Clinical trial NCT02548585: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 2 Diabetes Mellitus
Keywords: MEDI0382, diabetes
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2015-09-14
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: 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)
measure: Change From Baseline in Body Weight to the EOT (Cohort 4)
timeFrame: Baseline (Day 1) and EOT (Day 42)
Secondary outcomes:
measure: Percent Change From Baseline in MMT Glucose AUC0-4h to the EOT (Cohorts 1, 2, 3, 5, and 6)
timeFrame: 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)
measure: Change From Baseline in Body Weight to the EOT (Cohorts 1, 2, 3, 5, and 6)
timeFrame: 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)
measure: Percent Change From Baseline in Hemoglobin A1c (HbA1c) to the EOT (Cohorts 4, 5, and 6)
timeFrame: 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)
measure: Change From Baseline in Fructosamine to the EOT (Cohorts 4, 5, and 6)
timeFrame: 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)
measure: Change From Baseline in Fasting Glucose Prior to MMT to the EOT (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
measure: Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs
timeFrame: From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
measure: Number of Participants With Abnormal 12 Lead Electrocardiogram (ECG) Reported as TEAEs
timeFrame: From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
measure: Number of Participants With Abnormal Clinical Laboratory Reported as TEAEs
timeFrame: From Day 1 to follow-up period (28 days after the last study dose for each cohort [approximately 60 days])
measure: Number of Participants With Any Suicidal Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score (Cohorts 4, 5, and 6)
timeFrame: 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)
measure: Number of Participants With Any Suicidal Behaviour as Assessed by C-SSRS Score (Cohorts 4, 5, and 6)
timeFrame: 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)
measure: Terminal Elimination Half Life (t1/2) of MEDI0382 (Cohorts 1, 2, and 3)
timeFrame: 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
measure: Accumulation Ratio (Rac) of MEDI0382 (Cohorts 1, 2, and 3)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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
measure: Minimum Observed Plasma Concentration (Cmin) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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
measure: Number of Participants With Positive Anti-drug Antibodies to MEDI0382 (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: Day 1 up to 7-14 days post-last dose of MEDI0382 for all cohorts (Approximately 60 days)
measure: Percent Change From Baseline in Insulin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, 4, 5, and 6)
timeFrame: 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)
measure: Percent Change From Baseline in Proinsulin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4)
timeFrame: 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)
measure: Percent Change From Baseline in C-peptide AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4)
timeFrame: 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)
measure: Percent Change From Baseline in Incretin AUC0-4h After MMT to EOT (Cohorts 1, 2, 3, and 4)
timeFrame: 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)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
city: Erfurt
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Neu-Ulm
country: Germany
facility: Research Site
city: Neuss
country: Germany
facility: Research Site
Study officials:
affiliation: Universitätsklinikum Leipzig
name: Michael Stumvoll
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, Robertson D, Jain M, Petrone M, Rondinone C, Hirshberg B, Jermutus L. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018 Jun 30;391(10140):2607-2618. doi: 10.1016/S0140-6736(18)30726-8. Epub 2018 Jun 23.