Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH)
Conditions
Keywords
Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH, 0382
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
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.
Interventions
MEDI0382 high dose administered subcutaneously
DRUGPlacebo for MEDI0382 high dose
Placebo for MEDI0382 high dose administered subcutaneously
MEDI0382 low dose administered subcutaneously
DRUGPlacebo for MEDI0382 low dose
Placebo for MEDI0382 low dose administered subcutaneously
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Day 1 - Day 161 | The number and percentage of treatment emergent adverse events (TEAE) and serious adverse events (SAE) through the end of the follow-up period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Day 1 - Day 161 | Development of ADA during treatment and follow-up |
| Change From Baseline to Week 19 in Hepatic Fat Fraction (HFF) | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Liver Volume | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Liver Fat Volume | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Visceral Adipose Tissue | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Subcutaneous Adipose Tissue | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Liver Diffusion | Baseline to week 19 | 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. |
| Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Day 1 - Day 161 (Baseline, Week 6, Week 12, Week 16, Week 19 and Week 23) | Development of ADA titer (if confirmed positive) |
| Percent Change From Baseline to Week 19 in Abdominal Transversal Diameter | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Alanine Aminotransferase (ALT) | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Gamma Glutamyl Transferase (GGT) | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Aspartate Aminotransferase (AST) | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Body Weight | Baseline to week 19 | 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. |
| Change From Baseline to Week 19 in Body Mass Index (BMI) | Baseline to week 19 | 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. |
| Percent Change From Baseline to Week 19 in Abdominal Sagittal Diameter | Baseline to week 19 | 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. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MEDI0382 300 ug MEDI0382 300 ug | 25 |
| MEDI0382 600 ug MEDI0382 600 ug | 25 |
| Placebo Placebo | 24 |
| Total | 74 |
Baseline characteristics
| Characteristic | MEDI0382 300 ug | MEDI0382 600 ug | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 55.9 Years STANDARD_DEVIATION 10.5 | 59.4 Years STANDARD_DEVIATION 11.9 | 52.2 Years STANDARD_DEVIATION 13.5 | 55.9 Years STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized ASIAN | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized WHITE | 24 Participants | 24 Participants | 23 Participants | 71 Participants |
| Sex: Female, Male Female | 12 Participants | 15 Participants | 14 Participants | 41 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 10 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 20 / 26 | 22 / 24 | 9 / 24 |
| serious Total, serious adverse events | 1 / 26 | 1 / 24 | 0 / 24 |
Outcome results
Primary
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
Time frame: Day 1 - Day 161
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MEDI0382 300ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to discontinuation of investigational product | 2 Participants |
| MEDI0382 300ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any SAE (including events with outcome of death) | 1 Participants |
| MEDI0382 300ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE | 20 Participants |
| MEDI0382 300ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE with outcome of death | 0 Participants |
| MEDI0382 300ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to withdrawal from study | 0 Participants |
| MEDI0382 600ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any SAE (including events with outcome of death) | 1 Participants |
| MEDI0382 600ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE | 22 Participants |
| MEDI0382 600ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE with outcome of death | 0 Participants |
| MEDI0382 600ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to discontinuation of investigational product | 4 Participants |
| MEDI0382 600ug | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to withdrawal from study | 0 Participants |
| Placebo | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to withdrawal from study | 0 Participants |
| Placebo | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE leading to discontinuation of investigational product | 1 Participants |
| Placebo | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE | 9 Participants |
| Placebo | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any SAE (including events with outcome of death) | 1 Participants |
| Placebo | Safety (Including Hepatic Safety) and Tolerability of MEDI0382 Compared With Placebo: Number of Participants With TEAE and SAE | Participants with any AE with outcome of death | 0 Participants |
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Change From Baseline to Week 19 in Body Mass Index (BMI) | -0.349 kg/m2 | Standard Error 0.32 |
| MEDI0382 600ug | Change From Baseline to Week 19 in Body Mass Index (BMI) | -1.042 kg/m2 | Standard Error 0.3202 |
| Placebo | Change From Baseline to Week 19 in Body Mass Index (BMI) | -0.265 kg/m2 | Standard Error 0.3338 |
p-value: 0.85695% CI: [-1.007, 0.838]ANCOVA
p-value: 0.09895% CI: [-1.7, 0.147]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Change From Baseline to Week 19 in Hepatic Fat Fraction (HFF) | -1.25 Percent | Standard Error 1.294 |
| MEDI0382 600ug | Change From Baseline to Week 19 in Hepatic Fat Fraction (HFF) | -4.85 Percent | Standard Error 1.236 |
| Placebo | Change From Baseline to Week 19 in Hepatic Fat Fraction (HFF) | 0.16 Percent | Standard Error 1.262 |
p-value: 0.43995% CI: [-5.02, 2.2]ANCOVA
p-value: 0.00695% CI: [-8.54, -1.48]ANCOVA
Secondary
Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive)
Development of ADA titer (if confirmed positive)
Time frame: Day 1 - Day 161 (Baseline, Week 6, Week 12, Week 16, Week 19 and Week 23)
Population: Number Analyzed per Row reflects the participants with positive ADA results at each time point. With zero positive ADA results Number Analyzed is zero for Participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 16 | 60 ADA titer |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Baseline | 15 ADA titer |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 19 | 120 ADA titer |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 12 | 30 ADA titer |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 23 | 120 ADA titer |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 6 | 120 ADA titer |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 23 | 30 ADA titer |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 6 | 60 ADA titer |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 12 | 15 ADA titer |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 16 | 60 ADA titer |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): ADA Titer (if Confirmed Positive) | Week 19 | 30 ADA titer |
Secondary
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
Time frame: Day 1 - Day 161
Population: As-treated
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 12 | 8 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 23 | 7 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 6 | 2 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 19 | 8 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at baseline | 1 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 16 | 8 Participants |
| MEDI0382 300ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 2 | 0 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 16 | 9 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 19 | 9 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 23 | 9 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 2 | 0 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 12 | 6 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 6 | 1 Participants |
| MEDI0382 600ug | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at baseline | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 23 | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at baseline | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 2 | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 12 | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 16 | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 19 | 0 Participants |
| Placebo | Immunogenicity Profile Defined by Presence of Anti-drug Antibodies (ADA): Number of Participants With Development of ADA | Number of subjects with a positive result at Week 6 | 0 Participants |
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Abdominal Sagittal Diameter | 2.791 Percent change | Standard Error 1.4722 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Abdominal Sagittal Diameter | -1.044 Percent change | Standard Error 1.2793 |
| Placebo | Percent Change From Baseline to Week 19 in Abdominal Sagittal Diameter | -0.657 Percent change | Standard Error 1.2881 |
p-value: 0.08795% CI: [-0.524, 7.421]ANCOVA
p-value: 0.83495% CI: [-4.085, 3.312]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Abdominal Transversal Diameter | 0.605 Percent change | Standard Error 0.8585 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Abdominal Transversal Diameter | -0.100 Percent change | Standard Error 0.7458 |
