A Study to Evaluate the Safety and Tolerability of MEDI0382 in Overweight and Obese Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a Phase 2a, randomized, blinded, placebo-controlled study in up to 20 overweight or obese participants with type 2 diabetes mellitus. The participants will participate in the study for approximately 18 weeks, including screening, run-in and treatment periods and a safety follow-up.

Official Title
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A Phase 2a Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of MEDI0382 in Overweight/Obese Subjects With 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: Participants aged 18 to 74 years (inclusive) at screening. Provision of signed and dated written informed consent (with the exception of consent for genetic and non-genetic research) prior to any study specific procedures. Body mass index (BMI) between 27 and 35 kg/m^2 (inclusive) at screening. Hemoglobin A1c (HbA1c) range of 6.5% to 8.5% (inclusive) at screening (Note: Participants may be re-tested for the HbA1c entry criterion only once.). Willing and able to self-inject study drug for the duration of the study. Diagnosed with type 2 diabetes mellitus with glucose control managed with metformin monotherapy where no significant dose change (increase or decrease >= 500 mg/day) has occurred in the three months prior to screening. Female participants must have a negative pregnancy test at screening and randomization, and must not be lactating. Female participants of childbearing potential who are sexually active with a male partner must be using at least one highly effective method of contraception from screening and up to 4 weeks after the last dose of study drug. Exclusion Criteria: History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the study drug, put the participant at risk, influence the participant's ability to participate or affect the interpretation of the results of the study and/or any participant unable or unwilling to follow study procedures during the run-in period. Any participant who has received another study drug as part of a clinical study or a glucagon-like peptide-1 (GLP-1) analogue containing preparation within the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening. Concurrent participation in another study of any kind and repeat randomization in this study is prohibited. Any participant who has received any of the following medications prior to the start of the study: Herbal preparations or drugs licensed for control of body weight or appetite Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying Antimicrobials within the quinolone, macrolide or azole class Any change in antihypertensive medication Aspirin (acetylsalicylic acid) Paracetamol (acetaminophen) or paracetamol-containing preparations Ascorbic acid (vitamin C) supplements Severe allergy/hypersensitivity to any of the proposed study treatments, standardized meals, or excipients. 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 participant has been treated with daily SC insulin within 90 days prior to screening. Acute pancreatitis, pancreatic amylase, and/or pancreatic lipase > 3 × upper limit of normal range (ULN); history of chronic pancreatitis; or serum triglyceride levels > 11 mmol/L (1000 mg/dL) at screening. Significant inflammatory bowel disease, gastroparesis or other severe disease or surgery affecting the upper gastrointestinal 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 nonalcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease without portal hypertension or cirrhosis) and/or participants with any of the following results at screening: Aspartate transaminase (AST) >= 3 × ULN Alanine transaminase (ALT) >= 3 × ULN Total bilirubin (TBL) >= 2 × ULN Impaired renal function defined as estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73m^2 at screening. Poorly controlled hypertension defined as: Systolic blood pressure (BP) > 160 mm Hg Diastolic BP or >= 90 mm Hg Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG or any abnormalities that may interfere with the interpretation of serial ECG changes. Prolonged QT intervals corrected for heart rate or family history of long QT-segment at screening. PR (PQ) interval prolongation, intermittent second or third-degree atrioventricular (AV) block, or AV dissociation. Persistent or intermittent complete bundle branch block. Unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke within 3 months prior to screening, or participants 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. