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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04986202
Recruitment Status : Recruiting
First Posted : August 2, 2021
Last Update Posted : June 2, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief 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, 825 in Part B.

Condition or disease Intervention/treatment Phase
Heart Failure With Preserved Ejection Fraction Drug: AZD4831 Other: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1485 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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%
Actual Study Start Date : June 30, 2021
Estimated Primary Completion Date : November 20, 2024
Estimated Study Completion Date : November 20, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Part A 2.5 mg
AZD4831 2.5 mg
Drug: AZD4831
AZD4831

Experimental: Part A 5 mg
AZD4831 5 mg
Drug: AZD4831
AZD4831

Placebo Comparator: Part A Placebo
Placebo
Other: Placebo
Placebo

Experimental: Part B Dose based on Part A
AZD4831 Dose based on Part A
Drug: AZD4831
AZD4831

Placebo Comparator: Part B Placebo
Placebo
Other: Placebo
Placebo




Primary Outcome Measures :
  1. Kansas City Cardiomyopathy Questionnaire -Total Symptom Score [ Time Frame: Baseline - 16 weeks ]
    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

  2. Kansas City Cardiomyopathy Questionnaire -Total Symptom Score [ Time Frame: Baseline - 24 weeks ]
    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.

  3. Six Minute Walk Distance [ Time Frame: Baseline - 16 weeks ]
    Six Minute Walk Distance change from baseline at 16 weeks compared with placebo Part A

  4. Six Minute Walk Distance [ Time Frame: Baseline - 24 weeks ]
    Six Minute Walk Distance change from baseline at 24 weeks compared with placebo Part B


Secondary Outcome Measures :
  1. Kansas City Cardiomyopathy Questionnaire-Total Symptom Score [ Time Frame: Baseline - 24 and 48 weeks ]
    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.

  2. Six Minute Walk Distance [ Time Frame: Baseline - 24 and 48 weeks ]
    Six Minute Walk Distance change from baseline at 24 and 48 weeks compared with placebo Part A

  3. N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: Baseline - 16, 24 and 48 weeks ]
    NT-proBNP change from baseline at 16, 24, and 48 weeks compared with placebo Part A

  4. Left ventricular global longitudinal strain (LV-GLS) [ Time Frame: Baseline - 16 and 24 weeks ]
    LV-GLS change from baseline at 16 and 24 weeks compared with placebo Part A

  5. Left atrial volume index (LAVI) [ Time Frame: Baseline - 16 and 24 weeks ]
    LAVI change from baseline at 16 and 24 weeks compared with placebo Part A

  6. Left ventricular mass index (LVMI) [ Time Frame: Baseline - 16 and 24 weeks ]
    LVMI change from baseline at 16 and 24 weeks compared with placebo Part A

  7. Pharmacokinetics (AZD4831 plasma exposure) [ Time Frame: Day 1, Day 29, Day 85, Day 113, Day 169, Day 336, Day 365 ]
    Plasma concentrations of AZD4831 summarised by timepoint and dose level Part A

  8. High sensitivity CRP (hsCRP) [ Time Frame: Baseline - 16, 24 and 48 weeks ]
    hsCRP change from baseline at 16, 24, and 48 weeks compared with placebo Part A

  9. Interleukin 6 (IL-6) [ Time Frame: Baseline - 16, 24 and 48 weeks ]
    IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo Part A

  10. High sensitivity CRP (hsCRP) [ Time Frame: Baseline - 24 weeks ]
    hsCRP change from baseline at 24 weeks compared with placebo Part B

  11. N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: Baseline - 24 weeks ]
    NT-proBNP change from baseline at 24 weeks compared with placebo Part B

  12. Interleukin 6 (IL-6) [ Time Frame: Baseline - 24 weeks ]
    IL-6 change from baseline at 24 weeks compared with placebo Part B

  13. Pharmacokinetics (AZD4831 plasma exposure) [ Time Frame: Day 29, Day 85, Day 168, Day 197 ]
    Plasma concentrations of AZD4831 summarised by timepoint and dose level Part B


Other Outcome Measures:
  1. Adverse Events [ Time Frame: Baseline - week 52 ]
    Number of participants with Adverse Events Part A

  2. Vital Signs [ Time Frame: Baseline - week 52 ]
    Number of participants with outliers for vital signs Part A

  3. Clinical Laboratory [ Time Frame: Baseline - week 52 ]
    Number of participants with outliers for clinical laboratory measurements Part A

  4. Electrocardiogram (ECG) [ Time Frame: Baseline - week 52 ]
    Number of Participants With Abnormal ECG Part A

  5. Adverse Events [ Time Frame: Baseline - week 28 ]
    Number of participants with Adverse Events Part B

  6. Vital Signs [ Time Frame: Baseline - week 28 ]
    Number of participants with outliers for vital signs Part B

  7. Clinical Laboratory [ Time Frame: Baseline - week 28 ]
    Number of participants with outliers for clinical laboratory measurements Part B

  8. ECG [ Time Frame: Baseline - week 28 ]
    Number of Participants With Abnormal ECG Part B



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 signs and 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.

    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).

    11. Medical history of aborted sudden cardiac death or sustained ventricular tachycardia with haemodynamic compromise.

    12. Any primary cardiomyopathy (eg, genetic hypertrophic cardiomyopathy, obstructive hypertrophic, arrhythmogenic right ventricular cardiomyopathy/dysplasia), cardiomyopathies related to current toxic or infective conditions (eg, ongoing chemotherapy, myocarditis, septic cardiomyopathy), cardiomyopathies due to infiltrative diseases (eg, amyloidosis, sarcoidosis), peripartum cardiomyopathy, as well as HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease 13. Any past or planned organ transplantation (including cardiac). 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04986202


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04986202    
Other Study ID Numbers: D6580C00010
First Posted: August 2, 2021    Key Record Dates
Last Update Posted: June 2, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Heart failure
Heart failure with preserved ejection fraction
HFpEF
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases