Clinical Trials Register

Summary
EudraCT Number:	2022-001262-35
Sponsor's Protocol Code Number:	D1690C00078
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-11-07
Trial 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

2022-001262-35

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Trial to Evaluate the Effect of In-Hospital Initiation of Dapagliflozin on Clinical Outcomes in Patients Who Have Been Stabilized During Hospitalization for Acute Heart Failure

Multicentrické, randomizované, dvojitě zaslepené, placebem kontrolované klinické hodnocení s paralelními skupinami hodnotící účinek zahájení léčby dapagliflozinem během hospitalizace na klinické výsledky u pacientů, kteří byli stabilizováni během hospitalizace kvůli akutnímu srdečnímu selhání

A.3.1

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

Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68

A.3.2

Name or abbreviated title of the trial where available

DAPA ACT HF-TIMI 68

A.4.1

Sponsor's protocol code number

D1690C00078

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04363697

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	The Brigham and Women's Hospital, Inc.
B.1.3.4	Country	United States
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 Pharmaceuticals LP
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Brigham and Women's Hospital
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Brigham and Women's Hospital, Inc.
B.5.2	Functional name of contact point	DAPA ACT HF-TIMI 68 ProjectDirector
B.5.3	Address:
B.5.3.1	Street Address	75 Francis Street
B.5.3.2	Town/ city	Boston
B.5.3.3	Post code	MA 02115
B.5.3.4	Country	United States
B.5.4	Telephone number	617-278-0145
B.5.6	E-mail	DapaActHF@partners.org

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	No
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
D.3.9.1	CAS number	960404-48-2
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
D.3.9.4	EV Substance Code	SUB90205
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The study is evaluating the effect of In-hospital initiation of dapagliflozin in patients who have been stabilized during hospitalization for Acute Heart Failure

E.1.1.1

Medical condition in easily understood language

acute heart failure

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	LLT
E.1.2	Classification code	10000803
E.1.2	Term	Acute heart failure
E.1.2	System Organ Class	10007541 - Cardiac disorders

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 assess the effect of in-hospital initiation of dapagliflozin, as compared with placebo, on the clinical outcome of cardiovascular death or worsening heart failure in patients who have been stabilized during hospitalization for acute heart failure.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of in-hospital initiation of dapagliflozin in this patient population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 years (male or female)
2. Currently hospitalized for AHF defined as meeting all the following criteria:
a) Presentation with worsening symptoms of heart failure (e.g., worsening dyspnea or dyspnea at rest, progressive fatigue, rapid weight gain, worsening edema/abdominal distention/anasarca)
b) Objective signs or diagnostic testing consistent with volume overload (e.g., jugular venous distension, pulmonary basilar crackles, S3 gallop, ascites, hepatomegaly, peripheral edema, radiological evidence of pulmonary congestion, noninvasive or invasive hemodynamic evidence of elevated filling pressures)
c) Intensification of AHF therapy during admission defined as at least one of the following:
i. Augmentation of oral diuretic therapy [e.g., ≥2x outpatient regimen dose, addition of a second diuretic agent, or new initiation of diuretic therapy in a previously naïve patient]
ii. Initiation of intravenous diuretic therapy
iii. Initiation of intravenous vasoactive agent (e.g., inotrope or vasodilator)
3. Left ventricular ejection fraction (LVEF) measured within the past 12 months (including during the current hospitalization)
4. Elevated NT-proBNP or BNP during current hospitalization:
a) For patients with LVEF ≤40%: NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL (NT-proBNP ≥2400 pg/mL or BNP ≥600 pg/mL if patient in atrial fibrillation or atrial flutter)
b) For patients with LVEF >40%: NT-proBNP ≥1200 pg/mL or BNP ≥300 pg/mL (NT-proBNP ≥1800 pg/mL or BNP ≥450 pg/mL if patient in atrial fibrillation or atrial flutter)
5. Eligible patients will be randomized no earlier than 24 hours and up to 14 days after presentation while still hospitalized once they have been stabilized, as defined by:
a) No increase (i.e., intensification) in the dose of intravenous diuretics during the 12 hours prior to randomization
b) No use of intravenous vasodilators or inotropes during the 24 hours prior to randomization
Other protocol-defined inclusion criteria may apply.