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia. Hemoglobinopathy, hemolytic anemia or chronic anemia or any other condition known to interfere with the 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, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody. History of substance dependence, alcohol abuse, or excessive alcohol intake. Participants who use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study. Symptoms of depression or any other psychiatric disorder requiring treatment with medication. History of severe allergy/hypersensitivity, including to any component of the investigational product formulation or other biological agent, or ongoing clinically important allergy/hypersensitivity. Blood/plasma donation within 1 month of screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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 |
| --- | --- |
| Experimental: MEDI0382 Cohort 1<br>Participants will receive subcutaneous (SC) dose of MEDI0382 uptitrated weekly once daily up to 8 weeks during the up-titration period and thereafter once daily in 3-week treatment extension period (TEP). | Drug: MEDI0382<br>* Subcutaneous dose of MEDI0382 will be up-titrated weekly once daily up to 8 weeks during the uptitration period and thereafter once daily in 3-week TEP.<br>|
| Placebo Comparator: Placebo Cohort 1<br>Participants will receive SC dose of placebo matched to MEDI0382 once daily up to 8 weeks during the uptitration period and thereafter once daily through 3 week TEP. | Drug: Placebo<br>* Subcutaneous dose of placebo matched to MEDI0382 will be administered once daily up to 8 weeks during the up-titration period and thereafter once daily through 3 week TEP.<br>|
| Experimental: MEDI0382 Cohort 2<br>Participants will receive SC dose of MEDI0382 uptitrated weekly once daily up to 8 weeks during the up-titration period and thereafter once daily in 3-week TEP. | Drug: MEDI0382<br>* Subcutaneous dose of MEDI0382 will be up-titrated weekly once daily up to 8 weeks during the uptitration period and thereafter once daily in 3-week TEP.<br>|
| Placebo Comparator: Placebo Cohort 2<br>Participants will receive SC dose of placebo matched to MEDI0382 once daily up to 8 weeks during the up-titration period and thereafter once daily through 3 week TEP. | Drug: Placebo<br>* Subcutaneous dose of placebo matched to MEDI0382 will be administered once daily up to 8 weeks during the up-titration period and thereafter once daily through 3 week TEP.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Through the End of the Up-titration Period | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (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. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. | Baseline (Day -1) through Day 56 (end of Up-titration period) | 
| Number of Participants With TEAEs and TESAEs Through the End of the Follow-up Period | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A 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. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. | Baseline (Day-1) through 28 days post last dose (end of follow-up period; approximately up to 5 months) | 
| Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs Through the End of the Up-titration Period | Number of participants with abnormal ECGs reported as TEAEs are reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, QT intervals, and QTcF intervals from the primary lead of the digital 12-lead ECG. | Baseline (Day -1) through Day 56 (end of Up-titration period) | 
| Number of Participants With Abnormal ECGs Reported as TEAEs Through the End of the Follow-up Period | Number of participants with abnormal ECGs reported as TEAEs are reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, QT intervals, and QTcF intervals from the primary lead of the digital 12-lead ECG. | Baseline (Day-1) through 28 days post last dose (end of follow-up period; approximately up to 5 months) | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs Through the End of the Up-titration Period | Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, body temperature, and respiratory rate). | Baseline (Day -1) through Day 56 (end of Up-titration period) | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs Through the End of the Follow-up Period | Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, body temperature, and respiratory rate). | Baseline (Day-1) through 28 days post last dose (end of follow-up period; approximately up to 5 months) | 
