A Phase I First-in-human Study to Investigate Safety, Tolerability, and Pharmacokinetics of AZD4063 in Adults With Phospholamban R14del Dilated Cardiomyopathy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 23
- 试验地点
- 4
- 主要终点
- Number of participants with adverse events (AEs)
研究概览
简要总结
The purpose of the study is to assess the safety, tolerability and the pharmacokinetics (PK) of AZD4063 after single dose administration in participants with phospholamban (PLN) R14del dilated cardiomyopathy.
详细描述
This is a Phase 1, first in human, unblinded, ascending dose study which will consist of a SAD (single ascending dose) part and an Optional part.
The SAD part of the study will assess the single doses of AZD4063 across 4 cohorts. It will consist of:
- A Screening period
- A Treatment period: The participants will receive a single dose of AZD4063 by subcutaneous (SC) injection
- A Follow-up period
Optional cohorts may be added based on emerging safety, PK and PD data of the preceding cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must be 18 to 80 years of age inclusive, at the time of Screening
- •Participants with pre-existing positive screening for R14 del PLN mutation
- •Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography
- •Participants with New York Heart Association (NYHA) function class I-III
- •Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure
- •Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D)
- •Participants with Body mass index (BMI) within the range 18-35 kg/m2
- •Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception
- •All women of childbearing potential must have a negative pregnancy test at the Screening Visit.
排除标准
- •Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
- •Known to have tested positive for Human immunodeficiency virus (HIV)
- •Any known genetic mutation associated with hereditary electrical or structural disease
- •Congenital long QT syndrome
- •QTcF < 350 ms
- •Known Short QT syndrome (SQTS) or family history of SQTS
- •Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months
- •Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator
- •History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% > stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting)
- •Routinely scheduled outpatient intravenous infusions for heart failure
- •Uncontrolled hypertension
- •Significant primary valvular disease
- •Congenital heart disease
- •Left ventricular wall thickness of > 13 mm or with any relative with hypertrophic cardiomyopathy (HCM)
- •Recent acute presentation of myocarditis
- •Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis)
- •Alcohol consumption in excess
- •Any laboratory values with the following deviations:
- •Alanine Transaminase >2 upper normal limit (ULN)
- •Aspartate Transaminase >2 ULN
- •Total bilirubin > 2 x ULN
- •Estimated GFR < 30 mL/min/1.73 m2
- •Hemoglobin <10g/dL
- •Any vital sign values with the following deviations at Screening
- •Systolic blood pressure > 160 mmHg
- •Diastolic blood pressure > 100 mmHg
- •Pulse rate > 100 beats per minute
- •Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM)
- •History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity
- •Any history of cardiotoxic drug exposure with documented cardiomyopathy
- •Noncardiac condition that limits expected lifespan to less than 1 year
- •Participation in another clinical study with a study intervention administered in the last 3 months
- •Participants with a known hypersensitivity to AZD4063
- •Participants who have previously received AZD4063 as part of this study
- •Participants who are part of a gene therapy trial
研究组 & 干预措施
Cohort 3 (SAD): Dose 3 of AZD4063
Participants will receive Dose 3 of AZD4063 via SC injection in Cohort 3 of SAD.
干预措施: AZD4063 (Drug)
Cohort 2 (SAD): Dose 2 of AZD4063
Participants will receive Dose 2 of AZD4063 via SC injection in Cohort 2 of SAD.
干预措施: AZD4063 (Drug)
Cohort 4 (SAD): Dose 4 of AZD4063
Participants will receive Dose 4 of AZD4063 via SC injection in Cohort 4 of SAD.
干预措施: AZD4063 (Drug)
Optional Cohort 1 (SAD): Dose 5 of AZD4063
Participants will receive Dose 5 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings.
干预措施: AZD4063 (Drug)
Optional Cohort 2 (SAD): Dose 6 of AZD4063
Participants will receive Dose 6 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings.
干预措施: AZD4063 (Drug)
Optional Cohort 3 (SAD): Dose 7 of AZD4063
Participants will receive Dose 7 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings.
干预措施: AZD4063 (Drug)
Optional Cohort 4 (SAD): Dose 8 of AZD4063
Participants will receive Dose 8 of AZD4063 via SC injection in the optional cohort of the study. This additional cohort will be added depending on the findings.
干预措施: AZD4063 (Drug)
Cohort 1 (SAD): Dose 1 of AZD4063
Participants will receive Dose 1 of AZD4063 via SC injection in Cohort 1 of SAD.
干预措施: AZD4063 (Drug)
结局指标
主要结局
Number of participants with adverse events (AEs)
时间窗: Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210
The safety and tolerability of AZD4063 following the SC administration of single doses in participants with PLN R14del dilated cardiomyopathy will be evaluated.
Number of participants with adverse events (AEs)
时间窗: Cohort 1 (SAD): From Day 1 to Day 109, Cohorts 2 and 3 (SAD) From Day 1 to Day 99; For Cohorts 1,2 and 3 (MAD): Day 1 to Day 155
The safety and tolerability of AZD4063 following the SC administration of single and repeated doses in participants with PLN R14del dilated cardiomyopathy
次要结局
- Area under plasma concentration-time curve from 0 to infinity (AUCinf)(Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210)
- Area under the plasma concentration-curve from 0 to the last quantifiable concentration (AUClast)(Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210)
- Maximum plasma drug concentration (Cmax)(Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210)
- Renal clearance (CLR)(Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224))
- Cumulative amount of analyte excreted (Ae)(Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224))
- Fraction of dose excreted unchanged in urine (Fe)(Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224))
- Change in endomyocardial biopsy PLN messenger ribonucleic acid (mRNA levels) from baseline to estimated peak knockdown and estimated return-to-baseline(Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224))
- Renal clearance (CLR)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Cumulative amount of analyte excreted (Ae)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Fraction of dose excreted unchanged in urine (Fe)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Area under plasma concentration-time curve from 0 to infinity (AUCinf)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Area under the plasma concentration-curve from 0 to the last quantifiable concentration (AUClast)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Maximum plasma drug concentration (Cmax)(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)
- Change in endomyocardial biopsy PLN messenger ribonucleic acid (mRNA levels) from baseline to estimated peak knockdown and estimated return-to-baseline(Cohort 1 (SAD): Up to Day 95, Cohorts 2 and 3 (SAD): Up to Day 85; Cohorts 1,2,3 (MAD): Up to Day 141)