Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40%

Heart Failure With Preserved Ejection Fraction Clinical Trial

— ENDEAVOR  

Official title:

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%

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04986202
• Other study ID #: D6580C00010
• Secondary ID: 2020-005844-47
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: June 30, 2021
• Est. completion date: March 27, 2024

Study information

• Verified date: April 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is 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%. The study will consist of 2 separate parts, Part A and Part B, approximately 660 participants will be randomised in Part A, 820 in Part B.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 711
• Est. completion date: March 27, 2024
• Est. primary completion date: March 27, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 85 Years

Eligibility

Inclusion Criteria:

Part A

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) for patients with BMI =30 kg/m2.

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 rhythm evaluation.

7.At least one of the following:

1. 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.

2. Spectral tissue Doppler echocardiography - E/e' ratio (average of septal and lateral) = 13 at rest at the echocardiogram performed at Screening (Visit 1).

3. 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).

4. 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.

Part B

1. Participant must be = 40 to = 85 years of age, at the time of signing the informed consent.

2. Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure = 6 weeks before Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-care physician, with at least intermittent need for diuretic treatment.

3. LVEF >40% and evidence of structural heart disease (ie, left ventricular hypertrophy or

left atrial enlargement [defined by at least one of the following: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.]) documented by the most recent echocardiogram, or cardiac

magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no

echocardiogram is available, it can be performed at Screening (Visit 1).

4. 6MWD = 30 meters and = 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be < 50 meters

5. KCCQ-TSS = 90 points at Screening (Visit 1) and Randomisation (Visit 2).

6. NT-proBNP = 250 pg/mL (sinus rhythm) or = 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI = 30 kg/m2. 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 rhythm evaluation

7. Body mass index = 18.0 kg/m2 and = 45.0 kg/m2

8. Male or female of non-childbearing potential.

Exclusion Criteria:

Part A

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. Patients who underwent a successful atrial fibrillation/flutter cardioversion, can be enrolled in the study after 4 weeks.

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 (including but not limited to TSH =10 mIU/mL), or any clinically significant thyroid disease as judged by the investigator.

18. ALT or AST = 2 × ULN at Screening (Visit 1).

19. Pulmonary arterial 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 at Screening (Visit 1) and/or at Randomisation.

23 Any signs or confirmation of COVID-19 infection:

• Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks prior to Screening (Visit 1) or at Randomisation.

• Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 1).

24. Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil

29. Previous enrolment and randomisation in the present study. (Participants who where screened and screen failed and not randomised in Part A can be screened for possible entry to Part B).

All exclusion criteria in Part A are applicable to Part B with the following exceptions:

Exclusion criteria 4; 19

Exclusion Criteria specific for Part B only [criteria numeration for Part B]

4. Life expectancy < 2 years due to other reasons than cardiovascular disease.

11. HF due to any of the following: known infiltrative cardiomyopathy (eg, amyloid, sarcoid, lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), or uncorrected primary valvular disease.

18. 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]).

