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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05737940
Recruitment Status : Recruiting
First Posted : February 21, 2023
Last Update Posted : April 1, 2024
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE January 20, 2023
First Posted Date  ICMJE February 21, 2023
Last Update Posted Date April 1, 2024
Actual Study Start Date  ICMJE January 15, 2023
Estimated Primary Completion Date April 23, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2023)		 Change from baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2024)
  • Change from baseline in Mean pulmonary arterial pressure (mPAP) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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] [ Time Frame: 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 systemic vascular resistance [ Time Frame: 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.
  • Change from baseline in 6-minute walking distance (6MWD) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 antibody (ADAs) [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 using ADA parameter.
  • Number of participants with presence of Neutralising antibodies (NAbs) [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 using NAbs parameter.
  • Evaluation of positive ADA titer [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 as measured by ADAs.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2023)
  • Change from baseline in Mean pulmonary arterial pressure (mPAP) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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] [ Time Frame: 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 right ventricular strain/pulmonary arterial systolic pressure (RVS/PASP) [ Time Frame: Baseline to Week 25 ]
    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.
  • Change from baseline in inferior vena cava (IVC) diameter with inspiratory collapse [ Time Frame: Baseline to Week 25 ]
    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.
  • Change from baseline in systemic vascular resistance [ Time Frame: 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.
  • Change from baseline in 6-minute walking distance (6MWD) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 antibody (ADAs) [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 using ADA parameter.
  • Number of participants with presence of Neutralising antibodies (NAbs) [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 using NAbs parameter.
  • Evaluation of positive ADA titer [ Time Frame: On Day 1, Day 15, Day 29, Day 85, Day 169, and Day 211 ]
    To evaluate the immunogenicity of AZD3427 as measured by ADAs.
Current Other Pre-specified Outcome Measures
 (submitted: February 17, 2023)		 Number of participants with adverse events and serious adverse events [ Time Frame: 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Study of AZD3427 in Participants With Heart Failure and Pulmonary Hypertension Group 2
Official Title  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Pulmonary Hypertension (World Health Organization Group 2)
  • Heart Failure
Intervention  ICMJE
  • 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.
  • Drug: Placebo
    The participants will receive SC injection of placebo single dose every 2 weeks for 24 weeks.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: AZD3427
  • 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.
    Intervention: Drug: AZD3427
  • 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.
    Intervention: Drug: AZD3427
  • Placebo Comparator: Placebo
    The participants will receive single dose placebo every 2 weeks for 24 weeks from Day 1 to Day 155.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 17, 2023)		 220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2, 2025
Estimated Primary Completion Date April 23, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Austria,   Canada,   China,   Czechia,   Denmark,   Germany,   Italy,   Japan,   Netherlands,   Poland,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05737940
Other Study ID Numbers  ICMJE D8330C00003
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
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.
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.
URL: https://vivli.org/
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Parexel
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date March 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP