Safety and Tolerability Study of AZD4831 in Patients With Heart Failure.

NCT ID: NCT03756285

Last Updated: 2021-07-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-11
• Study Completion Date: 2020-05-07

Brief Summary

A randomized, double-blind, placebo-controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF). The study will be conducted at approximately 15 sites in 5 countries. Approximately 96 patients will be randomized to AZD4831 or placebo (treatment duration 90 days).

Detailed Description

This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection Fraction (HRmrEF). The study will be conducted at approximately 15 sites in 5 countries (USA, Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for eligibility, signing the informed consent and enrolled to the study at visit 1. The study will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for approximately 90 days. After approximately 30 days of treatment, an interim analysis will be done to analyse the safety, tolerability and target engagement. After the evaluation, the randomization to Part B may proceed. In Part B the approximate 59 remaining patients will be randomized and treated for approximately 90 days.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

AZD4831

AZD4831 tablets taken orally for for 90 days.

Group Type: EXPERIMENTAL

AZD4831

Intervention Type: DRUG

AZD4831 tablet taken orally for 90 days.

Placebo

Placebo tablets taken orally for 90 days.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablet taken orally for 90 days.

Interventions

AZD4831

AZD4831 tablet taken orally for 90 days.

Intervention Type: DRUG

Placebo

Placebo tablet taken orally for 90 days.

Intervention Type: DRUG

Eligibility Criteria

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

1. Stable NYHA II-IV and

2. Ejection fraction (EF) ≥ 40 % and

3. 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

4. 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
• Spectral 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

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's symptoms in judgment of investigator, including but not limited to:

1. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF

2. Anaemia: Hb <100 mg/L (10g/dL)

3. 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) ≥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

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Research Site

Chicago, Illinois, United States

Research Site

Boston, Massachusetts, United States

Research Site

Aarhus N, , Denmark

Research Site

Herlev, , Denmark

Research Site

Hvidovre, , Denmark

Research Site

Odense C, , Denmark

Research Site

Turku, , Finland

Research Site

Deventer, , Netherlands

Research Site

Dordrecht, , Netherlands

Research Site

Groningen, , Netherlands

Research Site

Gothenburg, , Sweden

Research Site

Lund, , Sweden

Research Site

Stockholm, , Sweden

Countries

United States; Denmark; Finland; Netherlands; Sweden

References

Lam CSP, Lund LH, Shah SJ, Voors AA, Erlinge D, Saraste A, Pirazzi C, Grove EL, Barasa A, Schou M, Aziz A, Svedlund S, Wijngaarden JV, Lindstedt EL, Gustavsson A, Nelander K, Garkaviy P, Gan LM, Gabrielsen A. Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results. J Card Fail. 2024 Jan;30(1):104-110. doi: 10.1016/j.cardfail.2023.04.003. Epub 2023 Apr 16.

Reference Type: DERIVED

PMID: 37072105 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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Redacted CSP

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Redacted SAP

Other Identifiers

D6580C00003

Identifier Type: -

Identifier Source: org_study_id