Assessment of Safety, Tolerability, Immunogenicity, and Pharmacokinetics of AZD3427

NCT ID: NCT04630067

Last Updated: 2022-10-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 105 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-17
• Study Completion Date: 2022-09-14

Brief Summary

This first-time-in-human (FTIH) study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single doses of AZD3427 in healthy volunteers and multiple doses of AZD3427 in patients with heart failure (HF).

Detailed Description

This is a multi-center single and multiple ascending dose study (SAD and MAD).

Part A (SAD) will include 7 cohorts (8 healthy volunteers in each cohort) and will randomize to AZD3427 or placebo, in a 6:2 ratio. One cohort will entirely include participants of Japanese descent.

Part B (MAD) will include 6 cohorts (8 heart failure patients in each cohort) and will randomize to AZD3427 or placebo in a 6:2 ratio. Of these, 3 cohorts will contain participants with heart failure with reduced ejection fraction [HFrEF] and the other 3 cohorts will comprise of participants with heart failure with HF with ejection fraction (EF) ≥ 41%. There will be a maximum screening period of 27 days. Participants in part A and B will undergo study drug administration on Day 1. In addition, participants in part B will return for 4 additional doses on Days 8, 15, 22, and 29. Participants will be followed for at least 50 days after the last dose of study drug.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

AZD3427: Cohort 1a

Participants will receive single SC dose A of AZD3427 on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 2a

Participants will receive single SC dose B of AZD3427 on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 3a

Participants will receive single SC dose C of AZD3427 on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 4a

Participants will receive single SC dose D of AZD3427 on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 5a

Participants will receive single IV dose E of AZD3427 on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 6a

Participants of Japanese descent will receive single SC dose anticipated equal to the highest dose of AZD3427 in the global cohorts on Day 1.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 7a

Participants will receive single SC dose F of AZD3427 on Day 1

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

Part A: Placebo

Participants will receive single SC or IV dose of placebo matched to AZD3427 on Day 1.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants will receive SC or IV dose of placebo matched to AZD3427 as per the arm they are randomized.

AZD3427: Cohort 1b

Participants with HFrEF will receive SC dose A of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 2b

Participants with HF with EF ≥ 41% will receive SC dose A of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 3b

Participants with HFrEF will receive SC dose B of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 4b

Participants with HF with EF ≥ 41% will receive SC dose B of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 5b

Participants with HFrEF will receive SC dose C of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

AZD3427: Cohort 6b

Participants with HF with EF ≥ 41% will receive SC dose C of AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: EXPERIMENTAL

AZD3427

Intervention Type: DRUG

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

Part B: Placebo

Participants with HFrEF or HF with EF ≥ 41% will receive SC dose of placebo matched to AZD3427 on Days 1, 8, 15, 22, and 29.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants will receive SC or IV dose of placebo matched to AZD3427 as per the arm they are randomized.

Interventions

AZD3427

Participants will receive SC or IV dose of AZD3427 as per the arm they are randomized.

Intervention Type: DRUG

Placebo

Participants will receive SC or IV dose of placebo matched to AZD3427 as per the arm they are randomized.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Part A will include healthy men and non-pregnant, non-lactating females of non-childbearing potential with a body mass index (BMI) of 18-30 kg/m^2 and a weight of 55-100 kg. One cohort will require participants be of Japanese descent
• Part B will include men and non-pregnant, non-lactating females of non-childbearing potential
• Participants have a BMI of 18-40 kg/m^2 and a weight of 55-136 kg
• Participants with a diagnosis of stage C HF New York Heart Association (NYHA) Class I-III on stable medical therapy for at least 12 weeks
• Participants with diagnosis of HFrEF will be defined as those with EF ≤ 40% and HF with EF ≥ 41%
• Participants either with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) > 125 pg/mL or BNP > 35 pg/mL (46)

Exclusion Criteria

Both Part A and Part B will exclude participants with any of the following:

• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study drug or planned surgical procedure before study completion
• History of vascular and left ventricular aneurysms or prior dissections
• Any history of joint hypermobility, Marfan's syndrome, or any connective tissue disorder
• Clinical signs and symptoms consistent with Coronavirus disease-19 or confirmed infection within the last 4 weeks
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity injection devices or to drugs with a similar chemical structure or class to AZD3427 or any component of AZD3427

In addition, Part A will exclude participants with any of the following:

• Alanine Aminotransferase (ALT) > Upper limit of normal (ULN)
• Aspartate Aminotransferase (AST) > ULN
• Total bilirubin > ULN (unless due to Gilbert's syndrome)
• Creatinine > ULN
• White blood cell (WBC) count < Lower limit of normal (LLN)
• Hemoglobin < LLN
• Prolonged QTcF > 450 m
• Shortened QTcF < 340 ms
• Family history of long QT syndrome
• PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
• PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third-degree atrioventricular (AV) block, or AV dissociation
• Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS > 110 ms. Participants with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of eg, ventricular hypertrophy or pre-excitation

In addition, Part B will exclude participants with any of the following:

• Atrial fibrillation or flutter occurring in the past year
• Clinically significant ventricular arrhythmias under treatment
• High-degree AV block II-III or sinus node dysfunction
• Implanted permanent pacemaker or implantable cardioverter defibrillator for which the participant is pacing-dependent
• Severe right-sided valvular heart disease; severe mitral regurgitation; moderate or severe mitral stenosis, severe aortic regurgitation and mild, moderate or severe aortic stenosis
• Other conditions where vasodilatory therapy may be contraindicated (hypertrophic obstructive cardiomyopathy, and restrictive cardiomyopathy)
• Congenital heart disease
• NYHA HF Class IV
• Occurrence in the last 6 months of acute coronary syndrome, percutaneous coronary intervention, cerebrovascular accident or transient ischemic attack, HF hospitalization; history or suspicion of cardiac amyloidosis
• ALT > 1.5 × ULN
• AST > 1.5 × ULN
• Total bilirubin > ULN (unless due to Gilbert's syndrome)
• Impaired renal function, defined as eGFR < 30 mL/min/1.73m^2 assessed by the Chronic Kidney Disease Epidemiology Collaboration equation
• WBC < LLN
• Hemoglobin < 10g/L
• PR (PQ) interval prolongation (> 220 ms)
• Participants with persistent BBB and QRS (ECG interval measured from the onset of the QRS complex to the J point) duration > 130 ms. Participants with intraventricular conduction delay and QRS duration < 130 ms

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ronald Goldwater, MD

Role: PRINCIPAL_INVESTIGATOR

Parexel Early Phase Clinical Unit (Baltimore), Harbor Hospital, 3001 S. Hanover St., Baltimore, MD 21225, United States of America (USA)

David Lanfear, MD

Role: PRINCIPAL_INVESTIGATOR

Henry Ford Hospital, USA, MI

Locations

Research Site

Little Rock, Arkansas, United States

Research Site

Glendale, California, United States

Research Site

Daytona Beach, Florida, United States

Research Site

Doral, Florida, United States

Research Site

Hallandale, Florida, United States

Research Site

Jacksonville, Florida, United States

Research Site

Owensboro, Kentucky, United States

Research Site

Brooklyn, Maryland, United States

Research Site

Detroit, Michigan, United States

Research Site

Houston, Texas, United States

Countries

United States

References

Connolly K, George R, Omar S, Matsson E, Astrand M, Althage M, Pettersen D, Mohamed E, Fang K, Lima JAC, Kujacic M, Odesjo H, Turton M, Johannesson P, Gabrielsen A, Ufnal M. Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study. J Am Heart Assoc. 2024 Aug 6;13(15):e034067. doi: 10.1161/JAHA.123.034067. Epub 2024 Jul 26.

Reference Type: DERIVED

PMID: 39056338 (View on PubMed)

Other Identifiers

D8330C00001

Identifier Type: -

Identifier Source: org_study_id