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction

Intervention

Drug:
• AZD4831
AZD4831

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
Australia	Research Site	Bedford Park
Australia	Research Site	Chermside
Australia	Research Site	Concord
Australia	Research Site	Frankston
Belgium	Research Site	Aalst
Belgium	Research Site	Dendermonde
Belgium	Research Site	Hasselt
Belgium	Research Site	Huy
Belgium	Research Site	Kortrijk
Belgium	Research Site	Leuven
Belgium	Research Site	Roeselare
Brazil	Research Site	Brasilia
Brazil	Research Site	Campina Grande do Sul
Brazil	Research Site	Campinas
Brazil	Research Site	Campinas
Brazil	Research Site	Canoas
Brazil	Research Site	Curitiba
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	São Paulo
Bulgaria	Research Site	Blagoevgrad
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Chicoutimi	Quebec
Canada	Research Site	Guelph	Ontario
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Trois-Rivières	Quebec
Canada	Research Site	Waterloo	Ontario
Canada	Research Site	York	Ontario
Czechia	Research Site	Brno
Czechia	Research Site	Broumov
Czechia	Research Site	Jaromer
Czechia	Research Site	Kolin
Czechia	Research Site	Louny
Czechia	Research Site	Plzen
Czechia	Research Site	Praha
Czechia	Research Site	Praha 2
Czechia	Research Site	Pribram
Czechia	Research Site	Zlin
Denmark	Research Site	Århus N
Denmark	Research Site	Copenhagen O
Denmark	Research Site	Hvidovre
Denmark	Research Site	København
Denmark	Research Site	København NV
Denmark	Research Site	Roskilde
Denmark	Research Site	Viborg
France	Research Site	Bayonne
France	Research Site	Dijon Cedex
France	Research Site	La Tronche
France	Research Site	Le Coudray Cedex
France	Research Site	Montauban
France	Research Site	Montpellier Cedex
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Pierre Benite
France	Research Site	Rennes Cedex 9
France	Research Site	Saint Brieuc
France	Research Site	Toulon
France	Research Site	Toulouse Cedex 9
France	Research Site	TOURCOING cedex
Hungary	Research Site	Balatonfüred
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Nyíregyháza
Japan	Research Site	Fukui-shi
Japan	Research Site	Higashiohmi-shi
Japan	Research Site	Iwakuni-shi
Japan	Research Site	Kanazawa-shi
Japan	Research Site	Kasugai-shi
Japan	Research Site	Kishiwada-shi
Japan	Research Site	Kure-shi
Japan	Research Site	Kyoto-shi
Japan	Research Site	Matsumoto-shi
Japan	Research Site	Minami-ku
Japan	Research Site	Nagano
Japan	Research Site	Naha
Japan	Research Site	Oita-shi
Japan	Research Site	Omihachiman-shi
Japan	Research Site	Otaru-shi
Japan	Research Site	Sagamihara-shi
Japan	Research Site	Toshima-ku
Japan	Research Site	Ueda-shi
Japan	Research Site	Uwajima-shi
Japan	Research Site	Yokohama-shi
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Den Bosch
Netherlands	Research Site	Den Haag
Netherlands	Research Site	Deventer
Netherlands	Research Site	Heerlen
Poland	Research Site	Bydgoszcz
Poland	Research Site	Lublin
Poland	Research Site	Rzeszow
Poland	Research Site	Skierniewice
Poland	Research Site	Tarnów
Poland	Research Site	Tczew
Poland	Research Site	Tychy
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Wolomin
Russian Federation	Research Site	Aramil
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Perm
Russian Federation	Research Site	St Petersburg
Russian Federation	Research Site	Tver
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Brezno
Slovakia	Research Site	Kosice
Slovakia	Research Site	Kosice
Slovakia	Research Site	Nitra
Slovakia	Research Site	Presov
Sweden	Research Site	Göteborg
Sweden	Research Site	Jönköping
Sweden	Research Site	Lund
Sweden	Research Site	Norrköping
Sweden	Research Site	Örebro
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei 112
Taiwan	Research Site	Taipei City
Taiwan	Research Site	Taoyuan
Turkey	Research Site	Eskisehir
Turkey	Research Site	Izmir
United States	Research Site	Alexander City	Alabama
United States	Research Site	Baltimore	Maryland
United States	Research Site	Buffalo	New York
United States	Research Site	Chapel Hill	North Carolina
United States	Research Site	Cleveland	Ohio
United States	Research Site	Evanston	Illinois
United States	Research Site	Hazel Crest	Illinois
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Miami	Florida
United States	Research Site	Miami Beach	Florida
United States	Research Site	New York	New York
United States	Research Site	Norfolk	Virginia
United States	Research Site	Ocala	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pinehurst	North Carolina
United States	Research Site	Rosedale	New York
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Tullahoma	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  Czechia,  Denmark,  France,  Hungary,  Japan,  Netherlands,  Poland,  Russian Federation,  Slovakia,  Sweden,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events	Number of participants with Adverse Events Part A	Baseline - week 52
Other	Vital Signs	Number of participants with outliers for vital signs Part A	Baseline - week 52
Other	Clinical Laboratory	Number of participants with outliers for clinical laboratory measurements Part A	Baseline - week 52
Other	Electrocardiogram (ECG)	Number of Participants With Abnormal ECG Part A	Baseline - week 52
Other	Adverse Events	Number of participants with Adverse Events Part B	Baseline- week 52
Other	Vital Signs	Number of participants with outliers for vital signs Part B	Baseline - week 52
Other	Clinical Laboratory	Number of participants with outliers for clinical laboratory measurements Part B	Baseline - week 52
Other	ECG	Number of Participants With Abnormal ECG Part B	Baseline - week 52
Other	AZD4831 Pharmacokinetics	Plasma concentrations of AZD4831 Part B	Baseline- week 4 and 24
Primary	Kansas City Cardiomyopathy Questionnaire -Total Symptom Score	Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 16 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome	Baseline - 16 weeks
Primary	Kansas City Cardiomyopathy Questionnaire -Total Symptom Score	Kansas City Cardiomyopathy Questionnaire-Total Symptom Score change from baseline at 24 weeks compared with placebo Part B. The score ranges from 0 to 100, where a higher score represents a better patient outcome.	Baseline - 24 weeks
Primary	Six Minute Walk Distance	Six Minute Walk Distance change from baseline at 16 weeks compared with placebo Part A	Baseline - 16 weeks
Primary	Six Minute Walk Distance	Six Minute Walk Distance change from baseline at 24 weeks compared with placebo Part B	Baseline - 24 weeks
Secondary	Kansas City Cardiomyopathy Questionnaire-Total Symptom Score	Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 and 48 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome.	Baseline - 24 and 48 weeks
Secondary	Six Minute Walk Distance	Six Minute Walk Distance change from baseline at 24 and 48 weeks compared with placebo Part A	Baseline - 24 and 48 weeks
Secondary	N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP change from baseline at 16, 24, and 48 weeks compared with placebo Part A	Baseline - 16, 24 and 48 weeks
Secondary	Left ventricular global longitudinal strain (LV-GLS)	LV-GLS change from baseline at 16 and 24 weeks compared with placebo Part A	Baseline - 16 and 24 weeks
Secondary	Left atrial volume index (LAVI)	LAVI change from baseline at 16 and 24 weeks compared with placebo Part A	Baseline - 16 and 24 weeks
Secondary	Left ventricular mass index (LVMI)	LVMI change from baseline at 16 and 24 weeks compared with placebo Part A	Baseline - 16 and 24 weeks
Secondary	Pharmacokinetics (AZD4831 plasma exposure)	Plasma concentrations of AZD4831 summarised by timepoint and dose level Part A	Day 1, Day 29, Day 85, Day 113, Day 169, Day 336, Day 365
Secondary	High sensitivity CRP (hsCRP)	hsCRP change from baseline at 16, 24, and 48 weeks compared with placebo Part A	Baseline - 16, 24 and 48 weeks
Secondary	Interleukin 6 (IL-6)	IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo Part A	Baseline - 16, 24 and 48 weeks
Secondary	High sensitivity CRP (hsCRP)	hsCRP primary assessment at 24 weeks Part B	Baseline - 24 weeks
Secondary	N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP primary assessment at 24 weeks Part B	Baseline - 24 weeks
Secondary	Interleukin 6 (IL-6)	IL-6 primary assessment at 24 weeks Part B	Baseline - 24 weeks