A Study of AZD3427 in Participants With Heart Failure and Pulmonary Hypertension Group 2

AstraZeneca260 enrolled

Overview

This study is intended to assess the ability of AZD3427 to reduce pulmonary vascular resistance (PVR) after 24 weeks of treatment in participants with heart failure (HF) and pulmonary hypertension (PH) Group 2

This study is a randomized, placebo-controlled, multi-centre, dose-ranging study of AZD3427 in participants with heart failure and pulmonary hypertension due to left heart disease (World Health Organisation \[WHO\] Group 2). Approximately 220 participants will be randomised to 4 treatment groups (in a 1:1:1:1 ratio) to receive a subcutaneous (SC) injection of AZD3427 or placebo every 2 weeks for 24 weeks. This study will evaluate 3 dose levels of AZD3427: Dose A, Dose B, and Dose C. Dose modification is not applicable for this study. The study will be conducted in approximately 60 study centres across an estimated 15 countries. The study will include approximately 16 study visits: 2 visits during the Screening Period,13 visits during the Treatment Period, and one visit during the Follow-up Period. The expected total duration of the study is 32 to 37 weeks, depending on the length of the Screening Period.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

260

Conditions

Pulmonary Hypertension (World Health Organization Group 2)Heart Failure

Interventions

AZD3427DRUG

The participants will receive AZD3427 SC injection single dose of either Dose A or Dose B or Dose C every 2 weeks for 24 weeks.

PlaceboDRUG

The participants will receive SC injection of placebo single dose every 2 weeks for 24 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Participant must be ≥ 18 years of age inclusive. 2. Participants must have a pre-existing diagnosis of HF, NYHA function class (FC) II to IV, and a pre-existing diagnosis of PH-LHD or likely or intermediate probability of Pulmonary hypertension due to left heart disease (PH-LHD) as per 2022 Pulmonary hypertension due to left heart disease European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Participants must be on stable HF standard of care medication, including diuretics. 3. Participants must have a combination of echocardiographic parameters that show intermediate or high probability of PH as per 2022 ESC/ERS guidelines. 4. Participants must have an on-study elevated pulmonary artery pressure from RHC performed as per RHC manual provided by the Sponsor, at Screening Visit 2: 1. PAWP ≥ 15 mmHg 2. mPAP ≥ 20 mmHg 5. Minimum body weight of 45 kg (inclusive). 6. Capable and willing of giving signed informed consent. Exclusion Criteria 1. Diagnosis of PH in World Health Organization (WHO) Group 1, WHO Group 3, WHO Group 4, or WHO Group 5. 2. Historical or current evidence of a clinically significant disease or disorder. 3. Decompensated HF or hospitalisation due to decompensated HF. 4. Any contraindications to RHC. 5. History of hypersensitivity to SC injections or devices. 6. History of hypersensitivity to drugs with a similar chemical structure or class to AZD3427 or any component of AZD3427 drug product, or ongoing clinically important allergy/hypersensitivity. 7. Known lung disease with Forced expiratory volume in the first second (FEV1) \< 30% of predicted. 8. Congenital long QT syndrome. 9. Cardiac ventricular arrhythmia which requires treatment. Participants with atrial fibrillation or flutter and controlled ventricular rate are permitted. 10. History of or anticipated heart transplant or ventricular assist device implantation. 11. Any known planned (scheduled) highly invasive Cardiovascular (CV) procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc). 12. Participants who have previously received AZD3427.

Locations (60)

Outcomes

Primary Outcomes

Change from baseline in Pulmonary Vascular Resistance (PVR)

To evaluate the effect of AZD3427 on PVR parameter compared with placebo as measured by right heart catheterization (RHC) after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Secondary Outcomes

Change from baseline in Mean pulmonary arterial pressure (mPAP)

To evaluate the effect of AZD3427 compared with placebo on mPAP parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in Pulmonary artery wedge pressure (PAWP)

To evaluate the effect of AZD3427 compared with placebo on PAWP parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in cardiac output

To evaluate the effect of AZD3427 compared with placebo on cardiac output parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in Stroke Volume (SV)

To evaluate the effect of AZD3427 compared with placebo on SV parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in Ejection fraction (EF)

To evaluate the effect of AZD3427 compared with placebo on EF parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Data from ClinicalTrials.gov

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Research Site

Beverly Hills, California, United States

Research Site

La Jolla, California, United States

Research Site

New Haven, Connecticut, United States

Research Site

Baltimore, Maryland, United States

Research Site

St Louis, Missouri, United States

Research Site

Omaha, Nebraska, United States

Research Site

Rock Hill, South Carolina, United States

Research Site

Linz, Austria

Research Site

Vienna, Austria

Research Site

Edmonton, Alberta, Canada

...and 50 more locations

Change from baseline in left ventricular global longitudinal strain (LVGLS)

To evaluate the effect of AZD3427 compared with placebo on LVGLS parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in pulmonary arterial systolic pressure (PASP)

To evaluate the effect of AZD3427 compared with placebo on PASP parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in right ventricle/left ventricle (RV/LV) ratio

To evaluate the effect of AZD3427 compared with placebo on RV/LV parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in right ventricular outflow tract acceleration time (RVOT AT)

To evaluate the effect of AZD3427 compared with placebo on RVOT AT parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in Tricuspid regurgitation velocity (TRV)

To evaluate the effect of AZD3427 compared with placebo on TRV parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in TAPSE/PASP [Tricuspid annular plane systolic excursion/ Pulmonary arterial systolic pressure]

To evaluate the effect of AZD3427 compared with placebo on TAPSE/PASP parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in systemic vascular resistance

To evaluate the effect of AZD3427 compared with placebo on systemic vascular resistance parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in 6-minute walking distance (6MWD)

To evaluate the effect of AZD3427 compared with placebo on function and symptoms using 6MWD parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ TSS)

To evaluate the effect of AZD3427 compared with placebo on function and symptoms using KCCQ TSS parameter after 24 weeks of treatment in participants with HF and PH Group 2. The score ranges from 0 to 100, where a higher score represents a better patient outcome.

Time frame: Baseline to Week 25

Change from baseline in New York Heart Association Functional Class (NYHA FC)

To evaluate the effect of AZD3427 compared with placebo on function and symptoms using NYHA FC parameter after 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 25

Change from baseline in serum creatinine

To evaluate the effect of AZD3427 compared with placebo using serum creatinine parameter after 12 and 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 13 and Week 25

Change from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)

To evaluate the effect of AZD3427 compared with placebo using NT-proBNP parameter after 12 and 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 13 and Week 25

Change from baseline in cystatin C

To evaluate the effect of AZD3427 compared with placebo using cystatin C parameter after 12 and 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 13 and Week 25

Change from baseline in eGFR (estimated glomerular filtration rate)

To evaluate the effect of AZD3427 compared with placebo using eGFR parameter after 12 and 24 weeks of treatment in participants with HF and PH Group 2.

Time frame: Baseline to Week 13 and Week 25

Pharmacokinetics (AZD3427 serum exposure)

Serum concentration of AZD3427 summarised by timepoints and dose level.

Time frame: On Day 15, Day 29, Day 85, Day 127, Day 169, and Day 211

Number of participants with presence of Anti-drug antibodies (ADAs)

To evaluate the immunogenicity of AZD3427 using ADA parameter.

Time frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211

Evaluation of positive ADA titer

To evaluate the immunogenicity of AZD3427 as measured by ADAs.

Time frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211