E.4

Principal exclusion criteria

1. Symptomatic hypotension in the past 24 hours
2. Concurrent use of two or more intravenous inotropic agents during the index hospitalization
3. eGFR <25 ml/min/1.73 m2 as measured by the CKD-EPI equation at screening or rapidly progressive renal disease
4. Current use of an SGLT2 inhibitor
5. Prior intolerance of SGLT2 inhibitors, including hypersensitivity to dapagliflozin, or to any excipient (inactive substance) in the study drug
6. Type 1 diabetes mellitus or history of diabetic ketoacidosis
7. (Only applies to patients with T2DM who are on insulin and/or a sulfonylurea) History of recurrent major hypoglycemia (i.e., resulting in severe impairment in consciousness or behavior, or requiring emergency external assistance)
8. Implantation of a cardiac resynchronization therapy (CRT) device or valve repair or replacement within 30 days prior to randomization or intent to do so during the trial
9. ST-segment elevation myocardial infarction or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 30 days prior to randomization or intent to undergo coronary revascularization during the trial
10. Untreated sustained ventricular arrhythmias or Mobitz type II or third-degree heart block (i.e., without an ICD or pacemaker, respectively)
11. History of heart transplantation or current transplant listing; mechanical circulatory support use (either durable or temporary) during the index hospitalization
12. History of heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, uncorrected primary valvular disease, complex congenital heart disease, or heart failure felt to be due to a transient process (e.g., stress [takotsubo] cardiomyopathy, tachycardia-induced cardiomyopathy) expected to resolve within 2 months.
13. History of end-stage liver disease
14. Women of child-bearing potential (unless using highly effective contraception method) or currently breastfeeding
15. Current participation in a clinical trial with an unlicensed drug or device
16. Study staff or their family members
17. Any condition that, in the opinion of the investigator, would make trial participation not in the best interest of the subject, or would compromise compliance with the trial protocol (e.g., active severe infection, active malignancy)
Other protocol-defined exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

Time to first occurrence of cardiovascular death or worsening heart failure defined as:
1. Worsening HF during the index admission requiring at least one of the following:
a) initiation or re-initiation of inotropic therapy for ≥24 hours
b) mechanical circulatory support
c) invasive ventilatory support for heart failure
d) heart transplantation
2. Readmission for worsening heart failure
3. Worsening heart failure leading to an urgent visit with administration of intravenous diuretic therapy (e.g., outpatient setting, emergency department) without associated hospital admission

E.5.1.1

Timepoint(s) of evaluation of this end point

will be evaluated during the Follow-up Visit(week 1 and month 1) and during the end of study visit ( month 2)

E.5.2

Secondary end point(s)

• Symptomatic hypotension leading to hospitalization or study drug discontinuation
• Worsening renal function that results in at least a doubling of serum creatinine, hospitalization, study drug discontinuation, dialysis, or renal death

E.5.2.1

Timepoint(s) of evaluation of this end point

will be evaluated during the Follow-up Visit(week 1 and month 1) and during the end of study visit ( month 2)

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability

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)

Yes

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

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

Canada

United States

Czechia

Hungary

Poland

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

Last visit of the last subject

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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:

1200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1200

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1000

F.4.2.2

In the whole clinical trial

2400

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)

Subjects would continue standard of care therapies for heart failure under the direction of the physician's care team at end of study. Specifically, patients could transition to open label dapagliflozin or any other SGLT2 inhibitor approved for clinical use in this population, as appropriate.

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

2023-01-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-10-20

P. End of Trial
P.	End of Trial Status	Ongoing

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