| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Kidney Disease with Type 2 Diabetes Mellitus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Kidney Disease with Type 2 Diabetes Mellitus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 14 weeks (Cohort 1 only) |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 14 weeks (Cohort 2 only and Cohorts 1 and 2 combined)
- To assess the effects of cotadutide at different dose levels compared to placebo on UACR after 26 weeks (Cohorts 1 and 2 separately and combined)
- To assess the effects of cotadutide at different dose levels compared to placebo on HbA1c and fasting glucose (Cohorts 1 and 2 separately)
- To assess the effects of cotadutide at different dose levels compared to placebo on glucose levels as measured by CGM (Cohorts 1 and 2 separately)
- To assess the effects of cotadutide at different dose levels compared to placebo on body weight (Cohorts 1 and 2 separately)
- To evaluate the immunogenicity profile of cotadutide compared to placebo (Cohorts 1 and 2 separately) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1/ Male and female subjects ≥ 18 and ≤ 79 years of age at the time of signing the informed consent.
2/ Estimated glomerular filtration rate ≥ 20 to < 90 mL/min/1.73 m2 determined at the screening visit or a documented occurrence in their medical history at least 3 months prior to randomisation.
3/ Receiving background standard of care treatment for renal disease and/or T2DM and being treated according to locally recognised guidelines, as appropriate.
4/ 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.
5/ Micro- or macroalbuminuria as defined by UACR > 50 mg/g or 5.7 mg/mmol.
6/ Diagnosed with T2DM with glucose control managed with any insulin and/or any oral therapy combination
7/ Haemoglobin A1c range of 6.5 % to 12.5% (inclusive) at screening
8/ Body mass index > 25 kg/m^2 at screening or > 23 kg/m^2 for participants enrolled in Japan
9/ Negative pregnancy test at screening (serum only) and randomisation (serum or urine) for female participants of childbearing potential and must not be breastfeeding.
10/ Female participants of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to 5 weeks after the last dose. |
|
| E.4 | Principal exclusion criteria |
1/ History or presence of significant medical or psychological conditions, including significant abnormalities in laboratory parameters or vital signs
2/ Receiving renal replacement therapy or expected to require it within 6 months of being randomised
3/ Renal transplant or on the waiting list for renal transplantation
4/ 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
5/ Received any of the following medications within the specified time frame prior to the start of the study (Visit 2):
(a) 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)
(b) 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)
(c) 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)
6/ 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)
7/ Participants with a known severe allergy/hypersensitivity to any of the proposed study interventions or excipients of the product.
8/ Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss) or recent episodes of severe hypoglycaemia
9/ Type 1 diabetes mellitus (T1DM), history of diabetic ketoacidosis, or clinical suspicion of T1DM (eg, undetectable levels of C peptide and positive tests for antibodies indicative of T1DM)
10/ Participants with recent acute or subacute renal function deterioration (eg, participants with large fluctuations of creatinine values documented within the 3 months prior to screening)
11/ 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
12/ History of acute or chronic pancreatitis
13/ 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:
(a) Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
(b) Alanine transaminase (ALT) ≥ 3 × ULN
(c) Total bilirubin ≥ 2 × ULN
14 Poorly controlled hypertension defined as:
(a) Systolic BP > 180 mm Hg
(b) 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
15/ 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
16/ 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
17/ Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
18/ 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
19/ Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
20/ Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change and percentage change in UACR versus placebo from baseline to the end of 14 weeks of dosing in Cohort 1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| baseline to the end of 14 weeks of dosing in Cohort 1 |
|
| E.5.2 | Secondary end point(s) |
1/ Change and percentage change in UACR versus placebo from baseline to the end of 14 weeks of dosing in Cohort 2 only and Cohorts 1 and 2 combined
2/ Change and percentage change in UACR versus placebo from baseline to the end of 26 weeks of dosing
3a/ Change in HbA1c versus placebo from baseline to the end of 14 and 26 weeks of dosing
3b/ Change in fasting glucose from baseline versus placebo after 14 and 26 weeks of dosing
4a/ 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
4b/ 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
5a/ Change and percentage change in body weight versus placebo from baseline to the end of 14 and 26 weeks of dosing
5b/ Proportion of participants achieving ≥ 5% and ≥ 10% body weight loss versus placebo from baseline to the end of 14 and 26 weeks of dosing
6/ ADAs during the titration treatment period and follow-up period |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/ baseline to the end of 14 weeks of dosing in Cohort 2 only and Cohorts 1 and 2 combined
2/ baseline to the end of 26 weeks of dosing
3a/ baseline to the end of 14 and 26 weeks of dosing
3b/ from baseline versus placebo after 14 and 26 weeks of dosing
4a/ - 5b/ baseline to the end of 14 and 26 weeks of dosing
6/ during the titration treatment period and follow-up period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, immunogenicity profile of cotadutide |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| open-label comparator study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Germany |
| Japan |
| New Zealand |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date of the last scheduled procedure shown in the SoA for the last participant in the study globally. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
