Heart Failure
Conditions
Keywords
Heart Failure with Preserved Ejection Fraction, Heart Failure with Reduced Ejection Fraction, Forearm blood flow
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)
Interventions
DRUGAZD3427
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.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum change from baseline in absolute forearm blood flow in the infused arm during AZD3427 IA infusions | Day 1 | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with anti-drug antibody (ADAs) in serum samples at baseline and at Day 8, Day 29, and Day 50 | Day 1, 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 | Day 1 | 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. |
| Change from baseline in forearm blood flow ratio between arms (infused arm:non-infused arm) after each AZD3427 IA infusion | Day 1 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with adverse events | From Screening (Day -42 to Day -1) until the Follow-up visit (Day 1, Day 2, Day 8, Day 29, and Day 50) | 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. |
Outcome results
None listed