Heart Failure with Left Ventricular Ejection Fraction > 40% MedDRA version: 20.0 Level: LLT Classification code 10019279 Term: Heart failure System Organ Class: 100000004849
Conditions
Interventions
Product Name: AZD4831 film-coated tablet 2.5 mg
Product Code: AZD4831
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: NA
Current Sponsor code: AZD4831
Concentration unit: mg milligram(s)
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion 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 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 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. Are the trial subjects under 18? no Number of subjects for this age range: 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
Exclusion criteria
Exclusion criteria: 1 eGFR 110 bpm or 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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);Secondary Objective: 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);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);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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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.;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) | — |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Czechia, Czech Republic, Denmark, France, Hungary, Japan, Netherlands, Poland, Russian Federation, Slovakia, Sweden, Taiwan, United States
Contacts
Public ContactInformation Centre
AstraZeneca
Outcome results
None listed