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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04515849
• Other study ID #: D5676C00001
• Secondary ID: 2020-000255-12
• Status: Completed
• Phase: Phase 2
• Start date: August 31, 2020
• Est. completion date: March 8, 2022

Study information

• Verified date: March 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 247
• Est. completion date: March 8, 2022
• Est. primary completion date: March 8, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

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):

1. 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)

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)

3. 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:

1. Aspartate transaminase (AST) = 3 × upper limit of normal (ULN)

2. Alanine transaminase (ALT) = 3 × ULN

3. Total bilirubin = 2 × ULN

• Poorly controlled hypertension defined as:

1. Systolic BP > 180 mm Hg

2. 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

Related Conditions & MeSH terms

• Chronic Kidney Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Kidney Diseases
• Renal Insufficiency, Chronic
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Cotadutide 100 micrograms
Cotadutide 100 micrograms administered subcutaneously
• Cotadutide 300 micrograms
Cotadutide 300 micrograms administered subcutaneously
• Cotadutide 600 micrograms
Cotadutide 600 micrograms administered subcutaneously
• Semaglutide
Semaglutide 1.0 miligrams administered subcutaneously
• Placebo
Placebo administered subcutaneously

Locations

Country	Name	City	State
Australia	Research Site	Box Hill
Australia	Research Site	Elizabeth Vale
Australia	Research Site	Fitzroy
Australia	Research Site	Heidelberg
Australia	Research Site	Melbourne
Australia	Research Site	Merewether
Australia	Research Site	Oaklands Park
Australia	Research Site	Wollongong
Australia	Research Site	Woolloongabba
Canada	Research Site	Barrie	Ontario
Canada	Research Site	Brampton	Ontario
Canada	Research Site	Concord	Ontario
Canada	Research Site	Etobicoke	Ontario
Canada	Research Site	Laval	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Oakville	Ontario
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
Canada	Research Site	Waterloo	Ontario
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Dortmund
Germany	Research Site	Dusseldorf
Germany	Research Site	Essen
Germany	Research Site	Ludwigshafen
Germany	Research Site	Magdeburg
Germany	Research Site	Mainz
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Münster
Japan	Research Site	Arakawa-ku
Japan	Research Site	Chitose-shi
Japan	Research Site	Fujisawa-shi
Japan	Research Site	Kamakura-shi
Japan	Research Site	Obihiro-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Shinjyuku-ku
New Zealand	Research Site	Auckland
New Zealand	Research Site	Auckland
New Zealand	Research Site	Christchurch
New Zealand	Research Site	Grafton
New Zealand	Research Site	Havelock North
New Zealand	Research Site	Tauranga
New Zealand	Research Site	Wellington
Poland	Research Site	Bialystok
Poland	Research Site	Krakow
Poland	Research Site	Krakow
Poland	Research Site	Lublin
Poland	Research Site	New York
Poland	Research Site	Poznan
Poland	Research Site	Warszawa
Spain	Research Site	Barcelona
Spain	Research Site	Cordoba
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	La Coruna
Spain	Research Site	Lérida
Spain	Research Site	Majadahonda
Spain	Research Site	Malaga
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Pozuelo de Alarcón
Spain	Research Site	Sevilla
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
United Kingdom	Research Site	London

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

Australia,  Canada,  Germany,  Japan,  New Zealand,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To characterise the exposure of cotadutide in participants who have CKD with T2DM	Cotadutide PK exposure (eg, concentrations predose and 4 hours postdose) at steady state. Cotadutide plasma concentrations prior to injection and 4 hours post injection at steady state at different dose levels and different visits over 26 weeks.	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to semaglutide on UACR and compared to placebo and semaglutide on urine albumin and urinary creatinine	Change and percentage change in UACR versus semaglutide from baseline to the end of 14 and 26 weeks dosing; Change and percentage change in urine albumin versus placebo and semaglutide from baseline to the end of 14 and 26 weeks dosing; Change and percentage change in urinary creatinine versus placebo and semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to semaglutide on HbA1c and fasting glucose	Change in HbA1c versus semaglutide from baseline to the end of 14 and 26 weeks dosing; Change in fasting glucose versus semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to semaglutide on body weight	Change and percentage change in body weight versus semaglutide from baseline to the end of 14 and 26 weeks dosing; Proportion of participants achieving = 5% and = 10% body weight loss versus semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to placebo and semaglutide on blood pressure	• Change in SBP, DBP versus placebo and/or semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to placebo and semaglutide on pulse rate	• Change in pulse rate versus placebo and/or semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Other	To assess the effects of cotadutide at different dose levels compared to placebo and semaglutide on rate pressure product	• Absolute change in rate pressure product versus placebo and/or semaglutide from baseline to the end of 14 and 26 weeks dosing	26 weeks
Primary	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	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	To evaluate the immunogenicity profile of cotadutide compared to placebo	ADAs during the titration treatment period and follow-up period	30 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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