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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

24 Aug 2023 → 26 Aug 2025

Decision date (initial)

2023-07-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2022-502382-25-00

ClinicalTrials.gov

NCT05737940

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Dose response

To evaluate the effect of AZD3427 on PVR after 24 weeks of treatment in participants with HF and PH Group 2

Secondary objectives 5

1. To evaluate the effect of AZD3427 on additional hemodynamic markers of cardiac function after 24 weeks of treatment in participants with HF and PH Group 2
2. To evaluate the effect of AZD3427 on function and symptoms after 24 weeks of treatment in participants with HF and PH Group 2
3. To evaluate the effect of AZD3427 on biomarkers of cardiac and renal function after 12 and 24 weeks of treatment in participants with HF and PH Group 2
4. To evaluate the PK of AZD3427 after repeat Q2W SC dosing in participants with HF and PH Group 2
5. To evaluate the immunogenicity of AZD3427

Conditions and MedDRA coding

Heart Failure and Pulmonary Hypertension due to Left Heart Disease (WHO Group 2)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Participant must be ≥ 18 years of age inclusive (or meet the minimum age of maturity according to local regulations in their country), at the time of signing the informed consent.
2. Participants must have a pre-existing diagnosis of HF, NYHA FC II to IV, and a pre-existing diagnosis of PH-LHD or likely or intermediate probability of PH-LHD as per 2022 ESC/ERS guidelines. Participants must be on stable HF standard of care medication, including diuretics, for at least 4 weeks prior to Screening Visit 1.
3. For progression to Screening Visit 2, participants must have a combination of echocardiographic parameters at Screening Visit 1 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: (a) PAWP ≥ 15 mmHg (b) mPAP ≥ 20 mmHg
5. Minimum body weight of 45 kg (inclusive).
6. For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at Screening Visit 1 by one of the following: (a) Postmenopausal, defined as amenorrhea for ≥ 12 months following cessation of all exogenous hormonal treatments, and with LH and FSH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilization.
7. Non-sterilized male study participants should be advised to use a condom for all sexual intercourse with a female partner of childbearing potential from first dose until 3 months after last dose. All male participants should refrain from fathering a child or donating sperm for 3 months after last dose.
8. Capable and willing of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
9. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.

Exclusion criteria 26

1. Diagnosis of PH in 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 including, but not limited to: (a) Myocardial infarction, stroke, transient ischaemic attack, coronary artery bypass grafting, percutaneous coronary intervention, implantable cardioverter defibrillator implantation (implanted standard pacemaker or CRT-P are not exclusionary), within 12 weeks prior to Screening Visit 1. (b) Sarcoidosis, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, complex congenital heart disease. Greater than moderate mitral or aortic valve regurgitation or greater than mild aortic or mitral stenosis. Severe tricuspid regurgitation due to primary valvular disease, eg, from endocarditis or mechanical destruction. (c) Any history of pulmonary embolism or deep vein thrombosis in the last 12 months. (d) Known coagulation disorders.
3. Decompensated HF or hospitalisation due to decompensated HF within 4 weeks prior to Screening Visit 1.
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. History of active malignancy within 2 years, with the exception of fully excised or treated basal cell carcinoma, or ≤ 2 squamous cell carcinomas of the skin. Participants who are under investigation for breast or cervical cancer, including participants with a pap smear of ≥ 3; all investigations must be resolved as negative for breast and cervical cancer at least 12 weeks before Screening Visit 1.
8. Current diagnosis of active hepatitis.
9. Known lung disease with FEV1 < 30% of predicted.
10. Known history of drug abuse within 24 months of Screening Visit 1.
11. Congenital long QT syndrome.
12. Cardiac ventricular arrhythmia which requires treatment. Participants with atrial fibrillation or flutter and controlled ventricular rate are permitted.
13. History of or anticipated heart transplant or ventricular assist device implantation.
14. Any known planned (scheduled) highly invasive CV procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc).
15. As judged by the investigator, any evidence of clinically important disease or disorder which in the investigator’s opinion makes it undesirable for the participant to participate in the study.
16. Plasma donation within 1 month prior to Screening Visit 1 or any blood donation/blood loss > 500 mL during the 3 months prior to Screening Visit 1.
17. Inhibitors of cGMP-specific phosphodiesterase type 5 (PDE5-I if taken for erectile dysfunction or other occasional, non-continuous uses) such as, but not limited to, Sildenafil and Tadalafil are prohibited for 48 hours before echocardiography and RHC (Screening Visits 1 and 2 and Visit 15).
18. Participants who have previously received AZD3427.
19. Participation in another clinical study with a study intervention administered in the last 6 months or 5 half-lives prior to Screening Visit 1 (whichever is longer), or planned participation in such study prior to end of the Follow-up Period. Note: Participants consented and screened, but not entered in this study or a previous study, are not excluded.
20. Known history of ADAs to relaxin or relaxin analogues.
21. Any laboratory values with the following deviations: (a) Estimated GFR < 30 mL/min/1.73 m2 at Screening Visit 1 assessed by the CKD-EPI equation. (b) Haemoglobin < 10 g/dL at Screening Visit 1. (c) Persistent electrolytes abnormalities not corrected before Screening Visit 1.
22. Abnormal vital signs defined as any of the following at Screening Visit 1: (a) Sitting SBP > 160 mmHg or sitting DBP > 110 mmHg after a period of rest. (b) Sitting SBP < 100 mmHg or sitting DBP < 50 mmHg. (c) Resting HR of < 50 bpm or > 115 bpm
23. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study centre)
24. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
25. Previous enrolment or randomisation in the present study.
26. For females only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in PVR from baseline to Week 25 compared with placebo, as measured by RHC

Secondary endpoints 5

1. Change from baseline to Week 25 in RHC parameters compared with placebo. Parameters include: • mPAP and PAWP. Change from baseline to Week 25 in echocardiographic parameters compared with placebo. Parameters include: • Cardiac output, SV, EF, LVGLS, PASP, RV/LV ratio, RVOT AT, TRV, TAPSE/PASP. • Systemic vascular resistance
2. Change in 6MWD and KCCQ TSS from baseline to Week 25 compared with placebo. Change in NYHA FC from baseline to Week 25 compared with placebo.
3. Change in serum creatinine, NT-proBNP, cystatin C, and eGFR from baseline to Week 13 and Week 25 compared with placebo.
4. AZD3427 serum PK concentrations.
5. Presence of ADAs and evaluation of ADA titres.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Third parties 9

Locations

9 EU/EEA countries · 34 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 92 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications