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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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)

Conditions
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Pulmonary Hypertension (World Health Organization Group 2), Heart Failure

Intervention / Treatment
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* Drug: AZD3427
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participant must be ≥ 18 years of age inclusive. 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/ESR) guidelines. Participants must be on stable HF standard of care medication, including diuretics. Participants must have a combination of echocardiographic parameters 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: PAWP ≥ 15 mmHg mPAP ≥ 20 mmHg Minimum body weight of 50 kg (inclusive). Capable of giving signed informed consent. Exclusion Criteria Diagnosis of PH in World Health Organization (WHO) Group 1, WHO Group 3, WHO Group 4, or WHO Group 5. Historical or current evidence of a clinically significant disease or disorder. Decompensated HF or any hospitalisation. 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. Known lung disease with Forced expiratory volume in the first second/Vital capacity (FEV1/VC) < 30%. 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 Cardiovascular (CV) procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc). Participants who have previously received AZD3427.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD3427 Dose A<br>The participants will receive single dose of AZD3427 Dose A every 2 weeks for 24 weeks from Day 1 to Day 155. | Drug: AZD3427<br>* 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.<br>|
| Experimental: AZD3427 Dose B<br>The participants will receive single dose of AZD3427 Dose B every 2 weeks for 24 weeks from Day 1 to Day 155. | Drug: AZD3427<br>* 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.<br>|
| Experimental: AZD3427 Dose C<br>The participants will receive single dose of AZD3427 Dose C every 2 weeks for 24 weeks from Day 1 to Day 155. | Drug: AZD3427<br>* 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.<br>|
| Placebo Comparator: Placebo<br>The participants will receive single dose placebo every 2 weeks for 24 weeks from Day 1 to Day 155. | Drug: Placebo<br>* The participants will receive SC injection of placebo single dose every 2 weeks for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | Baseline to Week 25 | 
| 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. | 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. | 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. | 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. | 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. | 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. | Baseline to Week 25 | 
| Change from baseline in right ventricular strain/pulmonary arterial systolic pressure (RVS/PASP) | To evaluate the effect of AZD3427 compared with placebo on RVS/PASP parameter after 24 weeks of treatment in participants with HF and PH Group 2. | Baseline to Week 25 | 
| Change from baseline in inferior vena cava (IVC) diameter with inspiratory collapse | To evaluate the effect of AZD3427 compared with placebo on IVC parameter after 24 weeks of treatment in participants with HF and PH Group 2. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Baseline to Week 13 and Week 25 | 
| Pharmacokinetics (AZD3427 serum exposure) | Serum concentration of AZD3427 summarised by timepoints and dose level. | On Day 15, Day 29, Day 85, Day 127, Day 169, and Day 211 | 
| Number of participants with presence of Anti-drug antibody (ADAs) | To evaluate the immunogenicity of AZD3427 using ADA parameter. | On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 | 
| Number of participants with presence of Neutralising antibodies (NAbs) | To evaluate the immunogenicity of AZD3427 using NAbs parameter. | 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. | On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension, Heart Failure, Left Heart Disease, WHO Group 2, Dose-ranging Study, Pulmonary vascular resistance