Clinical Trials Register

Summary
EudraCT Number:	2020-005844-47
Sponsor's Protocol Code Number:	D6580C00010
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:	2021-04-21
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

2020-005844-47

A.3

Full title of the trial

A Randomised, Double-blind, Placebo-controlled, Multi-center Sequential Phase 2b and Phase 3 Study to Evaluate the Efficacy and Safety of AZD4831 Administered for up to 48 Weeks in Participants with Heart Failure With Left Ventricular Ejection Fraction > 40%

Randomizované, dvojitě zaslepené, placebem kontrolované, multicentrické postupné klinické hodnocení fáze 2b a 3, jehož cílem je vyhodnotit účinnost a bezpečnost přípravku AZD4831 podávaného po dobu až 48 týdnů pacientům se srdečním selháním s ejekční frakcí levé komory >40 % (ENDEAVOR)

A.3.1

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

A Sequential Phase 2b and Phase 3 Study to Evaluate the Efficacy and Safety of AZD4831 in Participants with Heart Failure with Left Ventricular Ejection Fraction > 40%

A.3.2

Name or abbreviated title of the trial where available

ENDEAVOR

A.4.1

Sponsor's protocol code number

D6580C00010

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 Centre
B.5.3	Address:
B.5.3.1	Street Address	NA
B.5.3.2	Town/ city	NA
B.5.3.3	Post code	NA
B.5.3.4	Country	Sweden
B.5.4	Telephone number	NANANANA
B.5.5	Fax number	NANANANA
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	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	AZD4831 film-coated tablet 2.5 mg
D.3.2	Product code	AZD4831
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	NA
D.3.9.2	Current sponsor code	AZD4831
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	2.5
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	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	AZD4831 film-coated tablet 5 mg
D.3.2	Product code	AZD4831
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	NA
D.3.9.2	Current sponsor code	AZD4831
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.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

Heart Failure with Left Ventricular Ejection Fraction > 40%

E.1.1.1

Medical condition in easily understood language

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	10019279
E.1.2	Term	Heart failure
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1 To evaluate the effect of AZD4831 on KCCQ-TSS (change from baseline at 16 weeks Part A and change from baseline at 24 weeks Part B)
2 To evaluate the effect of AZD4831 on 6MWD (change from baseline at 16 weeks Part A and change from baseline at 24 weeks Part B)

E.2.2

Secondary objectives of the trial

1 To evaluate the effect of AZD4831 on KCCQ-TSS change from baseline at 24 and 48 weeks (Part A)
2 To evaluate the effect of AZD4831 on 6MWD change from baseline at 24 and 48 weeks (Part A)
3 To evaluate the effect of AZD4831 on NT-proBNP (Part A and Part B)
4 To evaluate the effect of AZD4831 on echocardiographic parameter LV-GLS, LAVI, LVMI (Part A)
5 To assess the pharmacokinetics of AZD4831 (Part A and Part B)
6 To evaluate the effect of AZD4831 on inflammatory biomarkers (Part A and Part B)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
2. Documented stable symptomatic HF (New York Heart Association Class II-IV) for at least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not qualify), with a medical history of typical symptoms of HF and receiving optimal therapy for HF as determined by the health-care physician.
3. LVEF > 40% at Screening (Visit 1). All participants will undergo a local echocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF > 40% eligibility criteria before randomisation.
4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be < 50 meters.
5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3)
6.NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1).
NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI > 30 kg/m2.
The ECG performed at Screening should be used for heart rhytm evaluation.
7.At least one of the following:
(a) Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in men.
(b) Spectral tissue Doppler echocardiography - E/e’ ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).
(c) Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280 cm/s) (PASP > 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directly measured pulmonary capillary wedge pressure > 15 mmHg at rest within the past 12 months or > 25 mmHg at exercise documented by right heart catheterisation within 12 months prior to Screening (Visit 1).
(d) HF decompensation within 6 months before Randomisation (Visit 3), defined as hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled visit without hospitalisation.
8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
9.Male or female of non-childbearing potential.

