E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with preserved Ejection Fraction (HFpEF) and heart failure with mid-range Ejection Fraction (HFmrEF) |
|
E.1.1.1 | Medical condition in easily understood language |
Heart failure - Failure of the heart to pump enough blood for circulation to the various parts of the body. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the effect of AZD4831 to placebo on target engagement |
|
E.2.2 | Secondary objectives of the trial |
To compare the effect of AZD4831 to placebo on coronary flow velocity reserve (CFVR)
To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT)
To assess the pharmacokinetics (PK) of AZD4831 after repeated dosing
To assess safety and tolerability of AZD4831 (Safety Objective) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Informed consent
1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this CSP
2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
Age
3. Patient must be 45 to 85 years of age inclusive, at the time of signing the informed consent form
Type of patient and disease characteristics
4. Signs and symptoms of HF in judgement of Investigator AND
a. Stable NYHA II-IV and
b. Ejection fraction (EF) ≥ 40 % and
c. Elevated NT-proBNP or BNP in the last 1 year defined as:
o Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus rhythm, NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF),
or
o Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 ng/L with sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF
d. And at least one of the following:
• Hospitalization with HF as primary cause in last 12 months
• Structural heart disease on echo according to ESC guidelines i.e. either enlarged Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM index > 95 g/m2 in women and > 115 g/m2 in men)
• Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg at exercise
• Sspectral tissue Doppler echocardiography - E/e’ ratio ≥13 at rest
Weight
5. Body Mass Index (BMI) range 18-40kg/m2
Sex
6. Male or female of nonchildbearing potential
Reproduction
7. Female patients must be 1 year post-menopausal or surgically sterile
8. Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period
Genetic sampling
9. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described above and provide informed consent for the genetic sampling and analysis |
|
E.4 | Principal exclusion criteria |
Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR <45 ml/min/1.73m2 or dialysis
Life expectancy < 3 years due to other reasons than cardiovascular disease
Any skin disorder, history of, or ongoing clinically significant allergy/hypersensitivity
Current decompensated HF
Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital or any primary cardiomyopathy) in judgment of investigator
Current hemodynamically significant valve disease in opinion of investigator
EF ever documented < 40%
Any current life-threatening dysrhythmia
Probable alternative primary reason for patient’s symptoms in judgment of investigator, including but not limited to:
a. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF
b. Anaemia: Hb <100 mg/L (10g/dL)
c. Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic O2, nebulizer or oral steroid therapy)
Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous coronary intervention (PCI) < 3 months
Known or clinically judged significant macrovascular coronary artery disease (CAD) that has not been revascularized
Heart transplantation or left ventricular assist device ever
Patients with known thyroid disease with or without treatment or thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) outside normal range levels
Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit of normal (ULN). Resampling will not be allowed during the same screening period if detected abnormal values do not have reasonable explanation and are not expected to return to normal level within few days.
Known positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in target engagement marker, defined as ex vivo zymosan stimulated MPO specific activity (MPO activity divided by MPO protein mass), normalised. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Change from baseline in CFVR measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE)
Change from baseline in Walking distance
Standard model population pharmacokinetic (PK) parameters to be reported in a separate report.
Relates to the Safety objective:
Adverse Events/Serious Adverse Events (AEs/SAEs) including incidence of maculopapular rash grade 3
Vital signs
Clinical chemistry/haematology parameters
Electrocardiogram (ECG) assessments |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
CFVR: at visit 2 and 5
6MWT: at visit 2, 5, and 7
PK parameter: at visit 3, 4, 5, 6, 7, and 8.
Safety:
From visit 1 to visit 8 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Denmark |
Finland |
Netherlands |
Sweden |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |