A Study of Cotadutide in Participants Who Have Chronic Kidney Disease With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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A Phase 2b, study to measure the effect of Cotadutide at different doses versus placebo or comparator (semaglutide) in participants who have Chronic Kidney Disease with Type 2 Diabetes Mellitus.

Detailed Description
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A Phase 2b randomised, double-blind, placebo-controlled and open-label active comparator study to evaluate the effect of Cotadutide at 100, 300 or 600 micrograms in participants who have Chronic Kidney Disease with Type 2 Diabetes Mellitus. The study plans to randomise approximately 225 subjects. Subjects will be randomised to receive double-blind Cotadutide or placebo at 100, 300 or 600 micrograms once daily for 26 weeks, or open-label semaglutide at 1.0 miligrams once a week for 26 weeks. Japanese participants will not be randomised to the semaglutide arm.

Official Title
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A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled, and Open-label Comparator Study of Cotadutide in Participants Who Have Chronic Kidney Disease With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus, Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Cotadutide 100 micrograms
* Drug: Cotadutide 300 micrograms
* Drug: Cotadutide 600 micrograms
* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Estimated glomerular filtration rate ≥ 20 to < 90 mL/min/1.73 m2 determined at the screening visit or a documented occurrence in medical history at least 3 months prior to randomisation. Receiving background standard of care treatment for renal disease and/or T2DM and being treated according to locally recognised guidelines, as appropriate. Receiving optimised and stable treatment with an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin II receptor antagonist for ≥ 3 months at screening at the maximum tolerated dose (MTD) unless contraindicated, not tolerated, or in the opinion of the investigator, not practically available or suitable. Micro- or macroalbuminuria as defined by UACR > 50 mg/g or 5.7 mg/mmol. Diagnosed with T2DM with glucose control managed with any insulin and/or any oral therapy combination including metformin, SGLT2 inhibitor, thiazolidinedione, or acarbose where no major dose changes (eg, > 50% increase in dose) have occurred within the 4 weeks prior to the start of the run-in period. Participants taking sulfonylureas or glitinides may be randomised following a 4-week washout period of the sulfonylurea/glitinide. Haemoglobin A1c range of 6.5 % to 12.5% (inclusive) at screening Body mass index > 25 kg/m2 at screening or > 23 kg/m2 for participants enrolled in Japan Exclusion Criteria: History or presence of significant medical or psychological conditions, including significant abnormalities in laboratory parameters or vital signs including ECG, which in the opinion of the investigator, would compromise the participant's safety or successful participation in the study. Receiving renal replacement therapy or expected to require it within 6 months of being randomised Renal transplant or on the waiting list for renal transplantation Received a GLP-1 analogue-containing preparation within the last 30 days or 5 half-lives of the drug, if known (whichever is longer), at the time of Visit 2 Received any of the following medications within the specified time frame prior to the start of the study (Visit 2): Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within the last 3 days prior to the start of the run-in period (Visit 2) Paracetamol (acetaminophen) or paracetamol-containing preparations at a total daily dose of greater than 3000 mg and within the last 3 days prior to the start of the run-in period (Visit 2) Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg and within the last 3 days prior to the start of the run-in period (Visit 2) Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives of the drug, if known (whichever is longer) Participants with a known severe allergy/hypersensitivity to any of the proposed study interventions or excipients of the product Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss) or recent episodes of severe hypoglycaemia Type 1 diabetes mellitus (T1DM), history of diabetic ketoacidosis, or clinical suspicion of T1DM Participants with recent acute or subacute renal function deterioration 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 History of acute or chronic pancreatitis Significant hepatic disease (except for non-alcoholic steatohepatitis or nonalcoholic fatty liver disease without portal hypertension or cirrhosis) and/or participants with any of the following results: Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN) Alanine transaminase (ALT) ≥ 3 × ULN Total bilirubin ≥ 2 × ULN Poorly controlled hypertension defined as: Systolic BP > 180 mm Hg Diastolic BP ≥ 90 mm Hg after 10 minutes of seated rest and confirmed by repeated measurement at screening. Participants who fail BP screening criteria may be considered for 24-hour ambulatory BP monitoring at the discretion of the investigator. Participants who maintain a mean 24-hour systolic BP ≤ 180 or diastolic BP < 90 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible 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 Decompensated heart failure or hospitalisation for heart failure in the 3 months prior to screening or symptoms consistent with New York Heart Association heart failure Class III/IV Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia History of neoplastic disease within 5 years prior to screening, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cotadutide 100 micrograms<br>Cotadutide 100 micrograms administered subcutaneously | Drug: Cotadutide 100 micrograms<br>* Cotadutide 100 micrograms administered subcutaneously<br>* Other names: MEDI0382;|
