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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female subjects aged ≥ 18 years at screening
- •Provision of signed and dated written informed consent
- •BMI between 27 and 40 kg/m2
- •HbA1c range of 6.5% to 8.5%
- •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
- •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
- •Female subjects of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating
- •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.
排除标准
- •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
- •Concurrent participation in another study of any kind and repeat randomisation in this study is prohibited
- •Severe allergy/hypersensitivity to any of the proposed study treatments
- •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
- •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
- •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
- •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])
- •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.
- •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
- •Severe congestive heart failure (New York Heart Association Class III or IV)
- •Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
- •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
- •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
- •Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody
- •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.
- •Involvement of any AstraZeneca, MedImmune, contract research organization, or study site employee or their close relatives
- •History of acute or chronic pancreatitis or other diseases of the pancreas
研究组 & 干预措施
Placebo Cohort 1
Participants will receive placebo matching with MEDI0382 subcutaneously once daily for 49 days.
干预措施: Placebo (Drug)
MEDI0382 Cohort 1
Participants will receive subcutaneous injection of MEDI0382 once daily for 49 days as Dose 1 for 7 days, followed by Dose 2 for 7 days, Dose 3 for 7 days, and Dose 4 for 28 days
干预措施: MEDI0382 (Drug)
PLacebo Cohort 2
Participants will receive placebo matching with MEDI0382 subcutaneously once daily for 49 days.
干预措施: Placebo (Drug)
MEDI0382 Cohort 2
Participants will receive subcutaneous injection of MEDI0382 once daily for 49 days as Dose 1 for 14 days, followed by Dose 2 for 14 days, Dose 3 for 14 days, and Dose 4 for 7 days.
干预措施: MEDI0382 (Drug)
结局指标
主要结局
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
时间窗: Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal
The MMTT test involved the consumption of a standardised liquid meal within 5 minutes and timed serial blood samples obtained for the measurement of glucose and parameters related to glucose metabolism through 240 minutes after consumption of the standardised meal (with no additional food intake during this time). The percent change in the MMTT plasma glucose AUC 0-4h from the baseline (Day -1) to Day 49 is reported.
Cohort 1: Percent Change From Baseline in Body Weight to Day 50
时间窗: Day 1 through Day 50
The percent change in body weight from baseline to Day 50 is reported.
次要结局
- Cohort 1: Percentage of Participants Achieving Greater Than or Equal to 5% Body Weight Loss From Baseline to Day 50(Day 1 through Day 50)
- Cohort 1 and Cohort 2: Number of Participants With Abnormal Electrocardiogram Reported as TEAEs(From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days))
- Cohort 1: Change From Baseline in Glycated Haemoglobin (HbA1c) to Day 49(Baseline (Day -1) through Day 49)
- Cohort 1: Change From Baseline in Fasting Plasma Glucose to Day 49(Baseline (Day -1) through Day 49)
- Cohort 1: Maximum Observed Concentration (Cmax) of MEDI0382(Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 2: Maximum Observed Concentration (Cmax) of MEDI0382(Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)
- Cohort 1 and Cohort 2: Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI0382(Baseline (Day 1), Day 29, Day 50, and Follow-up Visit 2 (28 days after the last dose [approximately 64 days]))
- Cohort 2: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382(Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)
- Cohort 1: Accumulation Ratio (Racc) of MEDI0382(Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 2: Trough Plasma Concentration (Ctrough) of MEDI0382(Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)
- Cohort 1: Change From Baseline in Body Weight to Day 50(Day 1 through Day 50)
- Cohort 1 and Cohort 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days))
- Cohort 1 and Cohort 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs(From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days))
- Cohort 1: Terminal Half Life (t1/2) of MEDI0382(Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 1: Trough Plasma Concentration (Ctrough) of MEDI0382(Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 1 and Cohort 2: Percent Change From Baseline in MMTT Plasma Glucose AUC 0-4h to Day 7(Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal)
- Cohort 1 and Cohort 2: Number of Participants With Injection Site Erythema(From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days))
- Cohort 1: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382(Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 1: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382(Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49)
- Cohort 2: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382(Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)
- Cohort 1 and Cohort 2: Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs(From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days))
- Cohort 2: Terminal Half Life (t1/2) of MEDI0382(Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)
- Cohort 2: Accumulation Ratio of MEDI0382(Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14)