (within 3 months of screening) use of drugs approved for weight loss (eg, orlistat, bupropion / naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those drugs used off-label. Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, including but not limited to, myocardial infarction, acute coronary syndrome or stroke, or subjects who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening. Severe congestive heart failure (New York Heart Association Class IV). History of neoplastic disease within 5 years prior to screening, except for adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer. History of substance dependence or a positive screen for drugs of abuse, likely to impact subject safety or compliance with study procedures, at the discretion of the investigator. History of psychosis or bipolar disorder. History of major depressive disorder within the past year with the subject being clinically unstable, or any history of suicide attempt or history of suicidal ideation within the past year. Recent (within 3 months of baseline biopsy) use of therapies associated with development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines). Recent (within 3 months of baseline biopsy) use of obeticholic acid or other therapy under investigation for NASH. High dose vitamin E (> 400 IU) unless on a stable dose for at least 1 year prior to the baseline biopsy, and not initiated after the biopsy was taken. Recent (within 3 months of baseline biopsy) use of GLP-1 receptor agonist or GLP-1 receptor agonist containing therapies. Any subject who has received another investigational product as part of a clinical study within the last 30 days or 5 half-lives of the therapy (whichever is longer) at the time of screening. Any prior exposure to MEDI0382 is not permitted. Concurrent participation in another interventional study of any kind or repeat randomization in this study. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients. Contra-indication to MRI: such as subjects with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field; subjects with history of extreme claustrophobia or subject cannot fit inside the MR scanner cavity. History of acute pancreatitis or current chronic pancreatitis. Subjects with serum triglyceride concentrations above 1000 mg/dL (11 mmol/L) at screening, as this can precipitate acute pancreatitis. Abnormal laboratory values including any of the following: AST or ALT > 5 × ULN. Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 30 mL/minute/1.73 m2 at screening (estimated according to chronic kidney disease epidemiology collaboration [CKD-EPI]). Albumin < 35 g/L. International normalized ratio (INR) > 1.3. Total Bilirubin (TBL) > 25 µmol/L in the absence of known Gilbert's disease. Platelets < 140-150,000/mm3 Any other clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results as judged by the investigator. Severely uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 180 mm Hg and/or diastolic blood pressure (DBP) ≥ 110 mm Hg on the average of 2 seated measurements after being at rest for at least 10 minutes at screening or randomization. Basal calcitonin level > 50 ng/L at screening, or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2). Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration < 11.5 g/dL [115 g/L] for male subjects or < 10.5 g/dL [105 g/L] for female subjects) at screening, or any other condition known to interfere with interpretation of HbA1c measurements Any positive results for human immunodeficiency virus (HIV) infection. Any AstraZeneca, MedImmune, contract research organization (CRO), or study site employee, or close relatives of any of the aforementioned employees. Females who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 101 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI0382 high dose<br>MEDI0382 high dose administered subcutaneously | Drug: MEDI0382 high dose<br>* MEDI0382 high dose administered subcutaneously<br>* Other names: Cotadutide high dose;|
| Placebo Comparator: Placebo for MEDI0382 high dose<br>Placebo for MEDI0382 high dose administered subcutaneously | Drug: Placebo for MEDI0382 high dose<br>* Placebo for MEDI0382 high dose administered subcutaneously<br>* Other names: Placebo high dose;|
| Experimental: MEDI0382 low dose<br>MEDI0382 low dose administered subcutaneoously | Drug: MEDI0382 low dose<br>* MEDI0382 low dose administered subcutaneously<br>* Other names: Cotadutide low dose;|
| Placebo Comparator: Placebo for MEDI0382 low dose<br>Placebo for MEDI0382 low dose administered subcutaneously | Drug: Placebo for MEDI0382 low dose<br>* Placebo for MEDI0382 low dose administered subcutaneously<br>* Other names: Placebo low dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | The number and percentage of treatment emergent adverse events (TEAE) and serious adverse events (SAE) through the end of the follow-up period | Day 1 - Day 161 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Development of ADA titer (if confirmed positive) | Day 1 - Day 161 (Baseline, Week 6, Week 12, Week 16, Week 19 and Week 23) | 
| Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Development of ADA during treatment and follow-up | Day 1 - Day 161 | 
| Change From Baseline to Week 19 in Hepatic Fat Fraction (HFF) | Change from baseline is defined as the week 19 post-baseline value minus the baseline value. The Analysis of Covariance (ANCOVA) model was used to fit change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Liver Volume | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Liver Fat Volume | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Visceral Adipose Tissue | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Subcutaneous Adipose Tissue | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Liver Diffusion | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Abdominal Sagittal Diameter | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Abdominal Transversal Diameter | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Alanine Aminotransferase (ALT) | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Gamma Glutamyl Transferase (GGT) | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Aspartate Aminotransferase (AST) | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Percent Change From Baseline to Week 19 in Body Weight | Percent change from baseline is calculated as the week 19 post-baseline value minus the baseline value divided by the baseline value *100. The Analysis of Covariance (ANCOVA) model was used to fit percent change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 
| Change From Baseline to Week 19 in Body Mass Index (BMI) | Change from baseline is defined as the week 19 post-baseline value minus the baseline value. The Analysis of Covariance (ANCOVA) model was used to fit change at week 19. The group of treatment was considered as a fixed effect of the model while the baseline value as covariate. Last observation carried forward (LOCF) method was applied to handle missing data. | Baseline to week 19 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH, 0382