| Experimental: Cotadutide 300 micrograms<br>Cotadutide 300 micrograms administered subcutaneously | Drug: Cotadutide 300 micrograms<br>* Cotadutide 300 micrograms administered subcutaneously<br>* Other names: MEDI0382;|
| Experimental: Cotadutide 600 micrograms<br>Cotadutide 600 micrograms administered subcutaneously | Drug: Cotadutide 600 micrograms<br>* Cotadutide 600 micrograms administered subcutaneously<br>* Other names: MEDI0382;|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Drug: Placebo<br>* Placebo administered subcutaneously<br>|
| Active Comparator: Semaglutide<br>Semaglutide 1.0 miligrams administered subcutaneously | Drug: Semaglutide<br>* Semaglutide 1.0 miligrams administered subcutaneously<br>* Other names: Ozempic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 14 weeks | Change and percentage change in UACR versus placebo from baseline to the end of 14 weeks of dosing | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 14 weeks | Change and percentage change in UACR versus placebo from baseline to the end of 14 weeks of dosing | 14 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 26 weeks | Change and percentage change in UACR versus placebo from baseline to the end of 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on HbA1c and fasting glucose | Change in HbA1c versus placebo from baseline to the end of 14 and 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on HbA1c and fasting glucose | Change in fasting glucose from baseline versus placebo after 14 and 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on glucose levels as measured by CGM | Change in 10-day average glucose levels as measured by CGM versus placebo from baseline to the end of 14 and 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on glucose levels as measured by CGM | Change in percentage time spent in hyperglycaemia (> 10 mmol/L), target range (3.9 -10 mmol/L), hypoglycaemia (< 3.9 mmol/L), and clinically significant hypoglycaemia (< 3.0 mmol/l) over 10 days as measured by CGM versus placebo from baseline to the end of 14 and 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on body weight | Change and percentage change in body weight versus placebo from baseline to the end of 14 and 26 weeks of dosing | 26 weeks | 
| To assess the effects of cotadutide at different dose levels compared to placebo on body weight | Proportion of participants achieving ≥ 5% and ≥ 10% body weight loss versus placebo from baseline to the end of 14 and 26 weeks of dosing | 26 weeks | 
| To evaluate the immunogenicity profile of cotadutide compared to placebo | ADAs during the titration treatment period and follow-up period | 30 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of Cotadutide by assessment of the following using CTCAE V4.0: The number of Treatment Emergent Adverse events (TEAEs) | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of Treatment Emergent Serious Adverse Events (TESAEs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of Cotadutide by assessment of the following using CTCAE V4.0: The number of Treatment-Emergent Serious Adverse Events (TESAEs) | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of Treatment Emergent Adverse Events of Special Interest (AESIs) as assessed by CTCAE V4.0 | Safety and tolerability of daily SC doses of Cotadutide by assessment of the following using CTCAE V4.0: The number of Treatment Emergent Adverse Events of Special Interest (AESIs) | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in blood pressure | Number of subjects with clinically significant changes in systolic and diastolic blood pressure (mmHg) | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in blood pressure | Percentage of subjects with clinically significant changes in systolic and diastolic blood pressure (mmHg) | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in heart rate | Number of subjects with clinically significant changes in heart rate | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in heart rate | Percentage of subjects with clinically significant changes in heart rate | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in haematology and clinical chemistry parameters | Percentage of subjects with clinically significant changes in in haematology and or clinical chemistry parameters | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in haematology and clinical chemistry parameters | Number of subjects with clinically significant changes in in haematology and or clinical chemistry parameters | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in ECG | Number of subjects with an ECG determined to be abnormal and clinically significant | 26 weeks | 
| To evaluate the safety and tolerability of cotadutide compared to placebo by assessment of changes in ECG | Percentage of subjects with an ECG determined to be abnormal and clinically significant | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI0382, T2DM, Cotadutide, Diabetic Kidney Disease