E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Heart Failure (HF) with Reduced Ejection Fraction |
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E.1.1.1 | Medical condition in easily understood language |
Heart Failure with reduced pump function to eject blood flow. |
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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 | 10007558 |
E.1.2 | Term | Cardiac failure chronic |
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 determine whether dapagliflozin is superior to placebo, when added to standard of care, in reducing the incidence of CV death or a HF event (hospitalization for HF or equivalent HF event, ie an urgent HF visit). |
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E.2.2 | Secondary objectives of the trial |
1) To compare the effect of dapagliflozin versus placebo on CV death or hospitalization for HF.
2) To compare the effect of dapagliflozin versus placebo on total number of recurrent HF hospitalizations and CV death.
3) To compare the effect of treatment with dapagliflozin versus placebo on the KCCQ total symptom score for HF symptoms and physical limitations.
4) To determine if dapagliflozin compared with placebo reduces the incidence of a worsening renal function composite outcome.
5) To determine whether dapagliflozin, compared with placebo, reduces the incidence of all cause mortality. |
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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 |
An echocardiographic sub-study is planned to be conducted in a subset
of patients (approx. 300-400 patients) in the Dapa-HF trial. The substudy is designed to evaluate the impact of dapagliflozin at a dose of 10 mg daily, compared to placebo, in addition to conventional heart failure treatment, on changes in cardiac structure and function as determined by echocardiography. |
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E.3 | Principal inclusion criteria |
• Provision of signed informed consent prior to any study specific procedures
• Male or female, aged ≥18 years
• Established documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least 2 months
• LVEF≤40%
• Elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) levels
• Patients should receive background standard of care for HFrEF and be
treated according to locally recognized guidelines
• eGFR ≥30 ml/min/1.73 m2 (CKD-EPI formula) at enrolment (visit 1)
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E.4 | Principal exclusion criteria |
• Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor
• Type 1 diabetes mellitus
• Symptomatic hypotension or systolic BP <95 mmHg
• Current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment
• MI, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment
• Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization
• Implantation of a cardiac CRT within 12 weeks prior to enrolment or intent to implant a CRT device
• Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization
• HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease
• Symptomatic bradycardia or second or third degree heart block without a pacemaker
• Severe (eGFR <30 mL/min/1.73 m2 by CKD-EPI), unstable or rapidly progressing renal disease at the time of randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to the first occurrence of any of the components of this composite:
1. CV death
2. Hospitalization for HF
3. An urgent HF visit |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated when 844 primary endpoint events are accrued. |
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E.5.2 | Secondary end point(s) |
1) Time to the first occurrence of either of the components of this composite:
1. CV death
2. Hospitalization for HF
2) Total number of (first and recurrent) HF hospitalizations and CV death.
3) Change from baseline measured at 8 months in the overall summary score of the KCCQ, a specific HF patient reported outcome questionnaire.
4) Time to the first occurrence of any of the components of this composite:
1. ≥50% sustained decline in eGFR
2. Reaching End Stage Renal Disease (ESRD)
- Sustained eGFR <15 ml/min/1.73m2 or,
- Chronic dialysis treatment or,
- Receiving a renal transplant
3. Renal death
5) Time to death from any cause. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from baseline of the total symptom score of the KCCQ will be evaluated at 8 months after randomization. All other secondary endpoints will be evaluated when 844 primary endpoint events are accrued. |
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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 | Yes |
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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
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 | 2 |
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 | 132 |
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 |
Argentina |
Brazil |
Bulgaria |
Canada |
China |
Czech Republic |
Denmark |
Germany |
Hungary |
India |
Japan |
Netherlands |
Poland |
Russian Federation |
Slovakia |
Sweden |
Taiwan |
United Kingdom |
United States |
Vietnam |
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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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The last visit of the last patient undergoing the study. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |