A Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics (PK) of MEDI0382 in Overweight and Obese Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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A Phase 1/2, multiple dose study with 6 cohorts of ascending doses designed to evaluate the efficacy, safety and pharmacokinetics (PK) of MEDI0382 in participants with Type 2 Diabetes Mellitus (T2DM).

Detailed Description
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This is a randomized, double-blind, placebo controlled study designed to evaluate the efficacy, safety, and PK of MEDI0382 administered as multiple daily SC doses to participants with T2DM. Approximately one hundred and seven participants will be enrolled across 6 cohorts. In cohorts 1-3 the participants will be randomized to MEDI0382 or placebo (2:1). In Cohort 4, participants will be randomized to MEDI0382 or placebo (1:1). In cohort 5 and 6 participants will be randomized to MEDI0382 or placebo (3:1).

Official Title
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A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Multiple-ascending-dose Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects With a History of Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: MEDI0382
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T2DM Must provide written informed consent Body mass index greater than (>) 27 and less than (<) 40 kg/m^2, inclusive Venous access suitable for multiple cannulations Vital signs within normal specified ranges Females must be non-lactating and non-childbearing potential Males must practice 2 effective contraceptive measures if sexually active Exclusion Criteria: Any concurrent condition that in the opinion of the investigator would interfere with the evaluation of the investigational product History or presence of gastrointestinal, renal, or hepatic disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs History of cancer within the last 10 years, with the exception of non-melanoma skin cancer Any clinically important illness (except for T2DM), medical/surgical procedure, or trauma within 4 weeks prior to dosing Fasting glucose greater than or equal to (>=) 200 mg/dL Positive Hepatitis B, Hepatitis C or human immunodeficiency virus test or use of antiretroviral medications at screening. Concurrent or previous use of a glucagon-like peptide 1 receptor agonist Current or previous use of systemic corticosteroids within the past 28 days prior to screening Use of any medicinal products or herbal preparations licensed for control of body weight or appetite is prohibited. Known or suspected history of alcohol or drug abuse within the past 3 years. Positive drug screen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo (matched to either 100 micrograms [mcg], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6). | Drug: Placebo<br>* Placebo administered subcutaneously.<br>|
| Experimental: Cohort 1: MEDI0382 100 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily from Day 1 to Day 7. | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|
| Experimental: Cohort 2: MEDI0382 150 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11). | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|
| Experimental: Cohort 3: MEDI0382 200 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15). | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|
| Experimental: Cohort 4: MEDI0382 200 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41). | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|
| Experimental: Cohort 5: MEDI0382 300 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22). | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|
| Experimental: Cohort 6: MEDI0382 300 mcg<br>Participants will receive MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17). | Drug: MEDI0382<br>* MEDI0382 administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Mixed-meal Test (MMT) Glucose Area Under the Concentration-time Curve From Time 0 to 4 Hours to the End of Treatment (EOT) (Cohort 4) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hours (hrs) after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post standardized meal intake (SMI) on Baseline (Day -1) and EOT (Day 41) | 
| Change From Baseline in Body Weight to the EOT (Cohort 4) |  | Baseline (Day 1) and EOT (Day 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 22 for Cohort 5; and Day 17 for Cohort 6) | 
| Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6) |  | Cohort 1: Baseline (Day 1) to EOT (Day 8); Cohort 2: Baseline (Day 1) to EOT (Day 12); Cohort 3: Baseline (Day 1) to EOT (Day 16); Cohort 5: Baseline (Day 1) to EOT (Day 22); Cohort 6: Baseline (Day 1) to EOT (Day 17) | 
| Percent Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6) |  | Cohort 4: Baseline (Day -2) to EOT (Day 42); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17) | 
| Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6) |  | Cohort 4: Baseline (Day -2) to EOT (Day 41); Cohort 5: Baseline (Day -2) to EOT (Day 22); Cohort 6: Baseline (Day -2) to EOT (Day 17) | 
| Change From Baseline in Fasting Glucose Prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | Cohort 1: Baseline (Day-1) to EOT (Day7); Cohort 2: Baseline (Day-1) to EOT (Day11); Cohort 3: Baseline (Day-1) to EOT (Day15); Cohort 4: Baseline (Day-1) to EOT (Day41); Cohort 5: Baseline (Day-1) to EOT (Day22); Cohort 6: Baseline (Day-1) to EOT (Day17) | 
