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Study to Evaluate the Effects of AZD3427 in Patients With Heart Failure

Primary Purpose

Heart Failure

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

AZD3427

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction, Forearm blood flow

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patient must be 18 to 75 years of age.
Patient with known clinical diagnosis of Stage C heart failure New York Heart Association (NYHA) Class I-III and on stable medical therapy for at least 12 weeks prior to screening with no significant dose change or new medications added during that period. Specifically:
1. Patients with a diagnosis of HFrEF, defined as ejection fraction ≤ 40%. OR
2. Patients with a diagnosis of HFpEF, defined as ejection fraction ≥ 50%.
Patients with suitable veins and arteries for cannulation or repeated puncture.
Patients who are able to lie flat for the duration of IA infusions and related procedures during Visit 2 (approximately 3 hours).
Body weight of at least 60 kg and body mass index within the range of 18 to 40 kg/m^2.
Male and/or female of nonchildbearing potential.
Capable of giving signed informed consent.

Exclusion Criteria:

History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.
Clinically significant valvular heart disease as judged by the investigator.
Congenital heart disease (patients with Patent Foramen Ovale may be included in the study).
Clinical diagnosis of heart failure NYHA Class IV.
Occurrence in the last 3 months of any of the following:
1. Acute coronary syndrome: myocardial infarction or unstable angina.
2. Percutaneous coronary intervention.
3. Cerebrovascular accident or transient ischaemic attack.
4. Heart failure hospitalisation.
History of prior dissections.
History or suspicion of cardiac amyloidosis.
Patients with conditions where vasodilator therapy may be contraindicated.
History of cancer in the last 5 years, except for non-melanoma skin cancer.
Any clinically important abnormalities in clinical chemistry, haematology or urinalysis.
Any positive result at Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus.
History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator.
Abnormal vital signs, after at least 10-minute supine rest, defined as any of the following at Screening:
1. Systolic blood pressure (BP) > 160 mmHg.
2. Diastolic BP > 90 mmHg.
Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead electrocardiogram as considered by the investigator.
1. Prolonged QTcF > 450 ms.
2. Family history of long QT syndrome.
3. Second or third-degree AV block, or sinus node dysfunction with significant sinus pause.
History of hypersensitivity to drugs with a similar chemical structure or class to AZD3427.
Participants who have previously received AZD3427.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patients with HFpEF or HFrEF

Arm Description

Patients will be enrolled in 2 cohorts in parallel: 1 cohort of patients with HFpEF and 1 cohort of patients with HFrEF. Patients will receive a sequence of 5 IA infusions into the brachial artery, consisting of a baseline saline infusion of approximately 20 minutes, followed by 3 sequential infusions of AZD3427 at ascending doses of approximately 10 minutes (each) and a washout saline infusion of approximately 15 minutes.

Outcomes

Primary Outcome Measures

Maximum change from baseline in absolute forearm blood flow in the infused arm during AZD3427 IA infusions

To determine whether AZD3427 produces a vasodilatory response in the forearm resistance vessels of HFpEF and HFrEF patients, as assessed by forearm blood flow parameters measured using venous occlusion plethysmography.

Secondary Outcome Measures

Number of patients with anti-drug antibody (ADAs) in serum samples at baseline and at Day 8, Day 29, and Day 50

To assess the immunogenicity of AZD3427.

Change from baseline in forearm blood flow ratio in the infused arm (AZD3427 infusion:baseline) after each AZD3427 IA infusion

Change from baseline in forearm blood flow ratio between arms (infused arm:non-infused arm) after each AZD3427 IA infusion

Full Information

NCT ID

NCT04890548

First Posted

May 13, 2021

Last Updated

December 2, 2021

Sponsor

AstraZeneca

Collaborators

Parexel

1. Study Identification

Unique Protocol Identification Number

NCT04890548

Brief Title

Study to Evaluate the Effects of AZD3427 in Patients With Heart Failure

Official Title

A Mechanistic Study to Evaluate the Vasodilatory Effects of AZD3427 in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) and Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Withdrawn

Why Stopped

Study start up timelines delayed into late autumn, and with COVID cases rising in the UK, the feasibility of successfully recruiting the study and ethical concerns about starting a study that AZ may not be able to complete.

Study Start Date

November 23, 2021 (Anticipated)

Primary Completion Date

August 2, 2022 (Anticipated)

Study Completion Date

August 2, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

Collaborators

Parexel

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The primary purpose of this mechanistic study is to evaluate the vasodilatory effects of AZD3427 in adult patients with heart failure and will be performed at approximately 2 study sites in the United Kingdom.

Detailed Description

The study will enroll patients in 2 cohorts in parallel: 1 cohort of patients with heart failure with preserved ejection fraction (HFpEF) and 1 cohort of patients with heart failure with reduced ejection fraction (HFrEF). Each cohort plans to enroll at least 7 evaluable patients. All patients will receive the same sequence of 5 intra-arterial (IA) infusions into the brachial artery, consisting of a baseline saline infusion of approximately 20 minutes, followed by 3 sequential infusions of AZD3427 at ascending doses of approximately 10 minutes (each) and a washout saline infusion of approximately 15 minutes. For each patient, the study will last at least 51 days and up to 99 days, including: A screening period of 1 to 42 days (which will include baseline echocardiography) A single-day treatment period during which patients will stay at study site until at least 4 hours after the end of infusions A follow-up period of 49 to 56 days after the end of the last infusion including: A follow-up phone call on Day 2 (within 24 ± 6 hours post-infusion) A follow-up visit on Day 8 (+ 3 days) A follow-up visit on Day 29 (± 2 days) A follow-up visit on Day 50 (+ 7 days)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

Keywords

Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction, Forearm blood flow

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Patients with HFpEF or HFrEF

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

AZD3427

Intervention Description

Patients will receive 5 IA infusions of AZD3427 into the brachial artery. The IA infusions of AZD3427 will be administered via a syringe pump, using a polypropylene syringe containing 0.9% (w/v) saline and delivered through an administration set comprising a syringe, extension tubing (PVC), and a 0.2- or 0.22-μm PVDF syringe filter.

Primary Outcome Measure Information:

Title

Maximum change from baseline in absolute forearm blood flow in the infused arm during AZD3427 IA infusions

Description

Time Frame

Day 1

Secondary Outcome Measure Information:

Title

Number of patients with anti-drug antibody (ADAs) in serum samples at baseline and at Day 8, Day 29, and Day 50

Description

To assess the immunogenicity of AZD3427.

Time Frame

Day 1, Day 8, Day 29 and Day 50

Title

Change from baseline in forearm blood flow ratio in the infused arm (AZD3427 infusion:baseline) after each AZD3427 IA infusion

Description

Time Frame

Day 1

Title

Change from baseline in forearm blood flow ratio between arms (infused arm:non-infused arm) after each AZD3427 IA infusion

Description

Time Frame

Day 1

Other Pre-specified Outcome Measures:

Title

Number of patients with adverse events

Description

Assessment of safety and tolerability of AZD3427 in HFpEF and HFrEF patients, following low-dose local IA infusion of 3 sequential ascending doses of AZD3427.

Time Frame

From Screening (Day -42 to Day -1) until the Follow-up visit (Day 1, Day 2, Day 8, Day 29, and Day 50)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patient must be 18 to 75 years of age. Patient with known clinical diagnosis of Stage C heart failure New York Heart Association (NYHA) Class I-III and on stable medical therapy for at least 12 weeks prior to screening with no significant dose change or new medications added during that period. Specifically: Patients with a diagnosis of HFrEF, defined as ejection fraction ≤ 40%. OR Patients with a diagnosis of HFpEF, defined as ejection fraction ≥ 50%. Patients with suitable veins and arteries for cannulation or repeated puncture. Patients who are able to lie flat for the duration of IA infusions and related procedures during Visit 2 (approximately 3 hours). Body weight of at least 60 kg and body mass index within the range of 18 to 40 kg/m^2. Male and/or female of nonchildbearing potential. Capable of giving signed informed consent. Exclusion Criteria: History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study. Clinically significant valvular heart disease as judged by the investigator. Congenital heart disease (patients with Patent Foramen Ovale may be included in the study). Clinical diagnosis of heart failure NYHA Class IV. Occurrence in the last 3 months of any of the following: Acute coronary syndrome: myocardial infarction or unstable angina. Percutaneous coronary intervention. Cerebrovascular accident or transient ischaemic attack. Heart failure hospitalisation. History of prior dissections. History or suspicion of cardiac amyloidosis. Patients with conditions where vasodilator therapy may be contraindicated. History of cancer in the last 5 years, except for non-melanoma skin cancer. Any clinically important abnormalities in clinical chemistry, haematology or urinalysis. Any positive result at Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator. Abnormal vital signs, after at least 10-minute supine rest, defined as any of the following at Screening: Systolic blood pressure (BP) > 160 mmHg. Diastolic BP > 90 mmHg. Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead electrocardiogram as considered by the investigator. Prolonged QTcF > 450 ms. Family history of long QT syndrome. Second or third-degree AV block, or sinus node dysfunction with significant sinus pause. History of hypersensitivity to drugs with a similar chemical structure or class to AZD3427. Participants who have previously received AZD3427.

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 requests 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 refer 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 URL

https://astrazenecagroup-dt.pharmacm.com/DT/Home

Learn more about this trial

Study to Evaluate the Effects of AZD3427 in Patients With Heart Failure

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