Pulmonary Hypertension (World Health Organization Group 2), Heart Failure
Conditions
Keywords
Pulmonary Hypertension, Heart Failure, Left Heart Disease, WHO Group 2, Dose-ranging Study, Pulmonary vascular resistance
Brief summary
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
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.
Interventions
DRUGAZD3427
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.
DRUGPlacebo
The participants will receive SC injection of placebo single dose every 2 weeks for 24 weeks.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Pulmonary Vascular Resistance (PVR) | Baseline to Week 25 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Mean pulmonary arterial pressure (mPAP) | Baseline to Week 25 | 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. |
| Change from baseline in Pulmonary artery wedge pressure (PAWP) | Baseline to Week 25 | 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. |
| Change from baseline in cardiac output | Baseline to Week 25 | 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. |
| Change from baseline in Stroke Volume (SV) | Baseline to Week 25 | 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. |
| Change from baseline in Ejection fraction (EF) | Baseline to Week 25 | 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. |
| Change from baseline in left ventricular global longitudinal strain (LVGLS) | Baseline to Week 25 | 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. |
| Change from baseline in pulmonary arterial systolic pressure (PASP) | Baseline to Week 25 | 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. |
| Change from baseline in right ventricle/left ventricle (RV/LV) ratio | Baseline to Week 25 | 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. |
| Change from baseline in right ventricular outflow tract acceleration time (RVOT AT) | Baseline to Week 25 | 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. |
| Change from baseline in Tricuspid regurgitation velocity (TRV) | Baseline to Week 25 | 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. |
| Change from baseline in TAPSE/PASP [Tricuspid annular plane systolic excursion/ Pulmonary arterial systolic pressure] | Baseline to Week 25 | 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. |
| Change from baseline in 6-minute walking distance (6MWD) | Baseline to Week 25 | 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. |
| Change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ TSS) | Baseline to Week 25 | 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. |
| Change from baseline in New York Heart Association Functional Class (NYHA FC) | Baseline to Week 25 | 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. |
| Change from baseline in serum creatinine | Baseline to Week 13 and Week 25 | 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. |
| Change from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) | Baseline to Week 13 and Week 25 | 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. |
| Change from baseline in cystatin C | Baseline to Week 13 and Week 25 | 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. |
| Change from baseline in eGFR (estimated glomerular filtration rate) | Baseline to Week 13 and Week 25 | 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. |
| Pharmacokinetics (AZD3427 serum exposure) | On Day 15, Day 29, Day 85, Day 127, Day 169, and Day 211 | Serum concentration of AZD3427 summarised by timepoints and dose level. |
| Number of participants with presence of Anti-drug antibodies (ADAs) | On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 | To evaluate the immunogenicity of AZD3427 using ADA parameter. |
| Evaluation of positive ADA titer | On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 | To evaluate the immunogenicity of AZD3427 as measured by ADAs. |
| Change from baseline in systemic vascular resistance | Baseline to Week 25 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events and serious adverse events | From Randomization (Day 1) up to Follow-up Visit (Day 211) | To evaluate the safety and tolerability of AZD3427 as compared to placebo in participants with HF and PH Group 2 |
Countries
Austria, Canada, China, Czechia, Denmark, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Outcome results
None listed