A Phase IIb Randomised, Double-blind, Placebo-controlled, Multi-centre, Dose-ranging Study of AZD3427 in Participants with Heart Failure and Pulmonary Hypertension due to Left Heart Disease (WHO Group 2)

Trial ID: 2022-502382-25-00
Protocol: D8330C00003
Sponsor: AstraZeneca AB

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Diseases & Conditions

Cardiac failure Pulmonary arterial hypertension

Objectives

The primary objective of this study is to evaluate the effect of **AZD3427** on pulmonary vascular resistance (PVR) after 24 weeks of treatment in participants with heart failure (HF) and pulmonary hypertension (PH) due to left heart disease (WHO Group 2). This is clinically relevant as PVR is a critical determinant of right ventricular afterload and can significantly impact the prognosis and management of patients with this condition.

Secondary objectives include:

Evaluating the effect of AZD3427 on additional hemodynamic markers of cardiac function after 24 weeks of treatment.
Assessing the effect of AZD3427 on function and symptoms after 24 weeks of treatment.
Investigating the effect of AZD3427 on biomarkers of cardiac and renal function after 12 and 24 weeks of treatment.
Evaluating the pharmacokinetics (PK) of AZD3427 after repeat bi-weekly subcutaneous dosing.
Assessing the immunogenicity of AZD3427.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of AZD3427 in this patient population.

Participants

The clinical trial involves a total of **58 participants** diagnosed with **Heart Failure and Pulmonary Hypertension due to Left Heart Disease (WHO Group 2)**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific criteria, including a pre-existing diagnosis of heart failure, classified as New York Heart Association Functional Class II to IV, and pulmonary hypertension due to left heart disease, as per the 2022 ESC/ERS guidelines. All participants are required to be on stable heart failure standard of care medication, including diuretics, for at least four weeks prior to the initial screening. Lifestyle considerations such as diet and physical activity are not specified, but participants must meet a minimum body weight of 45 kg. Female participants must be of non-childbearing potential, confirmed through postmenopausal status or irreversible surgical sterilization. Male participants are required to use contraception and refrain from fathering a child or donating sperm for a specified period post-treatment. The trial does not include any vulnerable populations, ensuring a focus on the general adult demographic affected by the specified medical conditions.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy, safety, and pharmacokinetics of AZD3427 in participants with **heart failure** and **pulmonary hypertension** due to left heart disease (WHO Group 2). The trial is structured as a Phase IIb, multi-center, dose-ranging study. The primary objective is to assess the effect of AZD3427 on pulmonary vascular resistance (PVR) after 24 weeks of treatment. The trial is expected to conclude by June 2025, with recruitment having commenced in July 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, pre-existing diagnoses, and stable medication regimens. The screening process involves two visits, where echocardiographic parameters and right heart catheterization (RHC) measurements are evaluated. Following successful screening, participants will be randomized to receive either AZD3427 or a placebo, administered via **subcutaneous injection**. The maximum daily dose is 30 mg, with a treatment period of up to 24 weeks.

Throughout the trial, participants will attend regular follow-up visits to monitor changes in PVR, echocardiographic parameters, and other secondary endpoints such as cardiac output, systemic vascular resistance, and serum biomarkers. The study will also assess AZD3427 serum pharmacokinetics and the presence of anti-drug antibodies (ADAs). The end-of-study visit will occur at Week 25, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last approximately 25 weeks, including the screening period. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial is conducted in accordance with ethical guidelines, ensuring informed consent and participant safety throughout the study duration.

Treatment

The clinical trial involves the administration of **AZD3427**, an investigational medication formulated as a **solution for injection**. The active substance, AZD3427, is a protein of other origin, developed by AstraZeneca AB. The medication is administered via **subcutaneous use**. The maximum daily dose is 30 mg, with a total treatment period of 24 weeks. The dosing schedule is designed to evaluate the effect of AZD3427 on pulmonary vascular resistance (PVR) in participants with heart failure and pulmonary hypertension due to left heart disease (WHO Group 2). Participant compliance with the dosing regimen will be monitored throughout the study.

