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

Heart Failure Clinical Trial

— Re-PHIRE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05737940
• Other study ID #: D8330C00003
• Status: Recruiting
• Phase: Phase 2
• Start date: April 24, 2023
• Est. completion date: June 2, 2025

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: June 2, 2025
• Est. primary completion date: April 23, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• AZD3427
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.
• Placebo
The participants will receive SC injection of placebo single dose every 2 weeks for 24 weeks.

Locations

Country	Name	City	State
Austria	Research Site	Eisenstadt
Austria	Research Site	Linz
Austria	Research Site	Wien
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Changsha
China	Research Site	Guangzhou
China	Research Site	Kunming
Czechia	Research Site	Praha 10
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 4
Denmark	Research Site	Aarhus
Denmark	Research Site	Copenhagen
Germany	Research Site	Berlin
Germany	Research Site	Cologne
Germany	Research Site	Frankfurt
Germany	Research Site	Jena
Italy	Research Site	Brescia
Italy	Research Site	Genoa
Italy	Research Site	Marche
Italy	Research Site	Milan
Italy	Research Site	Milano
Italy	Research Site	Trieste
Japan	Research Site	Kasugai-shi
Japan	Research Site	Kure-shi
Japan	Research Site	Matsumoto-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Okayama
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sunto-gun
Japan	Research Site	Toyama-shi
Netherlands	Research Site	Deventer
Netherlands	Research Site	Heerlen
Netherlands	Research Site	Tilburg
Poland	Research Site	Bialystok
Poland	Research Site	Gdansk
Poland	Research Site	Krakow
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Spain	Research Site	Majadahonda
Spain	Research Site	Sevilla
Spain	Research Site	Toledo
Spain	Research Site	Valencia
Sweden	Research Site	Göteborg
Sweden	Research Site	Huddinge
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Clydebank
United Kingdom	Research Site	London
United States	Research Site	Baltimore	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	La Jolla	California
United States	Research Site	Los Angeles	California
United States	Research Site	New Haven	Connecticut
United States	Research Site	Omaha	Nebraska
United States	Research Site	Rock Hill	South Carolina
United States	Research Site	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Countries where clinical trial is conducted

United States,  Austria,  Canada,  China,  Czechia,  Denmark,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of participants with adverse events and serious adverse events	To evaluate the safety and tolerability of AZD3427 as compared to placebo in participants with HF and PH Group 2	From Randomization (Day 1) up to Follow-up Visit (Day 211)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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