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

Heart Failure Clinical Trial

Official title:

A Phase Ia/b Randomized, Single-blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, Immunogenicity, and Pharmacokinetics of Single Ascending Doses of AZD3427 in Healthy Volunteers and Multiple Ascending Doses of AZD3427 in Patients With Heart Failure (HFrEF and HF With EF ≥ 41%)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04630067
• Other study ID #: D8330C00001
• Status: Completed
• Phase: Phase 1
• Start date: November 17, 2020
• Est. completion date: September 14, 2022

Study information

• Verified date: October 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: September 14, 2022
• Est. primary completion date: September 14, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

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

Locations

Country	Name	City	State
United States	Research Site	Brooklyn	Maryland
United States	Research Site	Daytona Beach	Florida
United States	Research Site	Detroit	Michigan
United States	Research Site	Doral	Florida
United States	Research Site	Glendale	California
United States	Research Site	Hallandale Beach	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Owensboro	Kentucky

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Experiencing Adverse Events and Serious Adverse Events	Assessment of the safety and tolerability of single and multiple ascending doses of AZD3427.	Part A: Day 1 until Day 50 or Early termination visit (E/T); Part B: Day 1 until Day 78 or E/T
Secondary	Maximum Observed Serum (peak) Drug Concentration (Cmax) of AZD3427	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Area Under the Serum Concentration-time Curve from Zero to the Last Quantifiable Concentration (AUClast)	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Area Under Serum Concentration-time Curve From Zero to Infinity (AUCinf)	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Area Under the Serum Concentration-time Curve from Zero to 168 Hours Post-dose Administration (AUC0-168)	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (tmax)	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Half-life Associated with Terminal Slope (?z) of a Semi-logarithmic Concentration-time Curve (t½?z)	Evaluation of the PK of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 5, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 32, 57, 71 and 78 or E/T
Secondary	Number of Participants Testing Positive for the Presence of Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) to AZD3427	Evaluation of the immunogenicity of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose), Days 15, 29, and 50 or E/T; Part B: Days 1, 15, 29 (Pre-dose), Days 57 and 78 or E/T
Secondary	Evaluation of Positive Anti-drug Antibodies Titer	Evaluation of the immunogenicity of single and multiple ascending doses of AZD3427.	Part A: Day 1 (pre-dose), Days 15, 29, and 50 or E/T; Part B: Days 1, 15, 29 (Pre-dose), Days 57 and 78 or E/T