Chinese Multiple Dose Escalation (MDE) High Dose Study

Study Overview
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Brief Summary
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A Phase 1 Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Cotadutide in Overweight/Obese Subjects with Chinese ancestry with Type 2 Diabetes Mellitus

Detailed Description
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This is a randomized, double-blinded, placebo-controlled study designed to evaluate the safety, tolerability, PK and efficacy of ascending doses of cotadutide in overweight or obese subjects with T2DM. This study will enroll subjects aged 18 to 74 years with a body mass index (BMI) ≥ 25 and ≤ 35 kg/m2. Subjects will have a diagnosis of T2DM and inadequate blood glucose control as defined by a HbA1c of 7% to 8.5%, and will be on metformin monotherapy in the three months prior to screening. Total 16 Chinese subjects will be randomized to cotadutide or placebo in a 3:1 ratio (cotadutide [n=12] and placebo [n=4]) at multicentre in China mainland. Those subjects who receive cotadutide once daily SC will be titrated to a maximum of 600 μg once daily SC, beginning at 50 μg once daily SC. The study has about 2 weeks screening period, a run-in period of 10 days and an up to 7-week up-titration treatment period followed by a 3-week treatment extension period at the dose of 600 μg and followed by a 28-day follow-up period.

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

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Experimental: Cotadutide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects aged 18 to 74 years Provision of signed and dated written informed consent prior to any study specific procedures BMI between 25 and 35 kg/m2 HbA1c range of 7% to 8.5% Willing and able to self-inject investigational product Diagnosed with T2DM with glucose control managed with metformin monotherapy where no significant dose change has occurred in the three months prior to screening. Women of child-bearing potential who are sexually active with a male partner must be using at least one highly effective method of contraception. And must have a negative serum or urine pregnancy test within 72 hours prior to the start of IP, and must not be breastfeeding. Exclusion Criteria Any subject who has received another IP 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 Concurrent participation in another randomization study of any kind; repeat randomization is prohibited Any subject who has received any of the following medications within the specified timeframe prior to the start of the study Herbal preparations for control of body weight or appetite Drugs licensed for control of body weight or appetite Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying Antimicrobials within the quinolone (eg, ciprofloxacin), macrolide (eg, clarithromycin) or azole class (eg, ketoconazole) Any change in antihypertensive medication Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily Paracetamol (acetaminophen) 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 Symptoms of acutely decompensated blood glucose control, recent severe hypoglycemia, a history of T1DM orDKA Acute pancreatitis at screening or history of acute pancreatitis or chronic pancreatitis or serum triglyceride levels > 11 mmol/L at screening Significant inflammatory bowel disease, gastroparesis or other severe disease or surgery affecting the upper GI tract, which may affect gastric emptying or could affect the interpretation of safety and tolerability data Significant hepatic disease (except for NASH or NAFLD without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening: AST ≥ 3 × ULN ALT ≥ 3 × ULN TBL ≥ 2 × ULN Impaired renal function defined as eGFR< 30 mL/minute/1.73m2 at screening Poorly controlled hypertension defined as: SBP > 160 mmHg DBP or ≥ 90 mmHg - After 10 minutes of supine rest and confirmed by repeated measurement at screening. Subjects who fail BP screening criteria may be considered for 24-hour ABPM at the discretion of the investigator. Subjects who maintain a mean 24-hour BP < 160/100 mmHg with a preserved nocturnal dip of > 15% will be considered eligible. 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, including QTc interval changes at screening, as judged by the investigator, and prolonged QTcF > 450 ms, or family history of long QT-segment at screening PR (PQ) interval prolongation, intermittent second (Wenckebach block while asleep is not exclusive), or third-degree 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 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 (NYHA Class III or IV) Basal calcitonin level ≥ 50 ng/L at screening or history/family history of medullary thyroid carcinoma or MEN2 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 HIV antibody History of substance dependence, alcohol abuse, or excessive alcohol intake 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. 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 or other biological agent, or ongoing clinically important allergy/hypersensitivity as judged by the investigator Blood/plasma donation within 1 month of screening Involvement of any AstraZeneca, the contract research organization, or the virtual study site employee or their close relatives For women only- currently pregnant (confirmed with positive pregnancy test) or breastfeeding

