Clinical trial NCT04630067: Assessment of Safety, Tolerability, Immunogenicity, and Pharmacokinetics of AZD3427
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%)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Heart Failure
Keywords: Heart failure with reduced ejection fraction
Heart failure with ejection fraction of ≥ 41%
AZD3427
First-time-in-human
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-11-16
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants Experiencing Adverse Events and Serious Adverse Events
timeFrame: Part A: Day 1 until Day 50 or Early termination visit (E/T); Part B: Day 1 until Day 78 or E/T
Secondary outcomes:
measure: Maximum Observed Serum (peak) Drug Concentration (Cmax) of AZD3427
timeFrame: 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
measure: Area Under the Serum Concentration-time Curve from Zero to the Last Quantifiable Concentration (AUClast)
timeFrame: 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
measure: Area Under Serum Concentration-time Curve From Zero to Infinity (AUCinf)
timeFrame: 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
measure: Area Under the Serum Concentration-time Curve from Zero to 168 Hours Post-dose Administration (AUC0-168)
timeFrame: 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
measure: Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (tmax)
timeFrame: 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
measure: Half-life Associated with Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz)
timeFrame: 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
measure: Number of Participants Testing Positive for the Presence of Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) to AZD3427
timeFrame: 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
measure: Evaluation of Positive Anti-drug Antibodies Titer
timeFrame: 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
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: Glendale
country: United States
facility: Research Site
state: California
city: Daytona Beach
country: United States
facility: Research Site
state: Florida
city: Doral
country: United States
facility: Research Site
state: Florida
city: Hallandale Beach
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Owensboro
country: United States
facility: Research Site
state: Kentucky
city: Brooklyn
country: United States
facility: Research Site
state: Maryland
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Houston
country: United States
facility: Research Site
state: Texas
Study officials:
affiliation: Parexel Early Phase Clinical Unit (Baltimore), Harbor Hospital, 3001 S. Hanover St., Baltimore, MD 21225, United States of America (USA)
name: Ronald Goldwater, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Henry Ford Hospital, USA, MI
name: David Lanfear, MD
role: PRINCIPAL_INVESTIGATOR
References: