A Phase I Randomised, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD1613 Following Multiple Ascending Dose Administration in Participants With Autosomal Dominant Polycystic Kidney Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 40
- 试验地点
- 15
- 主要终点
- Change From Baseline in Safety 12-Lead ECG QRS Duration
研究概览
简要总结
A study to investigate safety, tolerability, and pharmacokinetics of AZD1613 following subcutaneous or intravenous administration in participants with autosomal dominant polycystic kidney disease (ADPKD).
详细描述
This Phase I, randomised, single-blind, placebo-controlled study will assess the safety and tolerability of AZD1613 and characterise the pharmacokinetics (PK) of AZD1613 in participants with autosomal dominant polycystic kidney disease (ADPKD), following subcutaneous (SC) or intravenous (IV) administration. Inclusion of participants receiving placebo is appropriate for benchmarking the safety and tolerability of AZD1613. Furthermore, the safety and PK profile will be evaluated in Chinese participants with ADPKD to assess any potential race effect in this population.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This study will be single-blinded in order to minimize bias in the collection and evaluation of data during its conduct.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with ADPKD Mayo Class (IB-IE), as per clinical diagnosis (MIC) assessed centrally. Genetic testing results will not be used for eligibility purposes
- •eGFR = 45 to 90 mL/min /1.73m2
- •Body weight ≥ 45 kg and body mass index within the range 18 to 35 kg/m2 (inclusive).
- •Females are to be of non-childbearing potential
排除标准
- •As judged by the investigator, any evidence of cardiac, vascular, and other renal conditions which in the investigator's opinion makes it undesirable for the participant to participate in the study.
- •Positive hepatitis C antibody, hepatitis B virus surface antigen, or human immunodeficiency virus test, at screening.
- •History of QT prolongation associated with other medications that required discontinuation of that medication.
- •Congenital long QT syndrome.
- •History of ventricular arrhythmia requiring treatment. Patients with atrial fibrillation/flutter and controlled ventricular rate HR < 100 bpm can be eligible as judged by the investigator.
- •Haemoglobin below the lower limit of the normal range or any other clinically significant haematological abnormality as judged by the investigator.
- •Any clinically important abnormalities in clinical chemistry, haematology, coagulation, or urinalysis results other than those specifically described as exclusion criteria herein, as judged by the investigator.
- •Systolic BP > 160 mmHg or diastolic BP > 100mmHg or HR < 50 bpm or > 100 bpm at screening. Patients taking anti-hypertensive medication should be on a stable treatment regimen of antihypertensive therapy for at least 30 days prior to the screening visit.
- •Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, as considered by the investigator, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.
- •Kidney cyst interventions such as cyst aspiration or cyst fenestration within 12 weeks prior to screening and during the screening period, or such interventions planned or anticipated within the follow-up period.
研究组 & 干预措施
Part A - Cohort A1
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: AZD1613 - Part A (Drug)
Part A - Cohort A2
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: Placebo - Part A (Drug)
Part B - Chinese Cohort
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: AZD1613 - Part A (Drug)
Part B - Chinese Cohort
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: AZD1613 - Part B (Drug)
Part B - Chinese Cohort
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: Placebo - Part B (Drug)
Part A - Cohort A2
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: AZD1613 - Part A (Drug)
Part A - Cohort A1
Participants will receive 4 doses of AZD1613 or placebo on days 1, 29, 57 and 85.
干预措施: Placebo - Part A (Drug)
结局指标
主要结局
Change From Baseline in Safety 12-Lead ECG QRS Duration
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in QRS duration measured on single 12-lead safety ECGs. Unit: milliseconds (ms).
Change From Baseline in Total Bilirubin
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in total bilirubin. Unit: mg/dL.
Change From Baseline in Serum Creatinine
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in serum creatinine. Unit: mg/dL.
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR; CKD-EPI 2021)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in eGFR calculated using CKD-EPI 2021. Unit: mL/min/1.73 m².
Change From Baseline in Heart Rate (12-Lead Safety ECG)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in heart rate measured on single 12-lead safety ECGs. Unit: beats per minute (bpm).
Incidence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: From randomization (Day 1) through end of follow-up (up to Day 189 ±3 days)
Number of participants with at least one TEAE and SAE, including events leading to discontinuation or death; coded by system organ class and preferred term. Unit: participants.
Change From Baseline in Prothrombin Time (PT)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in prothrombin time. Unit: seconds (s).
Change From Baseline in Activated Partial Thromboplastin Time (aPTT)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in aPTT. Unit: seconds (s).
Change From Baseline in Body Temperature
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in oral body temperature. Unit: °C.
Change From Baseline in Respiratory Rate
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in respiratory rate. Unit: breaths per minute.
Change From Baseline in Safety 12-Lead ECG QTcF
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in QT interval corrected using Fridericia's formula (QTcF) measured on single 12-lead safety ECGs. Unit: milliseconds (ms).
Change From Baseline in Safety 12-Lead ECG PR Interval
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in PR interval measured on single 12-lead safety ECGs. Unit: milliseconds (ms).
Change From Baseline in ALT
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in alanine aminotransferase. Unit: U/L.
Change From Baseline in Diastolic Blood Pressure
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in supine diastolic blood pressure. Unit: mmHg.
Change From Baseline in Heart Rate (Vital Signs)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in supine heart rate. Unit: bpm.
Change From Baseline in AST
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in aspartate aminotransferase. Unit: U/L.
Change From Baseline in INR
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in international normalized ratio- (INR). Unit: unitless.
Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR)
时间窗: Baseline (Day -1) and scheduled visits through Day 189 ±3 days; UACR as triplicate first-morning voids per visit
Change from baseline in UACR (geometric mean of triplicates at each visit). Unit: mg/g.
Change From Baseline in Systolic Blood Pressure
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in supine systolic blood pressure. Unit: mmHg.
Change From Baseline in Oxygen Saturation (SpO2)
时间窗: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days
Change from baseline in pulse oximetry oxygen saturation. Unit: percent (%).
次要结局
- ADA Titer to AZD1613(Predose on dosing days and during follow-up through Day 189 ±3 days)
- Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau) of AZD1613(Over the dosing interval (τ = 28 days) at steady state; sampling through Day 189)
- Incidence of Anti-Drug Antibodies (ADA) to AZD1613(Predose on dosing days and during follow-up through Day 189 ±3 days)
- Maximum Observed Serum Concentration (Cmax) of AZD1613(Intensive PK sampling from Day 1 through Day 189 per protocol schedule)
- Area Under the Concentration-Time Curve to Last Quantifiable Concentration (AUClast) of AZD1613(Intensive PK sampling from Day 1 through Day 189 per protocol schedule)
- Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of AZD1613(Intensive PK sampling from Day 1 through Day 189 per protocol schedule)
- Time to Maximum Observed Serum Concentration (Tmax) of AZD1613(Intensive PK sampling from Day 1 through Day 189 per protocol schedule)
- Terminal Elimination Half-Life (t½) of AZD1613(Intensive PK sampling from Day 1 through Day 189 per protocol schedule)
- Change From Baseline in PD Markers of PAPPA-1 Inhibition(Baseline to scheduled post-dose time points through Day 189 ±3 days)