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%)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Number of Participants Experiencing Adverse Events and Serious Adverse Events
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
AZD3427: Cohort 1a
Participants will receive single SC dose A of AZD3427 on Day 1.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 2a
Participants will receive single SC dose B of AZD3427 on Day 1.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 3a
Participants will receive single SC dose C of AZD3427 on Day 1.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 4a
Participants will receive single SC dose D of AZD3427 on Day 1.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 5a
Participants will receive single IV dose E of AZD3427 on Day 1.
干预措施: AZD3427 (Drug)
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.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 7a
Participants will receive single SC dose F of AZD3427 on Day 1
干预措施: AZD3427 (Drug)
Part A: Placebo
Participants will receive single SC or IV dose of placebo matched to AZD3427 on Day 1.
干预措施: Placebo (Drug)
AZD3427: Cohort 1b
Participants with HFrEF will receive SC dose A of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 2b
Participants with HF with EF ≥ 41% will receive SC dose A of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 3b
Participants with HFrEF will receive SC dose B of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 4b
Participants with HF with EF ≥ 41% will receive SC dose B of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 5b
Participants with HFrEF will receive SC dose C of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
AZD3427: Cohort 6b
Participants with HF with EF ≥ 41% will receive SC dose C of AZD3427 on Days 1, 8, 15, 22, and 29.
干预措施: AZD3427 (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants Experiencing Adverse Events and Serious Adverse Events
时间窗: Part A: Day 1 until Day 50 or Early termination visit (E/T); Part B: Day 1 until Day 78 or E/T
Assessment of the safety and tolerability of single and multiple ascending doses of AZD3427.
次要结局
- Maximum Observed Serum (peak) Drug Concentration (Cmax) 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)
- Area Under the Serum Concentration-time Curve from Zero to the Last Quantifiable Concentration (AUClast)(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)
- Area Under Serum Concentration-time Curve From Zero to Infinity (AUCinf)(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)
- Area Under the Serum Concentration-time Curve from Zero to 168 Hours Post-dose Administration (AUC0-168)(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)
- Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (tmax)(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)
- Half-life Associated with Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz)(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)
- Number of Participants Testing Positive for the Presence of Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) to 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)
- Evaluation of Positive Anti-drug Antibodies Titer(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)