| Number of Participants With Abnormal Physical Examinations Reported as TEAEs Through the End of the Up-titration Period | Number of participants with abnormal physical examinations reported as TEAEs are reported. Abnormal physical examinations findings are defined as any abnormal finding in the following body systems: immunologic/allergy; head, ears, eyes, nose, and throat; respiratory; cardiovascular; gastrointestinal; musculoskeletal; neurological psychiatric; dermatologic; hematologic/lymphatic; and, endocrine. | Baseline (Day -1) through Day 56 (end of Up-titration period) | 
| Number of Participants With Abnormal Physical Examinations Reported as TEAEs Through the End of the Follow-up Period | Number of participants with abnormal physical examinations reported as TEAEs are reported. Abnormal physical examination findings are defined as any abnormal finding in the following body systems: immunologic/allergy; head, ears, eyes, nose, and throat; respiratory; cardiovascular; gastrointestinal; musculoskeletal; neurological psychiatric; dermatologic; hematologic/lymphatic; and endocrine. | Baseline (Day-1) through 28 days post last dose (end of follow-up period; approximately up to 5 months) | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs Through the End of the Up-titration Period | Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine. | Baseline (Day -1) through Day 56 (end of Up-titration period) | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs Through the End of the Follow-up Period | Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine. | Baseline (Day-1) through 28 days post last dose (end of follow-up period; approximately up to 5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Time Curve Over a Dosing Interval (AUCτ) of MEDI0382 | Area under the plasma concentration time curve over a dosing duration (AUCτ) of MEDI0382 is reported. | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dose on Days 1, 7, 14, 35, 42, 49 and 56; pre-dose on Days 22, 29, 70, 84; additional 48 and 72 hours post-dose on Day 84 | 
| Maximum Observed Serum Concentration (Cmax) of MEDI0382 | Maximum observed serum concentration (Cmax) of MEDI0382 is reported. | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dose on Days 1, 7, 14, 35, 42, 49 and 56; pre-dose on Days 22, 29, 70, 84; additional 48 and 72 hours post-dose on Day 84 | 
| Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 | Time to observed maximum serum concentration (Tmax) of MEDI0382 is reported. | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dose on Days 1, 7, 14, 35, 42, 49 and 56; pre-dose on Days 22, 29, 70, 84; additional 48 and 72 hours post-dose on Day 84 | 
| Trough Plasma Concentration (Ctrough) of MEDI0382 | Trough concentration is the lowest concentration reached by a drug before the next dose is administered. Trough plasma concentration (Ctrough) of MEDI0382 is reported. | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dose on Days 1, 7, 14, 35, 42, 49 and 56; pre-dose on Days 22, 29, 70, 84; additional 48 and 72 hours post-dose on Day 84 | 
| Observed Accumulation Ratio (Ro) of MEDI0382 Calculated Using AUC | The Ro was calculated using the AUC method which account for the overall exposure measured using the Day 1 and specified time point (Day I). Ro = AUCtrough [Day I]/AUCtrough [Day 1]; where I is the specified day. | Pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dose on Days 1, 7, 14, 35, 42, 49 and 56; pre-dose on Days 22, 29, 70, 84; additional 48 and 72 hours post-dose on Day 84 | 
| Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI0382 Treatment | Number of participants with positive ADA to MEDI0382 are reported. | Pre-dose (Day -2), Days 7, 14, 35, 42, 56; Day 21 of 3 week treatment extension, and 28 days post last dose (approximately 5 months) | 
| Change From Baseline in Daily (24 Hours) Average Glucose Levels Over Time as Measured by Continuous Glucose Monitoring (CGM) | Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. During 14 days follow-up (Day 91), last observation carried forward (LOCF) approach was used to calculate the value. | Baseline (Day -1) through Day 56 (end of the up-titration period), Day 77 (end of the treatment extension period) and Day 91 (end of the follow-up period) | 
| Change From Baseline in 7-day Average Glucose Levels Over Time as Measured by CGM | Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. | Baseline (Days -7 to -1), Days 1-7, Days 8-14, Days 15-21, Days 22-28, Days 29-35, Days 36-42, Days 43-49, Days 50-56 of the Up-titration period, and Days 71-77 of end of the treatment extension period | 
