Safety and Tolerability Study of MEDI0382 in Japanese Preobese or Obese Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: MEDI0382 100 μg
* Drug: MEDI0382 200 μg
* Drug: MEDI0382 300 μg
* Drug: PlaceboA
* Drug: MEDI0382 50 ug
* Drug: PlaceboB


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Placebo per day,SC injection on 48 days. | Drug: PlaceboA<br>* 1.0 mL liquid formulation per Vial<br>Drug: PlaceboB<br>* Solution for injection in 1.0 mL pre-filled syringe.<br>|
| Experimental: MEDI0382 100μg<br>50 μg/day,SC injection on the first 5 days and 100 μg/day,SC injection on 43 days | Drug: MEDI0382 100 μg<br>* Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose<br>Drug: MEDI0382 50 ug<br>* Solution for injection, 1.0 mL per vial, 50 ug<br>|
| Experimental: MEDI0382 200μg<br>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. | Drug: MEDI0382 100 μg<br>* Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose<br>Drug: MEDI0382 200 μg<br>* Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose<br>Drug: MEDI0382 50 ug<br>* Solution for injection, 1.0 mL per vial, 50 ug<br>|
| Experimental: MEDI0382 300μg<br>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 | Drug: MEDI0382 100 μg<br>* Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose<br>Drug: MEDI0382 200 μg<br>* Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose<br>Drug: MEDI0382 300 μg<br>* Solution for injection in 1.0 mL pre filled syringe, 300 μg per dose, 1 dose<br>Drug: MEDI0382 50 ug<br>* Solution for injection, 1.0 mL per vial, 50 ug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in 24-Hour Heart Rate at 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. | Baseline (Day -1) and Days 20 and 48. | 
| Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at 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. | Baseline (Day -1) and 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 | 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. | 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. | 
| Mean Percentage Change From Baseline in Body Weight at 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]). | Baseline (Day -1) and Day 48. | 
| Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | 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. | Baseline (Day -1) and Days 1, 6, 13, 20 and 48: predose and 6 hours (+/-15 minutes) postdose. | 
| Number of Patients Who Experienced Adverse Events (AEs) | 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. | Day 1 up to 14 days after the last dose of IP (approximately 9 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HbA1c at Day 48 | The mean change from baseline in HbA1c 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, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF). | Baseline (Day -1) and Day 48 (predose). | 
| Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | The mean change from baseline in fasting plasma glucose 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, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF). | Baseline (Day -1) and Day 48 (predose). | 
| Mean Change From Baseline in Fructosamine at Day 48 | The mean change from baseline in fructosamine 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 (LOCF). | 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 | Hyperglycaemia was defined as blood glucose >7.8 mmol/L or >140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the indicated timepoints is presented. | 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 | Hypoglycaemia was defined as blood glucose <3 mmol/L or <54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the timepoints is presented. | 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 | Hyperglycaemia was defined as blood glucose >7.8 mmol/L or >140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the dose levels (during titration) is presented, up to Day 47, per randomised group. | Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47. | 
| 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 | Hyp0glycaemia was defined as blood glucose <3 mmol/L or <54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the randomised dose levels (during titration) is presented, up to Day 47, per randomised group. | 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 | To evaluate pharmacokinetics (PK), blood samples were collected predose and Ctrough of MEDI0382 was determined. Results are presented for Days 2, 5, 34 and 48. | Blood samples collected predose on Days 1 to 6, 13, 20, 34 and 48. | 
| Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | The number of patients who were ADA positive at baseline and/or post-baseline are presented. Persistent positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at the last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. +ve = positive | Samples were collected predose on days 1, 13, 20 and 48, and 7 to 14 days after administration of last dose of IP. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI0382, Diabetes, D5674C00001, T2DM, Type 2 Diabetes