A Study to Investigate Different Doses of 0382 in Overweight and Obese Subjects With Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03244800
• Other study ID #: D5670C00011
• Status: Completed
• Phase: Phase 2
• Start date: September 4, 2017
• Est. completion date: January 23, 2018

Study information

• Verified date: November 2019
• Source: MedImmune LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: January 23, 2018
• Est. primary completion date: January 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria:

1. Male and female subjects aged = 18 years at screening

2. Provision of signed and dated written informed consent

3. BMI between 27 and 40 kg/m2

4. HbA1c range of 6.5% to 8.5%

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

6. 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

7. Female subjects of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating

8. 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.

Exclusion Criteria:

1. 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

2. Concurrent participation in another study of any kind and repeat randomisation in this study is prohibited

3. Severe allergy/hypersensitivity to any of the proposed study treatments

4. 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

5. 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

6. 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

7. 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])

8. 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.

9. 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

10. Severe congestive heart failure (New York Heart Association Class III or IV)

11. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia

12. 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

13. 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

14. Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody

15. 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.

16. Involvement of any AstraZeneca, MedImmune, contract research organization, or study site employee or their close relatives

17. History of acute or chronic pancreatitis or other diseases of the pancreas

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Overweight
• Type 2 Diabetes Mellitus

Intervention

Drug:
• MEDI0382
MEDI0382 will be administered subcutaneously once daily for 49 days.
• Placebo
Placebo will be administered subcutaneously once daily for 49 days.

Locations

Country	Name	City	State
Germany	Research Site	Berlin
Germany	Research Site	Magdeburg
Germany	Research Site	Mainz
Germany	Research Site	Neu-Ulm
Germany	Research Site	Neuss

Sponsors (1)

Lead Sponsor	Collaborator
MedImmune LLC

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal
Primary	Cohort 1: Percent Change From Baseline in Body Weight to Day 50	The percent change in body weight from baseline to Day 50 is reported.	Day 1 through Day 50
Secondary	Cohort 1: Change From Baseline in Glycated Haemoglobin (HbA1c) to Day 49	The change from baseline in Glycated haemoglobin (HbA1c) to Day 49 is reported.	Baseline (Day -1) through Day 49
Secondary	Cohort 1: Change From Baseline in Fasting Plasma Glucose to Day 49	The changes in the fasting plasma glucose level during the study period from baseline to Day 49 is reported.	Baseline (Day -1) through Day 49
Secondary	Cohort 1: Change From Baseline in Body Weight to Day 50	The changes in the body weight during the study period from baseline to Day 50 is reported.	Day 1 through Day 50
Secondary	Cohort 1: Percentage of Participants Achieving Greater Than or Equal to 5% Body Weight Loss From Baseline to Day 50	Participants achieving greater than or equal to 5% body weight loss from baseline to Day 50 is reported.	Day 1 through Day 50
Secondary	Cohort 1 and Cohort 2: Percent Change From Baseline in MMTT Plasma Glucose AUC 0-4h to Day 7	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) evaluation to Day 7 is reported.	Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised liquid meal
Secondary	Cohort 1 and Cohort 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are the events between first doses of study drug through 7 to 14 days after the last dose of study drug (approximately 64 days).	From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
Secondary	Cohort 1 and Cohort 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs	Treatment-emergent adverse events observed in participants with clinically significant vital signs abnormalities are reported. Vital sign parameters included blood pressure, heart rate, body temperature, and respiration rate.	From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
Secondary	Cohort 1 and Cohort 2: Number of Participants With Abnormal Electrocardiogram Reported as TEAEs	Treatment-emergent adverse events observed in participants with clinically significant ECG abnormalities are reported.	From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
Secondary	Cohort 1 and Cohort 2: Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs	An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator as medically significant was reported as an AE. Laboratory evaluations included haematology, serum chemistry, and urinalysis.	From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
Secondary	Cohort 1 and Cohort 2: Number of Participants With Injection Site Erythema	The injection site reactions observed during study visits were reported. Injection site reactions included (but are not limited to) local erythema, pain, tenderness, induration, swelling, pruritus, ulceration, and pigmentation.	From Day 1 through 7 to 14 days after the last dose of study drug (approximately 64 days)
Secondary	Cohort 1: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382	The area under the concentration-time curve during the dosing interval of MEDI0382 is reported.	Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Area Under the Concentration-time Curve During the Dosing Interval (AUCt) of MEDI0382	The area under the concentration-time curve during the dosing interval of MEDI0382 is reported.	Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1: Maximum Observed Concentration (Cmax) of MEDI0382	The maximum observed concentration of MEDI0382 is reported.	Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Maximum Observed Concentration (Cmax) of MEDI0382	The maximum observed concentration of MEDI0382 is reported.	Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382	The time to reach the maximum observed concentration of MEDI0382 is reported.	Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Time to Reach Maximum Observed Concentration (Tmax) of MEDI0382	The time to reach the maximum observed concentration of MEDI0382 is reported.	Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1: Terminal Half Life (t1/2) of MEDI0382	The t1/2 is the time measured for the concentration to decrease by one half after the dose of MEDI0382.	Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Terminal Half Life (t1/2) of MEDI0382	The t1/2 is the time measured for the concentration to decrease by one half after the dose of MEDI0382.	Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1: Accumulation Ratio (Racc) of MEDI0382	The Racc was calculated using the AUC method which account for the overall exposure measured using the specified time points on Day 22 and Day 49. Racc was calculated using the formula, Racc of Day 49 = AUCt of Day 49/AUCt of Day 22.	Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Accumulation Ratio of MEDI0382	The Racc was calculated using the AUC method which account for the overall exposure measured using the specified time points on Day 1, Day 7 and Day 14. Racc was calculated using the formulas: Racc of Day 7 = AUCt of Day 7/AUCt of Day 1; Racc of Day 14 = AUCt of Day 14/AUCt of Day 1.	Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1: Trough Plasma Concentration (Ctrough) of MEDI0382	Trough plasma concentration is the measured concentration from the plasma concentration-time data at the end of a dosing interval at steady state.	Cohort 1: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 22 and 49
Secondary	Cohort 2: Trough Plasma Concentration (Ctrough) of MEDI0382	Trough plasma concentration is the measured concentration from the plasma concentration time data at the end of a dosing interval at steady state.	Cohort 2: Predose and 1, 2, 4, 6, 8, and 12 hours postdose on Days 1, 7, and 14
Secondary	Cohort 1 and Cohort 2: Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI0382	Participants with positive serum antibodies to MEDI0382 are reported.	Baseline (Day 1), Day 29, Day 50, and Follow-up Visit 2 (28 days after the last dose [approximately 64 days])

External Links

•   A publication on the website: The Journal of Clinical Endocrinology & Metabolism
•   D5670C00011_protocol_amendment_2_ct
•   D5670C00011_Statistical_Analysis_Plan