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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03555994
• Other study ID #: D5670C00022
• Status: Completed
• Phase: Phase 2
• Start date: May 31, 2018
• Est. completion date: April 14, 2021

Study information

• Verified date: April 2021
• Source: MedImmune LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: April 14, 2021
• Est. primary completion date: April 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Overweight
• Type 2 Diabetes Mellitus

Intervention

Drug:
• MEDI0382
MEDI0382 administered subcutaneously
• Placebo
Placebo administered subcutaneously
• Liraglutide
Liraglutide administered subcutaneously

Locations

Country	Name	City	State
Netherlands	Research Site	Maastricht
Sweden	Research Site	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
MedImmune LLC

Countries where clinical trial is conducted

Netherlands,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)