| Placebo | Percent Change From Baseline to Week 19 in Abdominal Transversal Diameter | 0.991 Percent change | Standard Error 0.7443 |
p-value: 0.73595% CI: [-2.681, 1.908]ANCOVA
p-value: 0.30895% CI: [-3.226, 1.044]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Alanine Aminotransferase (ALT) | -10.414 Percent change | Standard Error 10.1837 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Alanine Aminotransferase (ALT) | -15.465 Percent change | Standard Error 10.1654 |
| Placebo | Percent Change From Baseline to Week 19 in Alanine Aminotransferase (ALT) | 8.863 Percent change | Standard Error 10.6258 |
p-value: 0.19595% CI: [-48.704, 10.15]ANCOVA
p-value: 0.10395% CI: [-53.674, 5.019]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Aspartate Aminotransferase (AST) | -3.447 Percent change | Standard Error 9.0121 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Aspartate Aminotransferase (AST) | -13.951 Percent change | Standard Error 8.9326 |
| Placebo | Percent Change From Baseline to Week 19 in Aspartate Aminotransferase (AST) | 5.693 Percent change | Standard Error 9.2942 |
p-value: 0.48595% CI: [-35.134, 16.854]ANCOVA
p-value: 0.13195% CI: [-45.288, 5.999]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Body Weight | -1.286 Percent change | Standard Error 0.8589 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Body Weight | -2.933 Percent change | Standard Error 0.8624 |
| Placebo | Percent Change From Baseline to Week 19 in Body Weight | -0.568 Percent change | Standard Error 0.8959 |
p-value: 0.56495% CI: [-3.191, 1.754]ANCOVA
p-value: 0.06295% CI: [-4.854, 0.122]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Gamma Glutamyl Transferase (GGT) | -5.876 Percent change | Standard Error 13.6449 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Gamma Glutamyl Transferase (GGT) | 11.600 Percent change | Standard Error 13.6079 |
| Placebo | Percent Change From Baseline to Week 19 in Gamma Glutamyl Transferase (GGT) | 4.514 Percent change | Standard Error 14.2134 |
p-value: 0.695% CI: [-49.802, 29.022]ANCOVA
p-value: 0.7295% CI: [-32.163, 46.336]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Liver Diffusion | 2.864 Percent change | Standard Error 2.9769 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Liver Diffusion | 2.932 Percent change | Standard Error 2.7798 |
| Placebo | Percent Change From Baseline to Week 19 in Liver Diffusion | 1.826 Percent change | Standard Error 2.9634 |
p-value: 0.80895% CI: [-7.493, 9.569]ANCOVA
p-value: 0.78695% CI: [-7.043, 9.255]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Liver Fat Volume | -2.466 Percent change | Standard Error 10.6732 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Liver Fat Volume | -29.121 Percent change | Standard Error 10.2021 |
| Placebo | Percent Change From Baseline to Week 19 in Liver Fat Volume | 8.274 Percent change | Standard Error 10.135 |
p-value: 0.46895% CI: [-40.174, 18.695]ANCOVA
p-value: 0.01295% CI: [-66.38, -8.409]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Liver Volume | -0.886 Percent change | Standard Error 2.7979 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Liver Volume | -8.669 Percent change | Standard Error 2.6504 |
| Placebo | Percent Change From Baseline to Week 19 in Liver Volume | 0.622 Percent change | Standard Error 2.6182 |
p-value: 0.69595% CI: [-9.191, 6.174]ANCOVA
p-value: 0.01695% CI: [-16.76, -1.822]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Subcutaneous Adipose Tissue | -2.240 Percent change | Standard Error 2.4326 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Subcutaneous Adipose Tissue | -1.778 Percent change | Standard Error 1.8751 |
| Placebo | Percent Change From Baseline to Week 19 in Subcutaneous Adipose Tissue | 1.042 Percent change | Standard Error 1.9478 |
p-value: 0.30295% CI: [-9.641, 3.076]ANCOVA
p-value: 0.30495% CI: [-8.316, 2.675]ANCOVA
Secondary
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.
Time frame: Baseline to week 19
Population: The intent-to-treat (ITT) population includes all enrolled participants who are randomized. ITT population was analyzed according to the randomized treatment group. The analyses include those participants who discontinue from study treatments but are still followed up for their scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MEDI0382 300ug | Percent Change From Baseline to Week 19 in Visceral Adipose Tissue | 3.359 Percent change | Standard Error 3.3107 |
| MEDI0382 600ug | Percent Change From Baseline to Week 19 in Visceral Adipose Tissue | -2.152 Percent change | Standard Error 2.8958 |
| Placebo | Percent Change From Baseline to Week 19 in Visceral Adipose Tissue | -2.901 Percent change | Standard Error 2.9198 |
p-value: 0.16695% CI: [-2.698, 15.218]ANCOVA
p-value: 0.85695% CI: [-7.537, 9.035]ANCOVA