The aim of the proposed study is to investigate the efficacy and safety of dapagliflozin in patients with an established diagnosis of HFrEF (with or without T2D) where the prevalence and unmet needs for reducing CV mortality and heart failure events…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main objective of the study is to investigate whether dapagliflozin,
compared with placebo, reduces the incidence of CV death or hospitalization for
HF or equivalent event (ie an urgent HF visit) when added to background
standard of care treatment.
Secondary outcome
The rationale for including CV death or hospitalization for HF, but excluding
non-hospitalized urgent HF visits, is that this is the more conventional
composite HF endpoint, may be regarded as including *harder* outcomes and will
allow direct comparison with other HF trials.
The rationale for including total number of hospitalizations (including
re-hospitalizations) for HF is to capture the impact of recurrent non-fatal HF
hospitalizations. Taken together with CV death, these events give a better
estimate of the full burden of HF on patients and healthcare systems than
time-to-first event analysis.
The rationale for the secondary renal composite EP is that renal dysfunction is
very common in heart failure, may lead to discontinuation of disease-modifying
therapies and is associated with poor outcomes.
All-cause mortality will be assessed as a secondary endpoint because it is
important to evaluate the effect of dapagliflozin on non-cardiovascular, as
well as cardiovascular, mortality and hence overall mortality.
Background summary
Despite advances in management and treatment of chronic heart failure (HF) with
reduced ejection fraction (HFrEF), HF continues to be a major cause of
mortality, initial and recurrent hospitalizations, and suboptimal quality of
life.
The prevalence and incidence of HF continues to increase globally. An estimated
38 million people are affected by HF worldwide with over 1 million
hospitalizations annually in the United States and Europe. The annual global
economic burden in 2012 was estimated to be $108 billion and is projected to
increase dramatically as the population ages.
The current treatment paradigm for HF involves the simultaneous targeting of
multiple pathways including the renin-angiotensin-aldosterone axis (RAA), the
autonomic system, and symptomatic treatment with diuretics.
Recently, in patients with type 2 diabetes (T2D) and high cardiovascular (CV)
risk, the sodium glucose co-transporter 2 (SGLT2) inhibitor, empagliflozin
(JARDIANCE*), demonstrated a marked reduction in CV mortality (38% relative
risk reduction [RRR]), allcause mortality (32% RRR) as well as 35% RRR in
hospitalization from HF compared with placebo when added to background standard
of care treatment.
In a secondary analysis of HF outcomes, empagliflozin reduced the risk of
hospitalization for HF or cardiovascular death by 28 % in patients with HF at
baseline.
Dapagliflozin (Forxiga*/Farxiga*) is a highly selective and reversible
inhibitor of human renal SGLT2, the major transporter responsible for glucose
reabsorption in the kidney. Dapagliflozin*s mechanism of action results in a
direct and insulin-independent elimination of glucose by the kidneys. In
addition to the improved glycaemic control, the persistent loss of glucose with
associated calories in the urine, results in a consistent and maintained
reduction of the total body weight. Further, dapagliflozin induces a diuresis,
natriuresis and a decrease in blood pressure without a concomitant increase in
heart rate.
Possible mechanisms for SGLT2 inhibitor benefit in patients with heart failure
could include osmotic diuresis and reductions in arterial stiffness, weight,
blood pressure, serum uric acid and albuminuria.
Data on the effect of SGLT2 inhibition in patients without diabetes is limited.
However, dapagliflozin has safely been administered in healthy volunteers over
a broad dose range.
Dapagliflozin has been investigated in a thorough T2D clinical development
program. In addition, the trial DECLARE-TIMI58 (D1693C00001) is ongoing and
includes >17,000 T2D patients with elevated CV risk to evaluate dapagliflozin
10 mg on CV outcome.
The aim of the proposed study is to investigate the efficacy and safety of
dapagliflozin in patients with an established diagnosis of HFrEF (with or
without T2D) where the prevalence and unmet needs for reducing CV mortality and
heart failure events as well as improving symptoms remain high.
Study objective
The aim of the proposed study is to investigate the efficacy and safety of
dapagliflozin in patients with an established diagnosis of HFrEF (with or
without T2D) where the prevalence and unmet needs for reducing CV mortality and
heart failure events as well as improving symptoms remain high.
Study design
This is a randomized, double-blind, parallel-group, multicentre phase 3 study.
Intervention
Patients will use either dapagliflozin 10 mg or placebo once daily in addition
to their standard of care hart failure medication.
Study burden and risks
The subjects visit the hospital at least 11 times over 15 months (depending on
when the subject is enrolled in the study). Median duration of the study is 33
months. The subjects are asked to keep in touch throughout the duration of the
study with the study doctor.
During the study several times a physical examination will be done, and blood
samples will be taken. Blood sampling may cause some discomfort. In women of
childbearing potential a pregnancy test is performed. The use of study
medication can cause side effects. The research is carried out in the
expectation that dapagliflozin may prevent the occurrence of cardiovascular
death and hospitalization for heart failure. In the future, the information
collected in this study will ensure that patients are better treated for
chronic heart failure with reduced ejectionfraction.
Louis Pasteurlaan 5
Zoetermeer 2719 EE
NL
Louis Pasteurlaan 5
Zoetermeer 2719 EE
NL
Listed location countries
Age
Inclusion criteria
1. Provision of signed informed consent prior to any study specific procedures
2. Male or female, aged *18 years at the time of consent
3. Established documented diagnosis of symptomatic HFrEF
4. LVEF*40% within the last 12 months prior to enrolment (Visit 1)
5. NT-proBNP >600 pg/ml
6. Patients should receive background standard of care for HFrEF
7. eGFR *30 ml/min/1.73 m2 at visit 1
Exclusion criteria
1. Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor
2. Type 1 diabetes mellitus (T1D)
3. Symptomatic hypotension or systolic BP <95 mmHg on 2 consecutive measurements
4. Current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment
5. MI, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment
6. Coronary revascularization 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
7. Implantation of a cardiac CRT within 12 weeks prior to enrolment or intent to implant a CRT device
8. Previous cardiac transplantation or implantation of a ventricular assistance device
(VAD) or similar device, or implantation expected after randomization
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003897-41-NL |
| CCMO | NL59837.091.16 |