A Study to Investigate the Effect of MEDI0382 on Hepatic Glycogen Metabolism in Overweight and Obese Subjects With Type 2 Diabetes Mellitus.

Study Overview
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Brief Summary
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A phase 2 study in two parts (A & B) designed to evaluate the effect of MEDI0382 on Hepatic Glycogen Metabolism in subjects with Type 2 Diabetes Mellitus (T2DM). Approximately 20 subjects will be enrolled in Part A and approximately 30 subjects in Part B.

Detailed Description
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This is a 2-part exploratory Phase 2 study. Part A is a randomised, double-blind, placebo-controlled study to evaluate the effect of MEDI0382 (also known as Cotadutide) administered once daily subcutaneously (SC) for 28 days on hepatic glycogen metabolism in overweight and obese subjects with T2DM. Part A is planned to randomise up to 20 subjects. Subjects from Part A will not be re-enrolled in Part B. Part B is an exploratory Phase 2 randomised, double-blind, placebo-controlled and open-label active comparator study to evaluate the effect of MEDI0382 on hepatic glycogen metabolism in overweight and obese subjects with T2DM. Part B is planned to randomise approximately 30 subjects (not to exceed a maximum of 35 subjects). Subjects in Part B will be randomised to receive double-blind MEDI0382 or placebo, or open-label liraglutide once daily for 35 days.

Official Title
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An Exploratory Phase 2, Randomised, Double-blind, Placebo-controlled, and Open-label Active Comparator Study to Evaluate the Effect of MEDI0382 on Hepatic Glycogen Metabolism in Overweight and Obese Subjects With Type 2 Diabetes Mellitus.

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: MEDI0382
* Drug: Placebo
* Drug: Liraglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) ≥ 27 and ≤ 40 kg/m2 (inclusive) at screening Glycated haemoglobin (HbA1c) ≤ 8.0% at screening Diagnosed with T2DM with glucose control managed with metformin monotherapy where no significant dose change (increase or decrease ≥ 500 mg/day) has occurred in the 3 months prior to screening Exclusion criteria: Any subject who has received another investigational product as part of a clinical study or a GLP-1 analogue-containing preparation within the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening Any subject who has received any of the following medications prior to the start of the study: Herbal preparations or drugs licensed for control of body weight or appetite (eg, orlistat, bupropion naltrexone, phentermine-topiramate, phentermine, lorcaserin) Opiates, domperidone, metoclopramide or other drugs known to alter gastric emptying Glucagon Warfarin Any contraindication to magnetic resonance imaging/MRS scanning including claustrophobia or dislike of confined spaces Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus (T1DM) or diabetic ketoacidosis, or if the subject has been treated with daily SC insulin within 90 days prior to screening Recurrent unexplained hypoglycaemic episodes (defined as glucose < 3.0 mmol/L or < 54 mg/dL on more than 2 occasions in 6 months prior to screening) Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper GI tract (including weightreducing surgery and procedures) which may affect gastric emptying or could affect the interpretation of safety and tolerability data Acute or chronic pancreatitis Significant hepatic disease (except for NASH or nonalcoholic fatty liver disease without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening: Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN) Alanine transaminase (ALT) ≥ 3 × ULN Total bilirubin ≥ 2 × ULN Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73m2 at screening (glomerular filtration rate estimated according to Modification of Diet in Renal Disease (MDRD) using MDRD Study Equation IDMS-traceable (International System of Units [SI] units) Poorly controlled hypertension defined as: Systolic blood pressure (BP) > 180 mm Hg Diastolic BP > 105 mm Hg After 10 minutes of supine rest and confirmed by repeated measurement at screening. Unstable angina pectoris, myocardial infarction, transient ischemic attack or stroke within 3 months prior to screening, 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 III or IV) Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia 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 Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody Substance dependence or history of alcohol abuse and/or excess alcohol intake (defined as > 21 units per week for a male subject, and >14 units per week for a female subject). Subjects must have a negative alcohol test result at screening and prior to randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI0382 (Part A)<br>MEDI0382 administered subcutaneously (Part A) | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously<br>|
| Placebo Comparator: Placebo (Part A)<br>Placebo comparator administered subcutaneously (Part A) | Drug: Placebo<br>* Placebo administered subcutaneously<br>|
| Active Comparator: Liraglutide (Part B)<br>Active comparator administered subcutaneously (Part B) | Drug: Liraglutide<br>* Liraglutide administered subcutaneously<br>|
| Experimental: MEDI0382 (Part B)<br>MEDI0382 administered subcutaneously (Part B) | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously<br>|
| Placebo Comparator: Placebo (Part B)<br>Placebo comparator administered subcutaneously (Part B) | Drug: Placebo<br>* Placebo administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect of MEDI0382 on hepatic glycogen levels versus placebo after 28 days (Part A) and 35 days (Part B) of treatment | Change in hepatic glycogen concentration adjusted for liver volume as measured by magnetic resonance spectroscopy (MRS) at Time (T) = 4 hours post standardised morning meal from baseline (Day -1) to the end of 28 days of treatment (Part A). Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as measured by magnetic resonance spectroscopy (MRS) at Time (T) = 24 hours post standardised morning meal from baseline (Day 1) to the end of 35 days of treatment (Day 36) (Part B). | 28 days post dosing (Part A) 35 days post dosing (Part B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect of MEDI0382 on hepatic glycogen levels versus liraglutide after 35 days of treatment (Part B only) | Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as measured by MRS at T = 24 hours post standardised morning meal from baseline (Day 1) to the end of 35 days of treatment (Day 36) (Part B only). | 35 days post dosing | 
| To assess the effect of MEDI0382 on hepatic fat fraction versus placebo after 35 days of treatment (Part B only) | Change in hepatic fat fraction from baseline as measured by magnetic resonance imaging (Day -1) to the end of 35 days of treatment (Part B only) | Baseline (Day -1) to Day 35 | 
| To characterise the immunogenicity profile of MEDI0382 exposure titrated up to a dose level of 300 μg | Development of anti-drug antibodies (ADA) and titre (if confirmed positive) | 28 days (Part A) and 35 days (Part B) post dosing | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of MEDI0382 by assessment of the following using CTCAE V4.0: The number of Treatment Emergent Adverse events (TEAEs) | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of Treatment Emergent Serious Adverse Events (TESAEs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of MEDI0382 by assessment of the following using CTCAE V4.0: The number of Treatment-Emergent Serious Adverse Events (TESAEs) | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of Treatment Emergent Adverse Events of Special Interest (AESIs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of MEDI0382 by assessment of the following using CTCAE V4.0: The number of Treatment Emergent Adverse Events of Special Interest (AESIs) | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in heart rate and blood pressure | Number of subjects with clinically significant changes in heart rate (BPM) or systolic and diastolic blood pressure (mmHg) | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in ECG | Number of subjects with an ECG determined to be abnormal and clinically significant | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in haematology and clinical chemistry parameters | Number of subjects with clinically significant changes in in haematology and or clinical chemistry parameters | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in heart rate and blood pressure | Percentage of subjects with clinically significant changes in heart rate (BPM) or systolic and diastolic blood pressure (mmHg) | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in ECG | Percentage of subjects with an ECG determined to be abnormal and clinically significant | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 
| Measures of safety and tolerability of daily SC doses of MEDI0382 titrated up to a dose level of 300μg (Parts A and B) by assessment of changes in haematology and clinical chemistry parameters | Percentage of subjects with clinically significant changes in in haematology and or clinical chemistry parameters | Post dosing (Day 1) to final follow-up (28 Days post last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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0382, T2DM, Cotadutide, Overweight, Obese, MEDI0382