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

A Randomized, Double Blind, Placebo-controlled, Parallel Group, Multicentre, Phase 2a Study to Assess Target Engagement, Safety and Tolerability of AZD4831 in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

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).

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: AZD4831; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Research Site
  • Herlev, Denmark, 2730
    • Research Site
  • Hvidovre, Denmark, 2650
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
• Finland
  • Turku, Finland, 20520
    • Research Site
• Netherlands
  • Deventer, Netherlands, 7416 SE
    • Research Site
  • Dordrecht, Netherlands, 3318 AT
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
• Sweden
  • Göteborg, Sweden, 41345
    • Research Site
  • Lund, Sweden, 22242
    • Research Site
  • Stockholm, Sweden, 171 76
    • Research Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD4831; AZD4831 tablets taken orally for for 90 days.	Drug: AZD4831; AZD4831 tablet taken orally for 90 days.
Placebo Comparator: Placebo; Placebo tablets taken orally for 90 days.	Drug: Placebo; Placebo tablet taken orally for 90 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in MPO Specific Activity	To compare the effect of AZD4831 to placebo on Target engagement, defined as ex vivo zymozan stimulated Myeloperoxidase (MPO) specific activity	Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	To compare the effect of AZD4831 to placebo on coronary flow velocity reserve (CFVR) measured in the mid-distal segment of the left anterior descending (LAD) coronary artery under adenosine infusion measured by Transthoracic Doppler Echocardiography (TDE).	Measurement on day 0 and 90.
Change From Baseline in Walking Distance	To compare the effect of AZD4831 to placebo on 6 minutes walking test (6MWT)	Measurement on day 0, 30 and 90. Change reported from day 0 to day 90.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• Redacted CSP
• Redacted SAP

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2018
• Primary Completion (Actual): May 7, 2020
• Study Completion (Actual): May 7, 2020

Study Registration Dates

• First Submitted: November 19, 2018
• First Submitted That Met QC Criteria: November 26, 2018
• First Posted (Actual): November 28, 2018

Study Record Updates

• Last Update Posted (Actual): July 19, 2021
• Last Update Submitted That Met QC Criteria: June 29, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure with Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: D6580C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No