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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04019561
Recruitment Status : Completed
First Posted : July 15, 2019
Last Update Posted : May 27, 2021
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Non-alcoholic Fatty Liver Disease (NAFLD) Non-alcoholic Steatohepatitis (NASH) Drug: MEDI0382 high dose Drug: Placebo for MEDI0382 high dose Drug: MEDI0382 low dose Drug: Placebo for MEDI0382 low dose Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 74 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : September 23, 2019
Actual Primary Completion Date : May 6, 2021
Actual Study Completion Date : May 6, 2021


Arm Intervention/treatment
Experimental: MEDI0382 high dose
MEDI0382 high dose administered subcutaneously
Drug: MEDI0382 high dose
MEDI0382 high dose administered subcutaneously
Other Name: Cotadutide high dose

Placebo Comparator: Placebo for MEDI0382 high dose
Placebo for MEDI0382 high dose administered subcutaneously
Drug: Placebo for MEDI0382 high dose
Placebo for MEDI0382 high dose administered subcutaneously
Other Name: Placebo high dose

Experimental: MEDI0382 low dose
MEDI0382 low dose administered subcutaneoously
Drug: MEDI0382 low dose
MEDI0382 low dose administered subcutaneously
Other Name: Cotadutide low dose

Placebo Comparator: Placebo for MEDI0382 low dose
Placebo for MEDI0382 low dose administered subcutaneously
Drug: Placebo for MEDI0382 low dose
Placebo for MEDI0382 low dose administered subcutaneously
Other Name: Placebo low dose




Primary Outcome Measures :
  1. To assess the safety (including hepatic safety) and tolerability of MEDI0382 compared with placebo [ Time Frame: Day 1 - Day 161 ]
    Number and percentage of subjects with treatment emergent adverse events and serious adverse events through the end of the follow-up period


Secondary Outcome Measures :
  1. Change in hepatic fat [ Time Frame: Basaeline - Week 19 ]
    Percent change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo

  2. Change in hepatic fat [ Time Frame: Baseline - Week 19 ]
    Absolute change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo

  3. Change in liver volume [ Time Frame: Baseline - Week 19 ]

    Changes from baseline to Week 19 in:

    liver fat volume assessed by MRI compared with placebo


  4. Change in liver fat volume [ Time Frame: Baseline - Week 19 ]

    Changes from baseline to Week 19 in:

    liver fat volume assessed by MRI compared with placebo


  5. Change in visceral adipose tissue [ Time Frame: Baseline - Week 19 ]
    Changes from baseline to Week 19 in visceral adipose tissue assessed by MRI compared with placebo

  6. Change in subcutaneous adipose tissue [ Time Frame: Baseline - Week 19 ]
    Changes from baseline to Week 19 in subcutaneous adipose tissue assessed by MRI compared with placebo

  7. Change in liver diffusion [ Time Frame: Baseline - Week 19 ]
    Changes from baseline to Week 19 in liver diffusion assessed by MRI compared with placebo

  8. Change in abdominal sagittal diameter (image based) [ Time Frame: Baseline - Week 19 ]
    Changes from baseline to Week 19 in abdominal sagittal diameter (image based)assessed by MRI compared with placebo.

  9. Change in abdominal transversal diameter (image based) [ Time Frame: Baseline - Week 19 ]
    Changes from baseline to Week 19 in abdominal transversal diameter (image based)assessed by MRI compared with placebo

  10. Change in circulating markers of hepatic inflammation [ Time Frame: Basaeline - Week 19 ]
    Changes from baseline to Week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT)

  11. To assess the effect of MEDI0382 on BMI [ Time Frame: Baseline - Week 19 ]
    Change and percent change from baseline to week 19 on BMI.

  12. To assess the dose response of MEDI0382 on HFF by MRI-PDFF [ Time Frame: Baseline - Week 19 ]
    Absolute change from baseline in HFF from baseline to week 19.

  13. To assess the dose response of MEDI0382 on body weight [ Time Frame: Baseline - Week 19 ]
    Change from baseline to week 19 on body weight.

  14. To assess the dose response of MEDI0382 on hepatic safety [ Time Frame: Baseline - Week 19 ]
    Measured by the incidences of treatment emergent adverse events and serious adverse events through the end of the follow up period.

  15. To assess the dose response of MEDI0382 on imaging parameters. [ Time Frame: Baseline - Week 19 ]

    Measured by the change in baseline to week 19 on:

    Liver fat volume visceral adipose tissue subcutaneous adipose tissue liver diffusion liver sagittal diameter liver transversal diameter


  16. To assess the dose response of MEDI0382 on circulating biomarkers of hepatic inflammation [ Time Frame: Baseline - Week 19 ]
    Measured by the change in baseline to week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT).