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
Interventional Model Description: Total 16 Chinese subjects will be randomized to cotadutide or placebo in a 3:1 ratio (cotadutide [n=12] and placebo [n=4]) at multicenter in China mainland.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cotadutide<br>Those subjects who were randomized to cotadutide once daily SC will begin at 50 μg once daily, then up-titrated to 100 μg once daily a week later, after that up-titration will be done at 100 μg increment weekly, till to a maximum of 600 μg once daily. | Drug: Experimental: Cotadutide<br>* Cotadutide: subcutaneous (SC) injection<br>|
| Placebo Comparator: Placebo<br>Placebo: Placebo subcutaneous injection | Other: Placebo<br>* Placebo subcutaneous injection<br>|

What is the study measuring?
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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), 98 days in total | 
| 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), 98 days in total | 
| Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs | 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 as measured by digitial 12-lead ECG. | Baseline until the follow-up period (28 days post last dose), 98 days in total | 
| Number of participants with abnormal vital signs reported as TEAEs | Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal findings in the vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse, Respiration rate, body temperature). | Baseline until the follow-up period (28 days post last dose), 98 days in total | 
| Number of Participants With Abnormal Physical Examinations Reported as TEAEs | 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 enocrine. | Baseline until the follow-up period (28 days post last dose), 98 days in total | 
| Area under the concentration-time curve (AUC) during the dosing interval (AUCtau) | To characterize the PK profile of Cotadutide | Day 1 of Up-titration treatment period through 3 days post lost dose, total of up to 73 days. | 
| Maximum observed concentration (Cmax) | To characterize the PK profile of Cotadutide | Day 1 of Up-titration treatment period through 3 days post lost dose, total of up to 73 days. | 
| Time to Cmax (tmax) | To characterize the PK profile of Cotadutide | Day 1 of Up-titration treatment period through 3 days post lost dose, total of up to 73 days. | 
| Trough plasma concentration (Ctrough) | To characterize the PK profile of Cotadutide | Day 1 of Up-titration treatment period through 3 days post lost dose, total of up to 73 days. | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs | 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 urinalysis. | Baseline until the follow-up period (28 days post last dose), 98 days in total | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-drug antibodies (ADAs) to Cotadutide | To characterize the immunogenicity of Cotadutide | Day 1 of Up-titration treatment period through end of study, 98 days in total | 
| Change in daily average glucose levels | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | baseline to the end of extension period, and during 14 days of the follow up period, 84 days in total. | 
| Change in 7-day average glucose levels | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | 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 of the up-titration period, Days 50-56, Days 57-63, Days 64 - 70 of the treatment extension period | 
| Change in percentage time spent in hyperglycemia (> 140 mg/dL) over 24hours and over 7days | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | 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 of the up-titration period, Days 50-56, Days 57-63, Days 64 - 70 of the treatment extension period | 
| Change in percentage time spent in target range (70 -140 mg/dL) over 24hours and over 7days | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | 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 of the up-titration period, Days 50-56, Days 57-63, Days 64 - 70 of the treatment extension period | 
| Change in percentage time spent in the range (< 54 mg/dL) over 24hours and over 7days | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | 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 of the up-titration period, Days 50-56, Days 57-63, Days 64 - 70 of the treatment extension period | 
| Change in estimated hemoglobin A1c (HbA1c) | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | Baseline through 21day treatment extension period, 70 days in total | 
| Change in fasting plasma glucose (mg/dL) | To assess the effects of cotadutide, titrated up to the dose of 600 μg, on additional measures of glucose control | Baseline through 21day treatment extension period, 70 days in total | 
| Change in HbA1c | To assess the effects of cotadutide, titrated up to the dose of 600 μg, on additional measures of glucose control | Baseline through 21day treatment extension period, 70 days in total | 
| Percentage change in body weight | To assess the effects of cotadutide, titrated up to the dose of 600 μg, on body weight | Baseline through 21day treatment extension period, 70 days in total | 
| Absolute change in body weight | To assess the effects of cotadutide, titrated up to the dose of 600 μg, on body weight | Baseline through 21day treatment extension period, 70 days in total | 
| Proportion of subjects achieving > 5% body weight loss | To assess the effects of cotadutide, titrated up to the dose of 600 μg, on body weight | Baseline through 21day treatment extension period, 70 days in total | 
| Change in coefficient of variation as measured by CGM over 7 days | To assess the effect of Cotadutide on glucose control as measured by continuous glucose monitoring (CGM) | 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 of the up-titration period, Days 50-56, Days 57-63, Days 64 - 70 of the treatment extension period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Cotadutide, MEDI0382, D5671C00005, Type 2 Diabetes mellitus, Obesity, Overweight