| Percent Change From Baseline in Glucose Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24h) After MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, 240 minutes, and 24 hrs post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4; Day 22 for Cohort 5; and Day 17 for Cohort 6) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. Serious adverse events (SAE) is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). | From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days]) | 
| Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs | TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of participants with TEAEs related to vital signs and physical examination abnormalities were reported. | From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days]) | 
| Number of Participants With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs | TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of participants with TEAEs related to ECG abnormalities were reported. | From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days]) | 
| Number of Participants With Abnormal Clinical Laboratory Reported as TEAEs | TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 28 days after the last study dose of each cohort (approximately 60 days). Number of participants with TEAEs related to laboratory abnormalities were reported. | From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days]) | 
| Number of Participants With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6) | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behaviour of participants. Yes/No responses are mapped to C-SSRS to assess whether participant experienced suicidal behaviour and suicidal ideation. Suicidal behaviour questions includes preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation questions includes wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act (without specific plan), and active suicidal ideation with specific plan and intent. Participants with yes response to any category for suicidal ideation were reported below. | Cohort 4: Day -1, and Days 13, 20, 27, 34, and 40; Cohort 5: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 36 days); Cohort 6: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 31 days) | 
| Number of Participants With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6) | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behaviour of participants. Yes/No responses are mapped to C-SSRS to assess whether participant experienced suicidal behaviour and suicidal ideation. Suicidal behaviour questions includes preparatory acts or behaviour, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation questions includes wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intent to act, active suicidal ideation with some intent to act (without specific plan), and active suicidal ideation with specific plan and intent. Participants with yes response to any category for suicidal behaviour were reported below. | Cohort 4: Day -1, and Days 13, 20, 27, 34, and 40; Cohort 5: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 36 days); Cohort 6: Day -1 and Day 7-14 post last dose of MEDI0382 (approximately 31 days) | 
| Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3) | Terminal elimination half Life is the time measured for the plasma concentration of MEDI0382 to decrease by one half. | Cohort (C) 1 (Day [D] 1 and [&] D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose | 
| Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3) | Accumulation ratio was calculated as, Rac obtained from area under the curve from time zero to end of dosing interval (AUC[0-tau]) of Nth day divided by AUC(0-tau) of Day 1. | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose; and additional 48 hr post C1D7, C2D11, C3D15 dose | 
| Area Under the Concentration Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose | 
| Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose | 
| Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | C1 (D1 & D7), C2 (D5 & D11), and C3 (D9 & D15): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose and additional 48 hr post dose for C1D7, C2D11, C3D15; C4 (D9 & D41), C5 (D16 & D22), and C6 (D11 & D17): pre-dose & 0.5, 1, 2, 4, 6, 8, 12, 24 hr post dose | 
| Number of Participants With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6) |  | Day 1 up to 7-14 days post-last dose of MEDI0382 for all cohorts (Approximately 60 days) | 
| Percent Change From Baseline in Insulin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4; Day 22 for Cohort 5; and Day 17 for Cohort 6) | 
| Percent Change From Baseline in Proinsulin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4) | 
| Percent Change From Baseline in C-peptide AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4) | Mixed-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4) | 
| Percent Change From Baseline in Incretin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4) | Mixes-meal test involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples were obtained for measurement of glucose and parameters related to glucose metabolism just before and 4 hrs after consumption of the standardized meal (with no additional food intake during this time). Incretins included glucagon-like peptide-1 (GLP-1; active and inactive both), glucagon, and gastric inhibitory peptide (GIP). | 0 minutes before; and 15, 30, 45, 60, 90, 120, 180, and 240 minutes post SMI on Baseline (Day -1) and EOT (Day 7 for Cohort 1; Day 11 for Cohort 2; Day 15 for Cohort 3; Day 41 for Cohort 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI0382, diabetes