  17. Immunogenicity profile defined by presence of anti-drug antibodies (ADA) [ Time Frame: Day 1 - Day 161 ]
    Development of ADA and titer (if confirmed positive) during treatment and follow up



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 101 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Subjects aged ≥ 18 years at the time of consent.
  3. Body mass index ≥ 30 kg/m2 at screening.
  4. 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).
  5. 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.
  6. Evidence of hepatic steatosis or liver fat (≥ 10%) by MRI.
  7. Women of childbearing potential:

    1. 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.
    2. Must have a negative urine pregnancy test within 72 hours prior to the first dose of investigational product; and not be breastfeeding.

Exclusion Criteria:

  1. 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.
  2. 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).
  3. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy or variceal bleeding.
  4. Prior or planned liver transplantation.
  5. 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.
  6. Evidence of alcohol dependence as assessed by the Alcohol Use Disorder Identification Test (AUDIT) questionnaire at screening
  7. A history of type 1 diabetes mellitus (T1DM), a history of diabetic ketoacidosis or current use of insulin-based therapies.
  8. 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
  9. Physician-diagnosed diabetic subjects with clinically significant gastroparesis (as judged by the investigator) or those treated for gastroparesis within 6 months prior to screening
  10. 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.
  11. 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.
  12. Severe congestive heart failure (New York Heart Association Class IV).
  13. 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.
  14. 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.
  15. 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.
  16. 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).
  17. Recent (within 3 months of baseline biopsy) use of obeticholic acid or other therapy under investigation for NASH.
  18. 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.
  19. Recent (within 3 months of baseline biopsy) use of GLP-1 receptor agonist or GLP-1 receptor agonist containing therapies.
  20. 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.
  21. Concurrent participation in another interventional study of any kind or repeat randomization in this study.
  22. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.
  23. 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.
  24. 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.
  25. Abnormal laboratory values including any of the following:

    1. AST or ALT > 5 × ULN.
    2. 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]).
    3. Albumin < 35 g/L.
    4. International normalized ratio (INR) > 1.3.
    5. Total Bilirubin (TBL) > 25 µmol/L in the absence of known Gilbert's disease.
    6. Platelets < 140-150,000/mm3
    7. Any other clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results as judged by the investigator.
  26. 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.
  27. 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).
  28. 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
  29. Any positive results for human immunodeficiency virus (HIV) infection.
  30. Any AstraZeneca, MedImmune, contract research organization (CRO), or study site employee, or close relatives of any of the aforementioned employees.
  31. Females who are pregnant or lactating.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04019561


Locations
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United States, Arizona
Research Site
Tucson, Arizona, United States, 85712
United States, California
Research Site
Canoga Park, California, United States, 91303
Research Site
Chula Vista, California, United States, 91911
Research Site
Coronado, California, United States, 92118
Research Site
La Jolla, California, United States, 92093
Research Site
Lincoln, California, United States, 95648
Research Site
Los Angeles, California, United States, 90057
Research Site
Montclair, California, United States, 91763
Research Site
Oxnard, California, United States, 93030
Research Site
Panorama City, California, United States, 91402
Research Site
Torrance, California, United States, 90505
Research Site
Westminster, California, United States, 92683
United States, Colorado
Research Site
Colorado Springs, Colorado, United States, 80907
United States, Florida
Research Site
Doral, Florida, United States, 33166
Research Site
Hialeah, Florida, United States, 33016
Research Site
Miami, Florida, United States, 33125
Research Site
Miami, Florida, United States, 33189
Research Site
Palmetto Bay, Florida, United States, 33157
United States, Georgia
Research Site
Columbus, Georgia, United States, 31904
United States, Louisiana
Research Site
Marrero, Louisiana, United States, 70072
United States, Nevada
Research Site
Las Vegas, Nevada, United States, 89104
Research Site
Las Vegas, Nevada, United States, 89109
Research Site
Las Vegas, Nevada, United States, 89113
United States, North Carolina
Research Site
Durham, North Carolina, United States, 27705
United States, Ohio
Research Site
Blue Ash, Ohio, United States, 45242
United States, Tennessee
Research Site
Chattanooga, Tennessee, United States, 37421
United States, Texas
Research Site
Austin, Texas, United States, 78758
Research Site
Houston, Texas, United States, 77002
Research Site
Houston, Texas, United States, 77084
Research Site
San Antonio, Texas, United States, 78215
Research Site
San Antonio, Texas, United States, 78229
United States, Virginia
Research Site
Fairfax, Virginia, United States, 22031
Research Site
Richmond, Virginia, United States, 23219
Puerto Rico
Research Site
San Juan, Puerto Rico, 00927
Sponsors and Collaborators
MedImmune LLC
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Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT04019561    
Other Study ID Numbers: D5671C00002
First Posted: July 15, 2019    Key Record Dates
Last Update Posted: May 27, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by MedImmune LLC:
Non-alcoholic fatty liver disease
NAFLD
Non-alcoholic steatohepatitis
NASH
0382
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases