heartfailure
Conditions
Interventions
In Part A, participants will undergo a screening period of up to 4 weeks,
followed by randomisation across 3 different treatment arms. Eligible
participants will be randomised at a 1:1:1 ratio and d
therefore, participants
who were randomised into Part A cannot be included in Part B.
Sponsors
Astra Zeneca
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Part A: 1. >= 40 to 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 = 250 pg/mL (sinus rhythm) or >= 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI = 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 = 40 to =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
Exclusion criteria
Exclusion criteria: Part A: 1 eGFR = 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 5000 pg/mL at Screening (Visit 1) 8. Documented history of ejection fraction =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 = 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A KCCQ-TSS change from baseline at 16 weeks compared with placebo 6MWD change from baseline at 16 weeks compared with placebo Part B KCCQ-TSS,primary assessment at 24 weeks 6MWD, primary assessment at 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A • KCCQ-TSS change from baseline at 24 and 48 weeks compared with placebo • 6MWD change from baseline at 24 and 48 weeks compared with placebo • NT-proBNP change from baseline at 16, 24 and 48 weeks compared with placebo • LV-GLS change from baseline at 16 and 24 weeks compared with placebo • LAVI change from baseline at 16 and 24 weeks compared with placebo • LVMI change from baseline at 16 and 24 weeks compared with placebo Concentrations will be summarised by timepoint and dose level. • hsCRP and IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo Safety Safety and tolerability will be evaluated in terms of AEs, Vital signs, Clinical laboratory, and ECG. Assessments related to AEs will cover: • Occurrence/Frequency • Seriousness • Death • AEs leading to discontinuation of IMP • AEoSIs related to skin reactions, including maculopapular rash, and infection Vital signs parameters include blood pressure, pulse rate, and body temperature; assessments will cover: • Observed value • Absolute change from baseline values over time • Orthostatic blood pressure A complete list of laboratory parameters is presented in Section 8.2.4; assessments will cover: • Observed value • Absolute change from baseline values over time • Treatment-emergent changes in selected laboratory parameters Electrocardiogram measurements assessments will cover: • Investigator evaluation Part B: • NT-proBNP, primary assessment at 24 weeks • hsCRP and IL-6, primary assessment at 24 weeks Safety • Occurrence and time to first occurrence of AE, SAE, SAE with outcome death, AE leading to discontinuation of study intervention, possibly related AE as assessed by investigator, possibly related SAE as assessed by investigator. • Observed laboratory value, change from baseline and time to first treatment emergent abnormality. • Observed vital sign value, change from baseline, and time to first treatment emergent abnormality. • Observed ECG ab | — |
Countries
Netherlands
Outcome results
None listed