Clinical trial NCT03244800: A Study to Investigate Different Doses of 0382 in Overweight and Obese Subjects With Type 2 Diabetes Mellitus.
Official title: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Different Doses of MEDI0382 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
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2017-08-10
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Phase 2 study with two cohorts of differing doses designed to evaluate the efficacy, safety and pharmacokinetics (PK) of MEDI0382 in patients with Type 2 Diabetes Mellitus (T2DM). Approximately 63 subjects will be enrolled across two cohorts.

Detailed description: This is a randomised, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of different doses of MEDI0382 administered as multiple SC doses to subjects with T2DM. Approximately 63 subjects will be enrolled across two cohorts.

For cohort 1, sufficient subjects will be invited to participate in the study such that a maximum of 39 subjects will complete dosing. Subjects in cohort 1 will be randomised using a ratio of 2:1 to one of 2 treatment arms to receive either MEDI0382 or placebo. A maximum of 26 will complete dosing in the active arm and 13 will complete dosing in the placebo arm.

For cohort 2, sufficient subjects will be invited to participate in the study such that a maximum of 24 subjects will complete dosing. Subjects in cohort 2 will be randomised using a ratio of 3:1 to receive either MEDI0382 or placebo. A maximum of 18 will complete dosing in the active arm and 6 will complete dosing in the placebo arm.

Eligibility criteria: Inclusion Criteria:

1. Male and female subjects aged ≥ 18 years at screening
2. Provision of signed and dated written informed consent
3. BMI between 27 and 40 kg/m2
4. HbA1c range of 6.5% to 8.5%
5. 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
6. Subjects prescribed oral dual therapy with a dipeptidyl peptidase-4 inhibitor, sulphonylurea, glitinide, or a sodium-glucose co-transporter 2 inhibitor in addition to metformin at screening may be eligible to enter the study following a 4-week washout period
7. Female subjects of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating
8. Females of childbearing potential who are sexually active with a nonsterilised male partner must use at least one highly effective method of contraception from screening and must agree to continue using such precautions through to the end of the study. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.

Exclusion Criteria:

1. History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product, put the subject at risk, influence the subject's ability to participate or affect the interpretation of the results of the study and/or any subject unable or unwilling to follow study procedures
2. Concurrent participation in another study of any kind and repeat randomisation in this study is prohibited
3. Severe allergy/hypersensitivity to any of the proposed study treatments
4. Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis, or if the subject has been treated with daily SC insulin within 90 days prior to screening
5. Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper GI tract (including weight-reducing surgery and procedures) which may affect gastric emptying or could affect the interpretation of safety and tolerability data
6. Significant hepatic disease (except for non-alcoholic steatohepatitis or non-alcoholic 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
7. Impaired renal function defined as estimated glomerular filtration rate (GFR) \< 60 mL/minute/1.73 m2 at screening (GFR estimated according to Modification of Diet in Renal Disease \[MDRD\] using the isotope dilution mass spectrometry \[IDMS\] traceable MDRD Study Equation \[SI units\])
8. Poorly controlled hypertension defined as:

   * Systolic BP \> 160 mm Hg
   * Diastolic BP ≥ 95 mm Hg after 10 minutes of seated rest and confirmed by repeated measurement at screening.
9. 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
10. Severe congestive heart failure (New York Heart Association Class III or IV)
11. Basal calcitonin level \> 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
12. Haemoglobinopathy, haemolytic anemia, or chronic anaemia (haemoglobin concentration \< 11.5 g/dL \[115 g/L\] for males, \< 10.5 g/dL \[105 g/L\] for females) at screening or any other condition known to interfere with interpretation of HbA1c measurement
13. 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
14. Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody
15. History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as an average weekly intake of \> 21 alcoholic drinks for men or \> 10 alcoholic drinks for women) within 3 years prior to screening, and/or a positive screen for drugs of abuse or alcohol at screening or on admission to the study unit. Subjects who use tricyclic antidepressants or benzodiazepines for an established clinical indication may be permitted to enter the study based upon the judgement of the investigator.
16. Involvement of any AstraZeneca, MedImmune, contract research organization, or study site employee or their close relatives
17. History of acute or chronic pancreatitis or other diseases of the pancreas

Primary outcomes:
measure: Cohort 1: Percent Change From Baseline in Plasma Glucose Area Under the Concentration-time Curve From Time 0 to 4 Hours (AUC0-4h) by Mixed-meal Tolerance Test (MMTT) to Day 49
timeFrame: Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal
measure: Cohort 1: Percent Change From Baseline in Body Weight to Day 50
timeFrame: Day 1 through Day 50
Secondary outcomes:
measure: Cohort 1: Change From Baseline in Glycated Haemoglobin (HbA1c) to Day 49
timeFrame: Baseline (Day -1) through Day 49
measure: Cohort 1: Change From Baseline in Fasting Plasma Glucose to Day 49
timeFrame: Baseline (Day -1) through Day 49
measure: Cohort 1: Change From Baseline in Body Weight to Day 50
timeFrame: Day 1 through Day 50
measure: Cohort 1: Percentage of Participants Achieving Greater Than or Equal to 5% Body Weight Loss From Baseline to Day 50
timeFrame: Day 1 through Day 50
measure: Cohort 1 and Cohort 2: Percent Change From Baseline in MMTT Plasma Glucose AUC 0-4h to Day 7
timeFrame: Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal
measure: Cohort 1 and Cohort 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
measure: Cohort 1 and Cohort 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs
timeFrame: From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
measure: Cohort 1 and Cohort 2: Number of Participants With Abnormal Electrocardiogram Reported as TEAEs
timeFrame: From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
measure: Cohort 1 and Cohort 2: Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs
timeFrame: From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
measure: Cohort 1 and Cohort 2: Number of Participants With Injection Site Erythema
timeFrame: From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
measure: Cohort 1: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382
timeFrame: Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382
timeFrame: Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1: Maximum Observed Concentration (Cmax) of MEDI0382
timeFrame: Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Maximum Observed Concentration (Cmax) of MEDI0382
timeFrame: Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382
timeFrame: Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382
timeFrame: Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1: Terminal Half Life (t1/2) of MEDI0382
timeFrame: Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Terminal Half Life (t1/2) of MEDI0382
timeFrame: Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1: Accumulation Ratio (Racc) of MEDI0382
timeFrame: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Accumulation Ratio of MEDI0382
timeFrame: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1: Trough Plasma Concentration (Ctrough) of MEDI0382
timeFrame: Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
measure: Cohort 2: Trough Plasma Concentration (Ctrough) of MEDI0382
timeFrame: Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
measure: Cohort 1 and Cohort 2: Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI0382
timeFrame: Baseline (Day 1), Day 29, Day 50, and Follow-up Visit 2 (28 days after the last dose [approximately 64 days])
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Neu-Ulm
country: Germany
facility: Research Site
city: Neuss
country: Germany
facility: Research Site
Study officials:
affiliation: Profil Institut für Stoffwechselforschung GmbH
name: Tim Heise, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Parker VER, Robertson D, Wang T, Hornigold DC, Petrone M, Cooper AT, Posch MG, Heise T, Plum-Moerschel L, Schlichthaar H, Klaus B, Ambery PD, Meier JJ, Hirshberg B. Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist. J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz047. doi: 10.1210/clinem/dgz047.