The primary objective of this study is to evaluate the target engagement of AZD4831, MPO inhibitor by measuring MPO specific activity in plasma following ex vivo stimulation of fresh blood samples with zymosan, in patients with HFpEF. MPO is known…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the effect of AZD4831 to placebo on target engagement.
Secondary outcome
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.
Background summary
Recent evidence suggests that MPO may provide a mechanistic link between
inflammation, oxidative stress, vascular dysfunction and impaired cardiac
remodelling. It is thus hypothesized that the MPO inhibitor AZD4831 will
improve coronary microvascular status as well as systemic endothelial function,
leading to improved diastolic function and overall status of HFpEF patients.
Study objective
The primary objective of this study is to evaluate the target engagement of
AZD4831, MPO inhibitor by measuring MPO specific activity in plasma following
ex vivo stimulation of fresh blood samples with zymosan, in patients with
HFpEF. MPO is known to influence vascular reactivity through consumption of
endothelial Nitric Oxide (NO) under inflammatory conditions. The objectives of
this study are also to evaluate the safety and tolerability of AZD4831 in
patients with HFpEF and HFmrEF and the incidence of maculopapular rash grade 3.
In addition, to assess the effect of AZD4831 on CFVR as a measure of myocardial
microvascular function.
Study design
Randomized, double blind, placebo-controlled, parallel group, multicentre,
phase 2a study
Intervention
All patients will be treated once daily with AZD4831 or placebo for in total
approximately 90 days. In part A the first 37 patients will be treated for
approximately 10 days with a starting dose at 2.5 mg AZD4831 or matching
placebo once daily. After 10 days the dose will be increased to 5 mg AZD4831 or
matching placebo once daily for approximately 80 days. When all patients in
part A have been treated for 30 days (visit 5) an interim analysis will be
performed. In part B the remaining 59 patients will be treated for
approximately 10 days with a starting dose at 2.5 mg AZD4831 or matching
placebo once daily. After 10 days the dose may be maintained at 2.5 mg or
increased to 5 mg or 10 mg AZD4831 or matching placebo once daily depending on
the outcome of the interim analysis.
Study burden and risks
A subject visits the hospital for a maximum of 8 times. Two of these visits may
be home visits (part A) or may be replaced by phone calls (part B). Blood is
taken by venipuncture at 8 visits. The maximum amount of blood that is taken
throughout the study will not exceed 250 ml. A subject is be tested for HIV,
Hepatitis B, Hepatitis C and for pregnancy (if applicable) A subject receives a
physical examination at 8 visits. At each visit an ECG will be made. CRVR
measurement is performed at 2 visits and an echocardiography at a maximum of 4
visits. Endo-Pat test, PWV/PWA and 6MWT is conducted at 3 visits. The subject
is asked to complete the KCCQ at 4 visits.
Prinses Beatrixlaan 582
Den Haag 2595 BM
NL
Prinses Beatrixlaan 582
Den Haag 2595 BM
NL
Listed location countries
Age
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) \u2265 40 % and c. Elevated
NT-proBNP or BNP in the last 1 year defined as: * Measured as out-patient:
NT-proBNP \u2265125 ng/L or BNP\u226535 ng/L with sinus rhythm, NT-proBNP
\u2265750 ng/L or BNP \u2265200 ng/L with atrial fibrillation (AF), OR *
Measured when hospitalized acutely: NT-proBNP \u2265500 (ng/L) or BNP \u2265125
ng/L with sinus rhythm, NT-proBNP \u22651250 (ng/L) or BNP \u2265350 ng/L with
AF d. And at least one of the following: \u2022 Hospitalization with HF as
primary cause in last 12 months \u2022 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)
\u2022 Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg
at exercise \u2022 Spectral tissue Doppler echocardiography - E/e\u2019 ratio
\u226513 at rest, Weight 5. Body Mass Index (BMI) range 18-40 kg/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 NA for
the Netherlands
Exclusion criteria
Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) eGFR <30 ml/min/1.73m2 or dialysis, Life expectancy <3 years due to
other reasons than cardiovascular disease, Any ongoing 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\u2019s 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 uncontrolled or clinically significant thyroid disease as judged
by the investigator, Alanine transaminase (ALT) or aspartate aminotransferase
(AST) \u22652 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002895-42-NL |
| CCMO | NL67808.056.18 |