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.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03555994

Enrollment

Registered

2018-06-14

Start date

2018-05-31

Completion date

2021-04-14

Last updated

2024-11-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes Mellitus

Keywords

0382, T2DM, Cotadutide, Overweight, Obese, MEDI0382

Brief 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.

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.

Interventions

DRUGMEDI0382

MEDI0382 administered subcutaneously

DRUGPlacebo

Placebo administered subcutaneously

DRUGLiraglutide

Liraglutide administered subcutaneously

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Hepatic Glycogen Concentration Adjusted for Liver Volume as Measured by MRS at T = 4 Hours Post Standardised Morning Meal From Baseline (Day -1) to the End of 28 Days of Treatment (Part A Only)	Day -1 to Day 28	To assess the effect of MEDI0382 on hepatic glycogen levels postprandially versus placebo after 28 days of treatment
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)	Day -1 to Day 36	To assess the effect of MEDI0382 on hepatic glycogen levels versus placebo after 35 days (Part B) of treatment

Secondary

Measure	Time frame	Description
Development of ADA	Baseline to (Follow-up Period) 28 days post last dose + (3-month poststudy)	—
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 Number of Participants withTreatment Emergent Adverse Events (TEAEs) as Assessed by CTCAE V4.0	Post dosing (Day 1) to final follow-up (28 Days post last dose)	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)
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 Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) as Assessed by CTCAE V4.0	Post dosing (Day 1) to final follow-up (28 Days post last dose)	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)
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)	Fom baseline (Day -1) to Day 35	To assess the effect of MEDI0382 on hepatic glycogen levels versus liraglutide after 35 days of treatment (Part B only)
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	Post dosing (Day 1) to final follow-up (28 Days post last dose)	Number of subjects with an ECG determined to be abnormal and clinically significant
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	Post dosing (Day 1) to final follow-up (28 Days post last dose)	Number of subjects with clinically significant changes in in haematology and or clinical chemistry parameters
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	Post dosing (Day 1) to final follow-up (28 Days post last dose)	Number of subjects with clinically significant changes in heart rate (BPM) or systolic and diastolic blood pressure (mmHg)
Change of Hepatic Fat Fraction From Baseline as Measured by Magnetic Resonance Imaging (Day -1) to the End of 35 Days of Treatment (Part B Only)	Day -1 to Day 36	—

Countries

Netherlands, Sweden, United Kingdom

Participant flow

Recruitment details

In Part A, a total of 21 participants participated in the study from 31 May 2018 (date first participant enrolled for Part A) to 23 November 2018 (date of last participant last visit for Part A) at one site in Sweden. In Part B, a total of 30 participants participated in the study from 17 December 2019 (date first participant enrolled for Part B) to 14 April 2021 (date of last participant last visit for Part B) at 2 sites (one in Sweden and one in the Netherlands).

Participants by arm

Arm	Count
Placebo (Part A) Placebo administered subcutaneously (Part A)	9
MEDI0382 (Part A) MEDI0382 administered subcutaneously (Part A)	12
Liraglutide (Part B) Active Comparator administered subcutaneously (Part B)	10
MEDI0382 (Part B) MEDI0382 administered subcutaneously (Part B)	9
Placebo (Part B) Placebo administered subcutaneously (Part B)	11
Total	51

Baseline characteristics

Characteristic	Placebo (Part A)	MEDI0382 (Part A)	Liraglutide (Part B)	MEDI0382 (Part B)	Placebo (Part B)	Total
Age, Continuous Age	69.3 Years STANDARD_DEVIATION 5.7	65.8 Years STANDARD_DEVIATION 7.3	65.2 Years STANDARD_DEVIATION 9.1	61.8 Years STANDARD_DEVIATION 7.5	64.0 Years STANDARD_DEVIATION 10.7	65.2 Years STANDARD_DEVIATION 8.2
Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized ASIAN	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized OTHER	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized WHITE	9 Participants	12 Participants	10 Participants	9 Participants	11 Participants	51 Participants
Sex: Female, Male Female	3 Participants	5 Participants	4 Participants	3 Participants	2 Participants	17 Participants
Sex: Female, Male Male	6 Participants	7 Participants	6 Participants	6 Participants	9 Participants	34 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 9	0 / 12	0 / 10	0 / 9	0 / 11
other Total, other adverse events	7 / 9	11 / 12	8 / 10	7 / 9	6 / 11
serious Total, serious adverse events	0 / 9	0 / 12	0 / 10	0 / 9	0 / 11

Outcome results

Primary

Change in Hepatic Glycogen Concentration Adjusted for Liver Volume as Measured by MRS at T = 4 Hours Post Standardised Morning Meal From Baseline (Day -1) to the End of 28 Days of Treatment (Part A Only)

To assess the effect of MEDI0382 on hepatic glycogen levels postprandially versus placebo after 28 days of treatment

Time frame: Day -1 to Day 28

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo (Part A)	Change in Hepatic Glycogen Concentration Adjusted for Liver Volume as Measured by MRS at T = 4 Hours Post Standardised Morning Meal From Baseline (Day -1) to the End of 28 Days of Treatment (Part A Only)	5.5 mmol/L
MEDI0382 (Part A)	Change in Hepatic Glycogen Concentration Adjusted for Liver Volume as Measured by MRS at T = 4 Hours Post Standardised Morning Meal From Baseline (Day -1) to the End of 28 Days of Treatment (Part A Only)	-100.2 mmol/L

p-value: 0.02390% CI: [-178.8, -32.6]ANCOVA

Primary

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)

To assess the effect of MEDI0382 on hepatic glycogen levels versus placebo after 35 days (Part B) of treatment

Time frame: Day -1 to Day 36

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo (Part A)	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)	-27.02 percent change from baseline
MEDI0382 (Part A)	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)	-1.15 percent change from baseline

p-value: 0.00890% CI: [-40.88, -10.86]ANCOVA

Secondary

Change of Hepatic Fat Fraction From Baseline as Measured by Magnetic Resonance Imaging (Day -1) to the End of 35 Days of Treatment (Part B Only)

Time frame: Day -1 to Day 36

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo (Part A)	Change of Hepatic Fat Fraction From Baseline as Measured by Magnetic Resonance Imaging (Day -1) to the End of 35 Days of Treatment (Part B Only)	-15.40 percent
MEDI0382 (Part A)	Change of Hepatic Fat Fraction From Baseline as Measured by Magnetic Resonance Imaging (Day -1) to the End of 35 Days of Treatment (Part B Only)	-26.26 percent
Placebo (Part B)	Change of Hepatic Fat Fraction From Baseline as Measured by Magnetic Resonance Imaging (Day -1) to the End of 35 Days of Treatment (Part B Only)	8.79 percent

p-value: 0.0790% CI: [-66.54, -3.58]ANCOVA

p-value: 0.0390% CI: [-20.13, -3.3]ANCOVA

Secondary

Development of ADA

Time frame: Baseline to (Follow-up Period) 28 days post last dose + (3-month poststudy)

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo (Part A)	Development of ADA	Baseline ADA result	0 Participants
Placebo (Part A)	Development of ADA	Post Study ADA result	0 Participants
Placebo (Part A)	Development of ADA	Day 28 ADA result for Part A Day 35 ADA result for Part B	0 Participants
Placebo (Part A)	Development of ADA	Follow-up ADA result	0 Participants
MEDI0382 (Part A)	Development of ADA	Post Study ADA result	0 Participants
MEDI0382 (Part A)	Development of ADA	Baseline ADA result	0 Participants
MEDI0382 (Part A)	Development of ADA	Follow-up ADA result	0 Participants
MEDI0382 (Part A)	Development of ADA	Day 28 ADA result for Part A Day 35 ADA result for Part B	1 Participants
Placebo (Part B)	Development of ADA	Follow-up ADA result	3 Participants
Placebo (Part B)	Development of ADA	Day 28 ADA result for Part A Day 35 ADA result for Part B	3 Participants
Placebo (Part B)	Development of ADA	Baseline ADA result	0 Participants
Placebo (Part B)	Development of ADA	Post Study ADA result	1 Participants
Liraglutide	Development of ADA	Day 28 ADA result for Part A Day 35 ADA result for Part B	0 Participants
Liraglutide	Development of ADA	Baseline ADA result	0 Participants
Liraglutide	Development of ADA	Follow-up ADA result	0 Participants
Liraglutide	Development of ADA	Post Study ADA result	0 Participants
Placebo (Part B)	Development of ADA	Day 28 ADA result for Part A Day 35 ADA result for Part B	0 Participants
Placebo (Part B)	Development of ADA	Baseline ADA result	0 Participants
Placebo (Part B)	Development of ADA	Post Study ADA result	0 Participants
Placebo (Part B)	Development of ADA	Follow-up ADA result	0 Participants

Secondary