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

Heart Failure Clinical Trial

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)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04890548
• Other study ID #: D8330C00002
• Status: Withdrawn
• Phase: Phase 1
• Start date: November 23, 2021
• Est. completion date: August 2, 2022

Study information

• Verified date: December 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: August 2, 2022
• Est. primary completion date: August 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Patient must be 18 to 75 years of age.

2. 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%.

3. Patients with suitable veins and arteries for cannulation or repeated puncture.

4. Patients who are able to lie flat for the duration of IA infusions and related procedures during Visit 2 (approximately 3 hours).

5. Body weight of at least 60 kg and body mass index within the range of 18 to 40 kg/m^2.

6. Male and/or female of nonchildbearing potential.

7. Capable of giving signed informed consent.

Exclusion Criteria:

1. 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.

2. Clinically significant valvular heart disease as judged by the investigator.

3. Congenital heart disease (patients with Patent Foramen Ovale may be included in the study).

4. Clinical diagnosis of heart failure NYHA Class IV.

5. 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.

6. History of prior dissections.

7. History or suspicion of cardiac amyloidosis.

8. Patients with conditions where vasodilator therapy may be contraindicated.

9. History of cancer in the last 5 years, except for non-melanoma skin cancer.

10. Any clinically important abnormalities in clinical chemistry, haematology or urinalysis.

11. Any positive result at Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus.

12. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator.

13. 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.

14. 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.

15. History of hypersensitivity to drugs with a similar chemical structure or class to AZD3427.

16. Participants who have previously received AZD3427.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• AZD3427
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of patients with adverse events	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.	From Screening (Day -42 to Day -1) until the Follow-up visit (Day 1, Day 2, Day 8, Day 29, and Day 50)
Primary	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.	Day 1
Secondary	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.	Day 1, Day 8, Day 29 and Day 50
Secondary	Change from baseline in forearm blood flow ratio in the infused arm (AZD3427 infusion:baseline) after each AZD3427 IA infusion	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.	Day 1
Secondary	Change from baseline in forearm blood flow ratio between arms (infused arm:non-infused arm) after each AZD3427 IA infusion	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.	Day 1