| Percentage Change From Baseline in Glucose Area Under Concentration Time-curve Over 4 Hours (AUC4Hrs) During a Standardized Breakfast, Lunch, and Evening Meal Over Time as Measured by CGM | Change from baseline in percentage of glucose AUC4Hrs during a standardized breakfast, lunch, and evening meal over time is reported. Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. | Baseline (Day -1) through Day 7 (end of Week 1), Day 56 (end of the up-titration period), and Day 77 (end of the treatment extension period) | 
| Change From Baseline in Coefficient of Variation (CV) in Glucose Over 7 Days as Measured by CGM | Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. Change from baseline in coefficient of variation in glucose over 7 days is reported. | Baseline (Days -7 to -1), Days 1-7, Days 8-14, Days 15-21, Days 22-28, Days 29-35, Days 36-42, Days 43-49, Days 50-56 of the Up-titration period, and Days 71-77 of end of the treatment extension period | 
| Change From Baseline in Percentage of Time Spent in Hyperglycemia, Normoglycemia, and Clinically Significant Hypoglycemia Over 24 Hours Time as Measured by CGM | Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. Hyperglycemia (> 140 mg/dL), normoglycemia (70 -140 mg/dL), and clinically significant hypoglycemia (< 54 mg/dL). | Baseline (Day -1), Days 7, 14, 21, 28, 35, 42, 49, 56 of the up-titration period, and Day77 (end of the treatment extension period) | 
| Change From Baseline in Percentage of Time Spent in Hyperglycemia, Normoglycemia, and Clinically Significant Hypoglycemia Over 7 Days as Measured by CGM | Continuous glucose monitoring is a minimally invasive device applied to the skin in the upper arm that provides a measure of interstitial glucose levels every 15 minutes. Data derived from CGM was used to calculate the average glucose level over 24-hour and 7-day periods to compare the glucose lowering efficacy of each dose level. Hyperglycemia (> 140 mg/dL), normoglycemia (70 -140 mg/dL), and clinically significant hypoglycemia (< 54 mg/dL). | Baseline (Days -7 to -1), Days 1-7, Days 8-14, Days 15-21, Days 22-28, Days 29-35, Days 36-42, Days 43-49, Days 50-56 of the Up-titration period, and Days 71-77 of end of the treatment extension period | 
| Change From Baseline in Estimated Hemoglobin A1c (HbA1c) Based on 7-day CGM Glucose Over Time | Change from baseline in estimated HbA1c based on 7-day glucose over time is reported. | Baseline (Days -7 to -1), Days 1-7, Days 8-14, Days 15-21, Days 22-28, Days 29-35, Days 36-42, Days 43-49, Days 50-56 of the Up-titration period, and Days 71-77 of end of the treatment extension period | 
| Change From Baseline in Fasting Plasma Glucose Over Time | Change from baseline in fasting plasma glucose over time is reported. During the Day 21, and Day 28, LOCF approach was used to calculate the value. | Baseline (Day -1), Days 7, 14, 21, 28, 35, 42, 49, 56 of the up-titration period, and Day77 (end of the treatment extension period) | 
| Change From Baseline in HbA1c | Change from baseline in HbA1c is reported. | Baseline (Day -1) through Day 77 (end of the treatment extension period) | 
| Absolute Change From Baseline in Body Weight | Absolute change from baseline in body weight is reported. | Baseline (Day -1) through Day 56 (end of the up-titration period) and Day 77 (end of the TEP) | 
| Percentage Change From Baseline in Body Weight | Percentage change from baseline in body weight is reported. | Baseline (Day -1) through Day 56 (end of the up-titration period) and Day 77 (end of the TEP) | 
| Absolute Change From Baseline in Body Weight to the End of Each Week of the Up-titration Period | Absolute change from baseline in body weight to the end of each week of the up-titration period is reported. | Baseline (Day -1), Days 7, 14, 35, 42, 49, and 56 | 
| Percentage Change From Baseline in Body Weight to the End of Each Week of the Up-titration Period | Percentage change from baseline in body weight to the end of each week of the up-titration period is reported. | Baseline (Day -1), Days 7, 14, 35, 42, 49, and 56 | 
| Percentage of Participants Achieving Greater Than 5% Body Weight Loss From Baseline to the End of the Treatment Extension Period | Percentage of participants achieving greater than 5% body weight loss from baseline is reported. | Baseline (Day -1) through Day 77 (end of the treatment extension period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI0382, diabetes, obesity, overweight, type 2 diabetes mellitus