Clinical Trials Register

Summary
EudraCT Number:	2016-003897-41
Sponsor's Protocol Code Number:	D1699C00001
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-11-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2016-003897-41

A.3

Full title of the trial

Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure with Reduced Ejection Fraction

Klinické hodnocení s cílem vyhodnotit vliv přípravku dapagliflozinu na výskyt zhoršení srdečního selhání nebo kardiovaskulárního úmrtí u pacientů s chronickým srdečním selháváním se sníženou ejekční frakcí.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate if dapagliflozin treatment is effective in patients with heart failure by reducing the number of hospitalizations and urgent visits due to heart failure, and by reducing the risk of death.

Vyhodnocení výsledků studie s Dapagliflozinem , zda tato terapie u pacientů se srdečním selháváním je účinná a dojde ke snížení počtu hospitalizací a akutních návštěv kvůli srd. selhávání včetně snížení rizika smrti.

A.3.2

Name or abbreviated title of the trial where available

DAPA HF

A.4.1

Sponsor's protocol code number

D1699C00001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	N/A
B.5.3.2	Town/ city	N/A
B.5.3.3	Post code	N/A
B.5.3.4	Country	United States
B.5.6	E-mail	information.center@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Forxiga
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dapagliflozin
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DAPAGLIFLOZIN PROPANEDIOL
D.3.9.1	CAS number	960404-48-2
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Forxiga
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dapagliflozin
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DAPAGLIFLOZIN PROPANEDIOL
D.3.9.1	CAS number	960404-48-2
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Heart Failure (HF) with Reduced Ejection Fraction

E.1.1.1

Medical condition in easily understood language

Heart Failure with reduced pump function to eject blood flow.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

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).

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 Kansas City Cardiomyopathy Questionnaire total symptom score for HF symptoms and physical limitations.
4) To determine if dapagliflozin compared with placebo reduces the incidence of a composite endpoint of worsening renal function.
5) To determine whether dapagliflozin, compared with placebo, reduces the incidence of all cause mortality.

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.

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 (New York Heart Association (NYHA) functional class II-IV), which has been present for at least 2 months

• Left ventricular ejection fraction (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)

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

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

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be evaluated after at least 844 primary endpoint events are accrued.

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.

6) Safety Mesures;
1. Serious Adverse Events (SAEs)
2. Discontinuation of IP due to Adverse Events (DAEs)
3. Changes in clinical chemistry/haematology parameters
4. Adverse events of interest (volume depletion, renal events, major hypoglycaemic events, fractures, Diabetic ketoacidosis (DKA), AEs leading to amputation)

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 after at least 844 primary endpoint events are accrued.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

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

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

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

The last visit of the last patient undergoing the study.

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

2250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2250

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

When applicable a legally representative, together with impartial witness, is allowed to sign the informed consent of behalf of a patient (i.e. illiterate patients).

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

270

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1650

F.4.2.2

In the whole clinical trial

4500

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-01-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-17

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