A Phase IIa, Randomised, Parallel, Double-Blind,Placebo-Controlled Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of MEDI0382 in Japanese Preobese or Obese Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control With Diet and Exercise
Overview
- Phase
- Phase 2
- Intervention
- PlaceboA
- Conditions
- Type 2 Diabetes
- Sponsor
- AstraZeneca
- Enrollment
- 61
- Locations
- 1
- Primary Endpoint
- Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This is a Phase 2a study designed to assess the safety and tolerability of MEDI0382 titrated up to a dose level of 100, 200 or 300 µg from 50 µg vs Placebo across 48 days in Japanese subjects.
The study D5674C00001 can be conducted with a reasonable expectation of safety and tolerability in Japanese T2DM patients. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382.
Detailed Description
This is a randomized, parallel-group, placebo-controlled, double-blind, multicenter Phase Ⅱa study to evaluate the safety, efficacy, and pharmacokinetics of MEDI0382 in Japanese preobese and obese subjects with type 2 diabetes who have inadequate glycemic control with diet and exercise. Subject fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1:1:1 ratio to four treatment arms. This is a Phase IIa study designed to evaluate the dose range for MEDI0382 to explore the safety profile, as well as blood glucose control and weight loss effects of MEDI0382 in Japanese patients with T2DM. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382, such that benefit-risk balance for the Japanese preobese and obese patients with T2DM in this study is considered favourable. A treatment period of 48 days is required to properly evaluate the dose range and safety and tolerability in three different doses. Inclusion of placebo in the study allows appropriate basis of AEs, glycaemic control, and weight loss. Benefits related to participation in this trial include close follow-up of a subject's diabetes and treatment with anti-diabetes agents. Although one of possible treatments is placebo, appropriate rescue therapy for worsening glycaemic control will be implemented if required.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Individuals whose HbA1c range of 7.0% to 10.5% (inclusive) at screening.
- •Individuals who are diagnosed with T2DM
- •Individuals whose current condition at enrolment (Visit 1) is drug naïve
- •BMI within the range of 24 - 40 kg/m2 (inclusive) at screening
Exclusion Criteria
- •Subjects with any of the following results at screening:
- •Aspartate transaminase (AST) ≥ 2.5 × upper limit of normal (ULN)
- •Alanine transaminase (ALT) ≥ 2.5 × ULN
- •Total bilirubin (TBL) ≥ 2 × ULN
- •Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/minute/1.73 m2 at screening
- •Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening
Arms & Interventions
placebo
Placebo per day,SC injection on 48 days.
Intervention: PlaceboA
placebo
Placebo per day,SC injection on 48 days.
Intervention: PlaceboB
MEDI0382 100μg
50 μg/day,SC injection on the first 5 days and 100 μg/day,SC injection on 43 days
Intervention: MEDI0382 100 μg
MEDI0382 100μg
50 μg/day,SC injection on the first 5 days and 100 μg/day,SC injection on 43 days
Intervention: MEDI0382 50 ug
MEDI0382 200μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days and 200 μg/day,SC injection on 36 days.
Intervention: MEDI0382 100 μg
MEDI0382 200μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days and 200 μg/day,SC injection on 36 days.
Intervention: MEDI0382 200 μg
MEDI0382 200μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days and 200 μg/day,SC injection on 36 days.
Intervention: MEDI0382 50 ug
MEDI0382 300μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days
Intervention: MEDI0382 100 μg
MEDI0382 300μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days
Intervention: MEDI0382 200 μg
MEDI0382 300μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days
Intervention: MEDI0382 300 μg
MEDI0382 300μg
50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days
Intervention: MEDI0382 50 ug
Outcomes
Primary Outcomes
Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48
Time Frame: Baseline (Day -1) and Days 20 and 48.
Twenty four-hour heart rate was determined using an ambulatory blood pressure monitoring (ABPM) device, and the mean change from baseline in the 24-hour heart rate is presented for Days 20 and 48.
Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48
Time Frame: Baseline (Day -1) and Day 48: 15 minutes before standardised meal, and then at 15, 30, 45, 60, 90, 120, 180 and 240 minutes (+/-5 minutes) after consumption of the standardised meal.
The MMT was conducted following a minimum 8-hour fast. Blood samples for glucose monitoring were taken 15 minutes before the patient consumed a standardised meal, and samples were taken at intervals after the meal, up to 4 hours. The MMT glucose AUC(0-4h) was calculated using a trapezoidal method, and the mean percentage change from baseline at Day 48 was analysed using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline as a covariate.
Mean Percentage Change From Baseline in Body Weight at Day 48
Time Frame: Baseline (Day -1) and Day 48.
The mean percentage change from baseline in body weight at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, the last on-treatment measurement, regardless of rescue medication, was used (last observation carried forward \[LOCF\]).
Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48
Time Frame: Baseline (Day -1) and Days 20 and 48.
Twenty four-hour BP was determined using an ABPM device, and the mean change from baseline in the 24-hour systolic BP and 24-hour diastolic BP are presented for Days 20 and 48.
Number of Patients Who Experienced Adverse Events (AEs)
Time Frame: Day 1 up to 14 days after the last dose of IP (approximately 9 weeks).
AEs were collected from Day 1 of treatment up to 14 days after the last dose of IP. Serious AEs (SAEs) were collected from signing of informed consent. The numbers of patients who experienced any AE, any SAE (including events with an outcome of death), and any AE leading to discontinuation of IP are presented.
Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48.
Time Frame: Baseline (Day -1) and Days 1, 6, 13, 20 and 48: predose and 6 hours (+/-15 minutes) postdose.
Digital ECGs were taken at baseline and predose and postdose on Days 1, 6, 13, 20 and 48. The mean change from baseline is presented.
Secondary Outcomes
- Mean Change From Baseline in Fasting Plasma Glucose at Day 48(Baseline (Day -1) and Day 48 (predose).)
- Mean Change From Baseline in HbA1c at Day 48(Baseline (Day -1) and Day 48 (predose).)
- Mean Change From Baseline in Fructosamine at Day 48(Baseline (Day -1) and Day 48 (predose).)
- Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47(Baseline (Day -8 to -2) and Days 5, 12, 19 and 47.)
- Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47(Baseline (Day -8 to -2) and Days 5, 12, 19 and 47.)
- Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels(Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47.)
- Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48(Blood samples collected predose on Days 1 to 6, 13, 20, 34 and 48.)
- Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels(Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47.)
- Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382(Samples were collected predose on days 1, 13, 20 and 48, and 7 to 14 days after administration of last dose of IP.)