Safety and Tolerability Study of Cotadutide in Japanese Obese Subjects With Type 2 Diabetes Melitus

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1 study designed to assess the safety and tolerability of MEDI0382 (Cotadutide) in Japanese T2DM patients.

Detailed Description
-----------------
This is a randomized, blinded, placebo-controlled study designed to evaluate the safety, tolerability, PK and efficacy of ascending doses of Cotadutide in Japanese obese subjects with T2DM. Approximately 20 subjects will be screened in total and 16 subjects will be randomized to Cotadutide or placebo in a 3:1 ratio. Those subjects who receive Cotadutide will be titrated up to HCTD. The study has a 2-week screening period, a run-in period of 9 days and an up to 7-week up-titration treatment period followed by a 3-week treatment extension period (if applicable), followed by a 28-day follow-up period.

Official Title
-----------------
A Phase 1 Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Cotadutide in Japanese Obese Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Cotadutide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Provision of signed and dated written informed consent prior to any mandatory study specific procedures, sampling, and analyses. Subject must be 20 to 74 years of age at screening. HbA1c range of 6.5% to 8.5% at screening and run-in visit. Willing and able to self-inject investigational product for the duration of the study. Individuals who are diagnosed with T2DM and have inadequate glycaemic control with diet and exercise. Individuals whose current condition at enrolment are drug naïve defined as Never received medical treatment for diabetes (insulin and/or other anti-diabetic agents [oral or injection]) OR Received medical treatment for diabetes for less than 30 days since diagnosis.Subjects also should not have a history of insulin therapy within 2 weeks of screening (with the exception of insulin therapy during a hospitalization for other causes or use in gestational diabetes) OR Previously received medical treatment for diabetes but have not been treated within 6 weeks of randomization. BMI within the range 25 to 35 kg/m2 at screening. Negative pregnancy test for female subjects. Female subjects of childbearing potential who are sexually active with a male partner must be willing to use at least one highly effective method of contraception from screening and up to 4 weeks after the last dose of investigational product. Exclusion Criteria Subjects with any of the following results at screening and run-in visit 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. Acute pancreatitis at screening or 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 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 NASH or non-alcoholic fatty liver disease without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening or run-in visit. Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN) Alanine transaminase (ALT) ≥ 3 × ULN Total bilirubin (TBL) ≥ 2 × ULN Impaired renal function defined as estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73m2 at screening or run-in visit (GFR estimated according to Modification of Diet in Renal Disease [MDRD] using MDRD Study Equation IDMS-traceable [International System of Units (SI)]). Poorly controlled hypertension defined as, For age ≤ 55 years; Systolic BP > 140 mmHg Diastolic BP ≥ 90 mmHg For age > 55 years; Systolic BP > 150 mmHg Diastolic BP ≥ 90 mmHg After 10 minutes of supine rest and confirmed by repeated measurement at screening or run-in visit. Subjects who fail BP screening criteria may be considered for 24-hour or day time ABPM at the discretion of the investigator. Subjects who maintain a mean 24-hour BP < 130/80 mmHg with a preserved nocturnal dip of > 15% or day time BP < 135/85 mmHg will be considered eligible Resting heart rate is ≥ 80 bpm at screening or run-in visit. Any clinically important abnormalities in rhythm, conduction, or morphology of the 12-lead ECG or any abnormalities that may interfere with the interpretation of serial ECG changes, including QTc interval changes at screening, as judged by the investigator. Prolonged QT intervals corrected for heart rate using Fridericia's formula (QTcF) > 450 msec, or family history of long QT-segment at screening or run-in visit. PR (PQ) interval prolongation (> 220 msec), intermittent second (Wenckebach block while asleep is not exclusive), or third-degree atrioventricular (AV) block, or AV dissociation at screening or run-in visit. Persistent or intermittent complete bundle branch block. A QRS duration < 120 msec is acceptable if there is no evidence of ventricular hypertrophy or preexcitation at screening or run-in visit. Abnormal findings during the exercise stress test, such as chest pain, dyspnoea, presyncope, arrhytmias, signs of cardiac ischemia on ECG as judged by the investigator. History of, unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke, or subjects who have undergone percutaneous coronary intervention or a coronary artery bypass graft 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. Hemoglobinopathy, hemolytic anemia or chronic anemia (hemoglobin, < 11.5 g/dL [115 g/L]) for males, < 10.5 g/dL (105 g/L) for females) at screening or run-in visit, 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 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 run-in