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%
- Conditions
- heartfailure10019280
- Registration Number
- NL-OMON51637
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 26
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:
(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.
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. Symptoms and signs are defined in Appendix G.
3 LVEF >40% and evidence of structural heart disease (ie, left ventricular
hypertrophy or left atrial enlargement [1]) 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
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 (Visit 3).
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 (Visit 3).
24. Any concomitant medications known to be a potent CYP3A4 inducers or
inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil
Part B:
1 eGFR < 30 mL/min/1.73m2 by 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
BP lowering medications or >= 180 mmHg irrespective of treatments at
Randomisation (Visit 2).
3 Heart rate > 110 bpm or < 50 bpm at Randomisation (Visit 2).
4 Life expectancy < 2 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Part A<br /><br>KCCQ-TSS change from baseline at 16 weeks compared with placebo<br /><br>6MWD change from baseline at 16 weeks compared with placebo<br /><br><br /><br>Part B<br /><br>KCCQ-TSS,primary assessment at 24 weeks<br /><br>6MWD, primary assessment at 24 weeks</p><br>
- Secondary Outcome Measures
Name Time Method