A Study of AZD3427 in Participants With Heart Failure and Pulmonary Hypertension Group 2 (Re-PHIRE)

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)

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

Study Overview

• Status: Completed
• Conditions: Heart Failure; Pulmonary Hypertension (World Health Organization Group 2)
• Intervention / Treatment: Drug: AZD3427; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Research Site
  • Vienna, Austria, 1100
    • Research Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2E1
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Research Site
    • Ottawa, Ontario, Canada, K1Y 4W7
      • Research Site
    • Toronto, Ontario, Canada, M5G 2N2
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Research Site
• China
  • Beijing, China, 100034
    • Research Site
  • Changsha, China, 430033
    • Research Site
  • Guangzhou, China, 510100
    • Research Site
  • Kunming, China, 650051
    • Research Site
• Czechia
  • Prague, Czechia, 10034
    • Research Site
  • Prague, Czechia, 12808
    • Research Site
  • Prague, Czechia, 140 21
    • Research Site
• Denmark
  • Aarhus, Denmark, 8200
    • Research Site
  • Copenhagen, Denmark, 2100
    • Research Site
• Germany
  • Berlin, Germany, 13353
    • Research Site
  • Cologne, Germany, 50937
    • Research Site
  • Frankfurt, Germany, 60596
    • Research Site
  • Jena, Germany, 07747
    • Research Site
• Italy
  • Brescia, Italy, 25123
    • Research Site
  • Genoa, Italy, 16132
    • Research Site
  • Marche, Italy, 60126
    • Research Site
  • Milan, Italy, 20138
    • Research Site
  • Milan, Italy, 20142
    • Research Site
  • Trieste, Italy, 34149
    • Research Site
• Japan
  • Bunkyō City, Japan, 113-8603
    • Research Site
  • Kasugai-shi, Japan, 487-0016
    • Research Site
  • Kure-shi, Japan, 737-8505
    • Research Site
  • Nagoya, Japan, 466-8560
    • Research Site
  • Sapporo, Japan, 060-8648
    • Research Site
  • Sunto-gun, Japan, 411-8611
    • Research Site
  • Toyama, Japan, 930-0194
    • Research Site
• Netherlands
  • Deventer, Netherlands, 7416 SE
    • Research Site
  • Heerlen, Netherlands, 6419 PC
    • Research Site
  • Tilburg, Netherlands, 5022 GC
    • Research Site
• Poland
  • Bialystok, Poland, 15-276
    • Research Site
  • Gdansk, Poland, 80-952
    • Research Site
  • Krakow, Poland, 31-202
    • Research Site
  • Warsaw, Poland, 04-628
    • Research Site
  • Warsaw, Poland, 02-005
    • Research Site
  • Wroclaw, Poland, 50-556
    • Research Site
• Spain
  • Majadahonda, Spain, 28222
    • Research Site
  • Seville, Spain, 41009
    • Research Site
  • Toledo, Spain, 45007
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Research Site
  • Huddinge, Sweden, 141 57
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0AY
    • Research Site
  • Clydebank, United Kingdom, G81 4DY
    • Research Site
  • London, United Kingdom, SW3 6NP
    • Research Site
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Research Site
    • La Jolla, California, United States, 92093
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Research Site
  • Missouri
    • St Louis, Missouri, United States, 63136
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Research Site
  • South Carolina
    • Rock Hill, South Carolina, United States, 29732
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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 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
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
Number of participants with presence of Anti-drug antibodies (ADAs)	To evaluate the immunogenicity of AZD3427 using ADA parameter.	On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2023
• Primary Completion (Actual): July 15, 2025
• Study Completion (Actual): August 25, 2025

Study Registration Dates

• First Submitted: January 20, 2023
• First Submitted That Met QC Criteria: February 17, 2023
• First Posted (Actual): February 21, 2023

Study Record Updates

• Last Update Posted (Estimated): September 24, 2025
• Last Update Submitted That Met QC Criteria: September 23, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Heart Failure; Pulmonary Hypertension; Left Heart Disease; Pulmonary vascular resistance; WHO Group 2; Dose-ranging Study
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Heart Failure; Hypertension, Pulmonary
• Other Study ID Numbers: D8330C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No