E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetic Cardiomyopathy (DbCM) / Stage B Heart Failure (SBHF) |
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E.1.1.1 | Medical condition in easily understood language |
Heart condition known as diabetic cardiomyopathy (DbCM) as a complication of a Type 2 diabetes mellitus (T2DM), that may progress to heart failure |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012647 |
E.1.2 | Term | Diabetic cardiomyopathy |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 demonstrate that AT-001 compared with placebo decreases the worsening of performance on a cardiopulmonary exercise test (CPET) in patients with Diabetic Cardiomyopathy (DbCM) / Stage B Heart Failure (SBHF) |
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E.2.2 | Secondary objectives of the trial |
To evaluate
• the efficacy of AT-001 compared with placebo in preventing progression from SBHF to Stage C Heart Failure
• the effect of AT-001 compared with placebo in patients with DbCM/SBHF on the levels of NT-proBNP
• the effect of AT-001 compared with placebo in patients with DbCM/SBHF on the score of the mKCCQ
• the effect of AT-001 compared with placebo in patients with DbCM/SBHF on the percentage of patients with any changes and clinically significant changes (>6%) in peak oxygen uptake
• the effect of AT-001 compared with placebo in patients with DbCM/SBHF on the significant worsening of DbCM from baseline
• the effect of AT-001 compared with placebo in patients with DbCM/SBHF on the changes in global longitudinal strain, left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, and right ventricular systolic pressure by echocardiography
• the safety of chronic administration of AT-001 to patients with DbCM/SBHF |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The study also includes 2 substudies:
Each substudy will be conducted only in the subset of patients who specifically consent to the substudy in writing. In the neuropathy substudy, patients will have the following assessments done at randomization (baseline), Month 27: 1) the Neuropathy Total Symptom Score (NTSS), and 2) the Modified Toronto Clinical Neuropathy Scale (mTCNS).
In the retinopathy substudy, patients will have the following assessments done at randomization (baseline), Month 27: 1) Color Fundus Photography and, if available, 2) Optical Coherence Tomography (OCT). |
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E.3 | Principal inclusion criteria |
1. Type 2 Diabetes Mellitus (T2DM)
2. One of the following age-related criteria:
Age ≥ 60 years OR
• Age ≥ 40 years to < 60 years AND at least 1 of the following 2 risk factors:
o Duration of diabetes ≥ 10 years
o eGFR < 60 mL/min/1.73 m2
3. Echocardiographic demonstration of the following, as confirmed by the central core lab:
• Left Ventricular Ejection Fraction (LVEF) >= 45% AND
• At least 1 of the following 5 abnormalities:
o Absolute value of Global longitudinal strain (GLS) < 16% (i.e., GLS >-16%)
o Left ventricular hypertrophy (LVH) defined as left ventricular mass index (LVMI) ≥ 95 g/m2 in women and ≥ 115 g/m2 in men
o Left atrial enlargement (LAE) defined as left atrial volume index (LAVi) ≥ 34 mL/m2
o Diastolic Dysfunction defined as E/E’ ≥ 13
o Right ventricular systolic pressure (RVSP) > 35 mmHg
4. CPET demonstration of both, as confirmed by the CPET core lab:
• Impaired functional capacity, i.e., Peak VO2 < 75% of predicted
• Ability of maximal effort, i.e., achieve a RER ≥1.05 |
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E.4 | Principal exclusion criteria |
1.Prior diagnosis of overt/symptomatic heart failure / stage C heart failure, including any prior or current symptom or sign that led to a diagnosis of overt/symptomatic heart failure / stage C heart failure.
