Clinical trial NCT03555994: A Study to Investigate the Effect of MEDI0382 on Hepatic Glycogen Metabolism in Overweight and Obese Subjects With Type 2 Diabetes Mellitus.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Keywords: 0382, T2DM, Cotadutide, Overweight, Obese, MEDI0382
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2018-06-14
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Day -1 to Day 28
measure: 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)
timeFrame: Day -1 to Day 36
Secondary outcomes:
measure: 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)
timeFrame: Fom baseline (Day -1) to Day 35
measure: 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)
timeFrame: Day -1 to Day 36
measure: Development of ADA
timeFrame: Baseline to (Follow-up Period) 28 days post last dose + (3-month poststudy)
measure: 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
timeFrame: Post dosing (Day 1) to final follow-up (28 Days post last dose)
measure: 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
timeFrame: Post dosing (Day 1) to final follow-up (28 Days post last dose)
measure: 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
timeFrame: Post dosing (Day 1) to final follow-up (28 Days post last dose)
measure: 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
timeFrame: Post dosing (Day 1) to final follow-up (28 Days post last dose)
measure: 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
timeFrame: Post dosing (Day 1) to final follow-up (28 Days post last dose)
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
Study officials:
affiliation: CTC Clinical Trial Consultants AB
name: Folke Sjöberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nottingham
name: MacDonald
role: PRINCIPAL_INVESTIGATOR
affiliation: Maastricht
name: Schrauwen
role: PRINCIPAL_INVESTIGATOR
References: