A Phase 1b, Double-blind, Placebo-controlled, Randomised Trial Investigating the Effect of AZD3427 on Renal Perfusion in HFrEF Patients With Renal Impairment Using Positron Emission Tomography (PET)

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

15 Oct 2024 → 21 Aug 2025

Decision date (initial)

2024-08-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Others

To evaluate the effect of AZD3427 on the volume of perfused renal cortex in participants with HFrEF and reduced eGFR.

Secondary objectives 1

1. To assess the safety and tolerability of a single dose of AZD3427 compared to placebo in participants with HFrEF and reduced eGFR.

Conditions and MedDRA coding

Heart failure with reduced ejection fraction

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-003476-PIP01-23

Plan to share IPD

Yes

IPD plan description

Qualified researcher´s can request access to anonymizied individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https;//astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclusure. Yes, indicates that AZ are accepting requests for IPD, but this does not means all requests will be shared.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participant must be > 20 years-old at the time of signing the informed consent.
2. Participant must have suitable veins for cannulation.
3. Participants must have a known clinical diagnosis of HF NYHA I to III for at least 12 months.
4. Participants must be on stable HF standard of care medication for at least 4 weeks prior to screening, with no significant dose change or new medications added during that period. If the participant is currently taking diuretics, then diuretics must also be stable for at least 4 weeks prior to screening. It is also expected that there will be no change in treatment between screening (Visit 1) and Visit 3 in terms of drugs known to affect renal haemodynamics, including but not limited to: ACE-Is, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, cyclooxygenase inhibitors, endothelin receptors antagonists, phosphodiesterase inhibitors, SGLT2is, and diuretics.
5. Participants must have a left ventricular ejection fraction of ≤ 40% based on echocardiography conducted within the last 6 months.
6. Participants must have an eGFR of 30 to 90 mL/min/1.73 m2 (inclusive) assessed by the CKD-EPI, 2021 (creatinine only) equation without including race (Inker et al 2021) at screening.
7. Participants must have a minimum BMI of 18.0 kg/m2 and a minimum body weight of 50 kg at screening.
8. For female participants, the participant must not be pregnant or lactating and must be of non-childbearing potential, confirmed at screening by one of the following: (a) Postmenopausal, defined as amenorrhoea for ≥ 12 months following cessation of all exogenous hormonal treatments, and with FSH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as irreversible surgical sterilisation.
9. All male participants should refrain from fathering a child or donating sperm until 3 months after dosing. Non-sterilised male study participants should avoid fathering a child either by true abstinence or use of a condom for all sexual intercourse with a female partner of childbearing potential from dosing until 3 months after dosing. Note that true abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. It is only acceptable if preferred and the usual lifestyle of the participant. The female partner has to be either of non-childbearing potential or has to use a highly effective contraception form of birth control until 3 months after dosing. The female partner should be stable on their chosen method of birth control for at least 3 months prior to dosing. Highly effective contraception form of birth control, ie, a form of birth control with a failure rate of less than 1% per year when used consistently and correctly, are: (a) Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o Oral o Intravaginal o Transdermal (b) Progestogen-only hormonal contraception associated with inhibition of ovulation: o Oral o Injectable o Implantable (c) Intrauterine device (d) Intrauterine hormone releasing system (e) Bilateral tubal occlusion of female partner
10. Male participants who have been sterilised are required to use one barrier method of contraception (condom) from the time of study intervention administration until 3 months after the dosing. The participant must have received medical assessment of the surgical success.
11. Capable of and willing to give signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria 29

1. History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant’s ability to participate in the study.
2. Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of screening or planned surgical or other procedure before study completion.
3. Clinically significant, as judged by the investigator, ventricular arrhythmias requiring pharmacological treatment.
4. 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, within 12 weeks prior to screening. (b) Primary cardiomyopathy other than dilated, including but not limited to sarcoidosis, amyloidosis, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, complex congenital heart disease.
5. Decompensated HF or hospitalisation due to any cause < 4 weeks prior to screening.
6. Severe heart valve disease.
7. Diagnosis of polycystic kidney disease or anatomical causes of chronic kidney disease.
8. One kidney, renal artery stenosis, or glomerulonephritis.
9. Anticipated dialysis or renal transplantation within 1 year.
10. Condition where vasodilatory therapy maybe contraindicated for example but not limited to severe aortic stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy.
11. 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.
12. 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.
13. Any clinically important abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.
14. Known or suspected history of drug abuse as judged by the Investigator.
15. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator, within the 6 months prior to screening.
16. History of hypersensitivity to injection devices or to drugs with a similar chemical structure or class to AZD3427 or any component of the AZD3427 preparation, or to dopamine or any component of the dopamine preparation, or ongoing clinically important allergy/hypersensitivity.
17. Participants who cannot communicate reliably with the Investigator.
18. Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
19. Known history of ADAs to relaxin or relaxin analogues.
20. Active infections that significantly affect the patient’s health status or in the opinion of the Investigator, may put the participant at risk (eg, HIV, Hepatitis, tuberculosis, etc.).
21. Plasma donation within 1 month prior to screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.
22. If on treatment with other drugs with potential to significantly influence on eGFR (eg, SGLT2i, ACE-I), the participant must have been on a stable dose for at least 4 weeks prior to screening. PDE-5 inhibitors such as sildenafil (eg, taken for erectile dysfunction or other as-needed reasons) and NSAIDs such as diclofenac and ibuprofen should not be taken for 2 days before the PET Sessions 2 and 3 (Visit 2 and Visit 3); paracetamol is allowed.
23. Currently participating in or previous participation in another clinical study within 30 days prior to the Screening Visit or previous participation in another PET imaging trial within the last 12 months, 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.
24. Haemoglobin < 100 g/L at Screening.
25. Abnormal vital signs defined as any of the following at screening: (a) Sitting SBP > 160 mmHg or sitting DBP > 110 mmHg after a period of at least 5 minutes of rest; (b) Sitting SBP < 100 mmHg or sitting DBP < 50 mmHg; (c) Resting pulse rate of < 50 bpm or > 115 bpm.
26. Involvement of any AstraZeneca, CRO, or study centre employee or their close relatives, including any involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
27. Judgement by the Investigator that the participant should not participate in the study if they have any ongoing or recent (ie, during the Screening Period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
28. Previous enrolment or randomisation in the present study.
29. 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. The volumetric fraction (%) of the renal cortex with increased perfusion from baseline to Day 8, compared to placebo, as measured by quantitative parametric mapping using PET.

Secondary endpoints 1

1. Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, and ECG.

Investigational products

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

Test 1

Placebo 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

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 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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