The study also includes a **placebo** control, referred to as "Placebo for AZD3427 or AZD3427 Diluent." The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same pharmaceutical form and route as AZD3427, ensuring consistency in administration procedures. The use of a placebo allows for a robust comparison of the efficacy and safety of AZD3427 against a non-active control.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the effect of AZD3427 on **pulmonary vascular resistance (PVR)** after 24 weeks of treatment in participants with heart failure (HF) and pulmonary hypertension (PH) due to left heart disease (WHO Group 2). The primary endpoint is the change in PVR from baseline to Week 25 compared with placebo, as measured by right heart catheterization (RHC). Secondary endpoints include changes from baseline to Week 25 in RHC parameters such as mean pulmonary artery pressure (mPAP) and pulmonary artery wedge pressure (PAWP), as well as echocardiographic parameters including cardiac output, stroke volume (SV), ejection fraction (EF), left ventricular global longitudinal strain (LVGLS), pulmonary artery systolic pressure (PASP), right ventricular/left ventricular (RV/LV) ratio, right ventricular outflow tract acceleration time (RVOT AT), tricuspid regurgitation velocity (TRV), and tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP). Additionally, systemic vascular resistance, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS), and New York Heart Association Functional Class (NYHA FC) will be assessed. Changes in serum creatinine, NT-proBNP, cystatin C, and estimated glomerular filtration rate (eGFR) from baseline to Week 13 and Week 25 will also be evaluated. AZD3427 serum pharmacokinetic (PK) concentrations and the presence of anti-drug antibodies (ADAs) along with ADA titres will be monitored. These efficacy parameters will be collected and analyzed at specified timepoints to determine the therapeutic impact of AZD3427 compared to placebo.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be ≥ 18 years of age inclusive (or meet the minimum age of maturity according to local regulations in their country), at the time of signing the informed consent.
Participants must have a pre-existing diagnosis of HF, NYHA FC II to IV, and a pre-existing diagnosis of PH-LHD or likely or intermediate probability of PH-LHD as per 2022 ESC/ERS guidelines. Participants must be on stable HF standard of care medication, including diuretics, for at least 4 weeks prior to Screening Visit 1.
For progression to Screening Visit 2, participants must have a combination of echocardiographic parameters at Screening Visit 1 that show intermediate or high probability of PH as per 2022 ESC/ERS guidelines.
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: (a) PAWP ≥ 15 mmHg (b) mPAP ≥ 20 mmHg
Minimum body weight of 45 kg (inclusive).
For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at Screening Visit 1 by one of the following: (a) Postmenopausal, defined as amenorrhea for ≥ 12 months following cessation of all exogenous hormonal treatments, and with LH and FSH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization.
Non-sterilized male study participants should be advised to use a condom for all sexual intercourse with a female partner of childbearing potential from first dose until 3 months after last dose. All male participants should refrain from fathering a child or donating sperm for 3 months after last dose.
Capable and willing of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.

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Exclusion Criteria

Diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5.
Historical or current evidence of a clinically significant disease or disorder including, but not limited to: (a) Myocardial infarction, stroke, transient ischaemic attack, coronary artery bypass grafting, percutaneous coronary intervention, implantable cardioverter defibrillator implantation (implanted standard pacemaker or CRT-P are not exclusionary), within 12 weeks prior to Screening Visit 1. (b) Sarcoidosis, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, complex congenital heart disease. Greater than moderate mitral or aortic valve regurgitation or greater than mild aortic or mitral stenosis. Severe tricuspid regurgitation due to primary valvular disease, eg, from endocarditis or mechanical destruction. (c) Any history of pulmonary embolism or deep vein thrombosis in the last 12 months. (d) Known coagulation disorders.
Decompensated HF or hospitalisation due to decompensated HF within 4 weeks prior to Screening Visit 1.
Any contraindications to RHC.
History of hypersensitivity to SC injections or devices.
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.
History of active malignancy within 2 years, with the exception of fully excised or treated basal cell carcinoma, or ≤ 2 squamous cell carcinomas of the skin. Participants who are under investigation for breast or cervical cancer, including participants with a pap smear of ≥ 3; all investigations must be resolved as negative for breast and cervical cancer at least 12 weeks before Screening Visit 1.
Current diagnosis of active hepatitis.
Known lung disease with FEV1 < 30% of predicted.
Known history of drug abuse within 24 months of Screening Visit 1.
Congenital long QT syndrome.
Cardiac ventricular arrhythmia which requires treatment. Participants with atrial fibrillation or flutter and controlled ventricular rate are permitted.
History of or anticipated heart transplant or ventricular assist device implantation.
Any known planned (scheduled) highly invasive CV procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc).
As judged by the investigator, any evidence of clinically important disease or disorder which in the investigator’s opinion makes it undesirable for the participant to participate in the study.
Plasma donation within 1 month prior to Screening Visit 1 or any blood donation/blood loss > 500 mL during the 3 months prior to Screening Visit 1.
Inhibitors of cGMP-specific phosphodiesterase type 5 (PDE5-I if taken for erectile dysfunction or other occasional, non-continuous uses) such as, but not limited to, Sildenafil and Tadalafil are prohibited for 48 hours before echocardiography and RHC (Screening Visits 1 and 2 and Visit 15).
Participants who have previously received AZD3427.
Participation in another clinical study with a study intervention administered in the last 6 months or 5 half-lives prior to Screening Visit 1 (whichever is longer), or planned participation in such study prior to end of the Follow-up Period. Note: Participants consented and screened, but not entered in this study or a previous study, are not excluded.
Known history of ADAs to relaxin or relaxin analogues.
Any laboratory values with the following deviations: (a) Estimated GFR < 30 mL/min/1.73 m2 at Screening Visit 1 assessed by the CKD-EPI equation. (b) Haemoglobin < 10 g/dL at Screening Visit 1. (c) Persistent electrolytes abnormalities not corrected before Screening Visit 1.
Abnormal vital signs defined as any of the following at Screening Visit 1: (a) Sitting SBP > 160 mmHg or sitting DBP > 110 mmHg after a period of rest. (b) Sitting SBP < 100 mmHg or sitting DBP < 50 mmHg. (c) Resting HR of < 50 bpm or > 115 bpm
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre)
Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Previous enrolment or randomisation in the present study.
For females only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	21 Jul 2023	13
Czechia	Not Recruiting	21 Jul 2023	13
Denmark	Not Recruiting	21 Jul 2023	9
Germany	Not Recruiting	21 Jul 2023	14
Italy	Not Recruiting	21 Jul 2023	8
The Netherlands	Not Recruiting	21 Jul 2023	—
Poland	Not Recruiting	21 Jul 2023	78
Spain	Not Recruiting	21 Jul 2023	18
Sweden	Not Recruiting	21 Jul 2023	14
Netherlands	—	—	9