visit. Subjects 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 (eg, anti-depressants, anti-psychotics) at screening. However, subjects who use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study. History of severe allergy/hypersensitivity, including to any component of the investigational product formulation including excipients or other biological agent, any of the proposed study treatments, or ongoing clinically important allergy/hypersensitivity. Any subject who has received another investigational product as part of a clinical study or a 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. Any subject who has received any of the following medications within the specified timeframe prior to the start of the study. Herbal preparations within one week prior to the start of screening or drugs licensed for control of body weight or appetite within 30 days (or 5 half-lives of the drug) prior to the start of screening Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying and within 2 weeks prior to the start of dosing Antimicrobials within the quinolone, macrolide or azole class within 2 weeks prior to the start of dosing Any change in antihypertensive medication within 3 months prior to screening Any change in thyroid replacement therapy within 2 months prior to screening Aspirin at a total daily dose of greater than 150 mg Paracetamol or paracetamol-containing preparations at a total daily dose of greater than 3000 mg Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg Concurrent participation in another study of any kind and repeat randomization in this study. Received Cotadutide in another clinical study prior to enrolment in this study.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Drug: Placebo<br>* Placebo administered subcutaneously<br>|
| Experimental: Cotadutide<br>Cotadutide administered subcutaneously | Drug: Cotadutide<br>* Cotadutide administered subcutaneously<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Incidence of treatment-emergent serious adverse events (TESAEs) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Clinically important changes in 12-lead electrocardiogram (ECG) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Vital signs as measured by pulse rate (bpm) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Vital signs as measured by blood pressure (mmHg) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| ABPM (Ambulatory blood pressure monitoring) to measure pulse rate (bpm) and blood pressure (mmHg) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Physical examination (abnormality to be reported as part of adverse events) | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 
| Clinical laboratory evaluations | To assess the safety and tolerability of Cotadutide | Baseline until the follow-up period, 28 days post-last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve (AUC) during the dosing interval (AUCtau) | To characterize the PK profile of Cotadutide | Day1 of Up-titration treatment period to Day 21 of Treatment extension period, total of up to 10 weeks | 
| Maximum observed concentration (Cmax) | To characterize the PK profile of Cotadutide | Day1 of Up-titration treatment period to Day 21 of Treatment extension period, total of up to 10 weeks | 
| Time to Cmax (tmax) | To characterize the PK profile of Cotadutide | Day1 of Up-titration treatment period to Day 21 of Treatment extension period, total of up to 10 weeks | 
| Trough plasma concentration (Ctrough) | To characterize the PK profile of Cotadutide | Day1 of Up-titration treatment period to Day 21 of Treatment extension period, total of up to 10 weeks | 
| Anti-drug antibodies (ADAs) to Cotadutide | To characterize the immunogenicity of Cotadutide | At baseline through end of study, 98 days in total | 
| Change in average glucose levels (mg/dL) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in coefficient of variation | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in percentage time spent in hyperglycemia (> 140 mg/dL) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in percentage time spent in normoglycemia (70 -140 mg/dL) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in percentage time spent in clinically significant hypoglycemia (< 54 mg/dL) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in estimated hemoglobin A1c (HbA1c) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | At baseline through end of study, 98 days in total | 
| Change in fasting plasma glucose (mg/dL) | To assess the effect of Cotadutide on glucose control as measured by additional measrues of glucose control | At baseline through end of study, 98 days in total | 
| Change in HbA1c | To assess the effect of Cotadutide on glucose control as measured by additional measrues of glucose control | At baseline through end of study, 98 days in total | 
| Percentage change in body weight | To assess the effect of Cotadutide on body weight | At baseline through end of study, 98 days in total | 
| Absolute change in body weight (kg) | To assess the effect of Cotadutide on body weight | At baseline through end of study, 98 days in total | 
| Proportion of subjects achieving > 5% body weight loss | To assess the effect of Cotadutide on body weight | At baseline through end of study, 98 days in total | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, Cotadutide, MEDI0382, D5671C00003, Type 2 Diabetes