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

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.

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: MEDI0382; Drug: Liraglutide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229 ER
    • Research Site
• Sweden
  • Uppsala, Sweden, 752 37
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: MEDI0382 (Part A); MEDI0382 administered subcutaneously (Part A)	Drug: MEDI0382; MEDI0382 administered subcutaneously
PLACEBO_COMPARATOR: Placebo (Part A); Placebo comparator administered subcutaneously (Part A)	Drug: Placebo; Placebo administered subcutaneously
ACTIVE_COMPARATOR: Liraglutide (Part B); Active comparator administered subcutaneously (Part B)	Drug: Liraglutide; Liraglutide administered subcutaneously
EXPERIMENTAL: MEDI0382 (Part B); MEDI0382 administered subcutaneously (Part B)	Drug: MEDI0382; MEDI0382 administered subcutaneously
PLACEBO_COMPARATOR: Placebo (Part B); Placebo comparator administered subcutaneously (Part B)	Drug: Placebo; Placebo administered subcutaneously

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: MedImmune LLC
• Investigators: Principal Investigator: MacDonald, Nottingham; Principal Investigator: Schrauwen, Maastricht

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 31, 2018
• Primary Completion (ACTUAL): April 14, 2021
• Study Completion (ACTUAL): April 14, 2021

Study Registration Dates

• First Submitted: April 18, 2018
• First Submitted That Met QC Criteria: June 1, 2018
• First Posted (ACTUAL): June 14, 2018

Study Record Updates

• Last Update Posted (ACTUAL): April 30, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: 0382, T2DM, Cotadutide, Overweight, Obese, MEDI0382
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: D5670C00022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No