E.4

Principal exclusion criteria

1 eGFR < 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaboration formula) at Screening (Visit 1).
2. Systolic blood pressure < 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 blood pressure lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation
3. Heart rate > 110 bpm or < 50 bpm at Randomisation
4. Life expectancy < 3 years due to other reasons than cardiovascular disease.
5. History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria).
6. Presence of any disease or condition rather than HF constituting the main reason for limiting the ability to exercise/reduced exercise capacity.
7. Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1)
8. Documented history of ejection fraction ≤ 40%. i.e. HF with recovered ejection fraction. Transient ejection fraction decrease e.g. in the setting of an MI does not apply
9. Any planned cardiovascular procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement), aortic aneurysm surgery, etc.
10. Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation therapy device within 12 weeks prior to Screening (Visit 1) or between Screening and Randomisation (Visit 3).
14. Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/without anaemia requiring ongoing or planned IV iron treatment.
15. Participants with hyperthyroidism, uncontrolled hypothyroidism, or any clinically significant thyroid disease as judged by the investigator.
18. ALT or AST ≥ 2 × ULN at Screening (Visit 1).
19. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support within 12 months prior to Screening (Visit 1).
20. Any active infection requiring oral, intravenous or intramuscular treatment.
24. Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil

E.5 End points

E.5.1

Primary end point(s)

1. KCCQ-TSS change from baseline at 16 weeks compared with placebo (Part A)
2. 6MWD change from baseline at 16 weeks compared with placebo (Part A)
3. KCCQ-TSS change from baseline at 24 weeks compared with placebo (Part B)
4. 6MWD change from baseline at 24 weeks compared with placebo (Part B)

E.5.1.1

Timepoint(s) of evaluation of this end point

1.Baseline to 16 weeks Part A
2.Baseline to 16 weeks Part A
3.Baseline to 24 weeks Part B
4.Baseline to 24 weeks Part B

E.5.2

Secondary end point(s)

1. KCCQ-TSS change from baseline at 24 and 48 weeks compared with placebo (Part A)
2. 6MWD change from baseline at 24 and 48 weeks compared with placebo (Part A)
3. NT-proBNP change from baseline at 16, 24, and 48 weeks compared with placebo (Part A)
4. LV-GLS, LAVI, LVMI change from baseline at 16 and 24 weeks compared with placebo (Part A)
5. PK Concentrations will be summarised by timepoints and dose level (Part A)
6. hsCRP and IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo (Part A)
7. NT-proBNP change from baseline at 24 weeks compared with placebo (Part B)
8. hsCRP and IL-6 change from baseline at 24 weeks compared with placebo (Part B)
9. PK Concentrations will be summarised by timepoints and dose level (Part B)
10. To assess the safety and tolerability of AZD4831 as compared with placebo in participants with HF (Part A and Part B). Safety and tolerability will be evaluated in terms of AEs, Vital signs, Clinical laboratory, and ECG.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Baseline to 24 and 48 weeks (Part A)
2. Baseline to 24 and 48 weeks (Part A)
3. Baseline to 16, 24, and 48 weeks (Part A)
4. Baseline to 16 and 24 weeks (Part A)
5 and 9 Summarised by timepoints and dose level (Part A and Part B)
6. Baseline and at 16, 24, and 48 weeks (Part A)
7. Baseline to 24 weeks (Part B)
8. Baseline to 24 weeks (Part B)
10. Change from baseline to end of study (Part A and Part B)

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

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)

Yes

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

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

Canada

Japan

Taiwan

United States

France

Poland

Sweden

Bulgaria

Czechia

Denmark

Hungary

Russian Federation

Slovakia

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 end of the study is defined as the date of the last protocol specified visit/assessment (including telephone contact) of the last participant in the study. This would be the last participant in Part B, or Part A (the last Week 52 visit [including telephone contact] for Part A) in the event that Part B is never started.

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

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:

445

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1040

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

290

F.4.2

For a multinational trial

F.4.2.1

In the EEA

889

F.4.2.2

In the whole clinical trial

1485

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

2021-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-03-27

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