2. Any prior echocardiographic measurement indicating ejection fraction (EF) < 40%
3. History of acute coronary syndrome (ACS), including acute myocardial infarction
4. History or planned coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)
5. Prior diagnosis of coronary artery disease (CAD) by angiogram (including prior symptoms that led to a diagnosis of CAD) defined as ≥ 50% stenosis of major coronary artery
6. History of severe mitral, aortic, tricuspid, or pulmonary valve disease, or moderate valve disease requiring intervention
7. History of any clinically significant arrhythmia (including permanent atrial fibrillation or history of paroxysmal atrial fibrillation requiring hospitalization)
8. History of stroke
9. History of congenital, infective, toxic (e.g., chemotherapy or radiation), infiltrative (e.g., amyloidosis, sarcoidosis, or hemochromatosis), post-partum, or hypertrophic cardiomyopathy
10. Myocarditis induced by active autoimmune disease (e.g., Graves’ disease or systemic lupus erythematosus)
11. Pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1)
12. Blood pressure (BP) > 140 mmHg (systolic) or > 90 mmHg (diastolic) at screening
13. History of hospitalization for hypertensive emergency
14. BMI > 40 kg/m2
15. Antihyperglycemic treatment has not been stable in the 12 weeks prior to screening in the opinion of the Investigator
16. Treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS) has not been stable in the 12 weeks prior to screening in the opinion of the Investigator
17. Use of thiazolidinediones at screening and/or after randomization
18. Planned start of a SGLT2-inhibitor during the study
19. Any current or prior use of a loop diuretic
20. Pregnant or breastfeeding women
21. Females of childbearing potential not willing to use a highly effective form of birth control from screening until the Study Closeout Visit, or Post-Treatment Follow-up Visit, whichever occurs later
22. Severe disease or short life expectancy (<12 months) making implementation of the protocol or interpretation of the study results difficult (This includes clinically significant hematopoietic, renal, hepatic (including hepatitis B and C), endocrine, pulmonary, neurological, psychiatric, immunological (including HIV-AIDS), dermatological, or gastrointestinal diseases or active malignant tumor [except for non-melanoma skin cancer] or conditions capable of altering the absorption, metabolism, or elimination of drugs, or conditions that would impact the performance of a CPET [e.g., chronic lung or neuro-muscular disease].)
23. Morbid obesity or any other condition that prevents the obtainment of a good quality echocardiogram at baseline
24. History of substance abuse (including alcohol)
25. History of clinically significant drug allergy or drug hypersensitivity reactions
26. Severe lower extremity complications (such as skin ulcers, osteomyelitis and gangrene) and/or history of non-traumatic amputations
27. Prior diagnosis of proliferative diabetic retinopathy
28. Investigators, site personnel directly affiliated with this study, and their immediate families (Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.)
29. Any other condition that, in the opinion of the Investigator, precludes the patient from following and completing the protocol
30. Use of any investigational drug within 5 half-lives prior to screening
31. HbA1c > 8.5% at Screening
32. Hemoglobin (Hb) < 10.0 g/dL at Screening
33. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin (except in case of Gilbert’s syndrome) > 1.5 x upper limit of normal (ULN) at Screening
34. An eGFR < 30 mL/min/1.73 m2 (as calculated by the MDRD formula) at Screening
35. UACR > 300 mg/g at Screening
36. History of hospitalisation due to COVID-19 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes in CPET performance (peak oxygen uptake [peak VO2]) from baseline to Month 15 (>=15 months and ≤ 18 months after randomization) and possibly to Month 27 (>= 27 months and ≤ 30 months after randomization) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to Month 15 (>=15 months and ≤ 18 months after randomization) and possibly to Month 27 (>= 27 months and ≤ 30 months after randomization) |
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E.5.2 | Secondary end point(s) |
• Changes in NT-proBNP from baseline to Month 15
• Progression to SCHF, defined by the occurrence of at least 1 of the following events by Month 27:
o CV death
o Hospitalization for HF
o Urgent HF visit
o New diagnosis of HF (requiring initiation of a loop diuretic)
• Changes in NT-proBNP
• Changes in the mKCCQ score from baseline to Month 27
• Percentage of patients with a clinically significant decrease in peak VO2 (i.e., > 6%) from baseline to Month 27
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
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) | Yes |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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 |
Czech Republic |
France |
Germany |
Hong Kong |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 54 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 54 |