NCT02950805已完成1 期
A Phase 1b Randomized Blinded Placebo-Controlled, Cross-Over Study to Assess the Effect of AZD5634 on Mucociliary Clearance as Well as Safety, Tolerability, and Pharmacokinetic Parameters Following Single Inhaled Dose Administration to Patients With Cystic Fibrosis.
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Percentage of average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
研究概览
简要总结
This study will assess the effect of inhaled AZD5634 on Mucociliary clearance (MCC) in patients with Cystic fibrosis (CF) after single-dose administration.
详细描述
The primary pharmacodynamic endpoint will be the average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles (colloids) at Visits 2 and 3 (%MCC 0-60, whole).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated written informed consent prior to any study-specific procedures.
- •Male or female patients aged 18-60 years old inclusive.
- •Diagnosed of CF at Screening as evidenced in medical records by one of the following criteria:
- •sweat chloride ≥ 60 mmol/L
- •presence of 2 mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.
- •Chronic sinopulmonary disease or pancreatic insufficiency.
- •FEV1measurement at Screening ≥ 40% of the predicted normal value of age, height, gender, and race.
- •Stable CF regimen for at least 2 months before Screening.
- •Body mass index (BMI) between 15-30 kg/m2 inclusive.
- •Female patients are not pregnant and do not plan to become pregnant during the study, are not lactating, or are of non-childbearing potential. Females of childbearing potential must provide a negative serum pregnancy test and have a date of last menstruation consistent with non-pregnancy, negative urine pregnancy tests at each visit, and must be using at least one highly effective method of contraception.
- •Ability of the patient to correctly perform the inhalation procedure after training during the Screening Visit.
排除标准
- •Had a pulmonary exacerbation requiring change in antibiotics and/or hospitalization within 28 days before the first dose of Investigational product.
- •History of lung transplant or any other transplantation.
- •Currently being treated with ivacaftor monotherapy at Screening or received ivacaftor monotherapy within 30 days before Screening.
- •History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the Investigator, to drugs in a similar class to AZD
- •History or presence of hepatic cirrhosis.
- •Creatinine clearance <60 mL/min/m2 using the Cockroft-Gault Equation.
- •Liver function test results >2x upper limit of normal (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], or bilirubin)
- •History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study.
- •Received treatment with the following medications within the 3 weeks before Screening: strong or moderate Cytochrome P450 (CYP) 3A inhibitors, as classified by the Food and Drug Administration (FDA).
- •Likely to require treatment during the study with drugs not permitted by the study protocol.
- •Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results.
- •Serum potassium levels are outside the normal range (3.5-5.1 mmol/L).
- •Serum sodium levels <135 mmol/L.
- •Abnormal vital signs, after 5 minutes rest, at Screening or Visit 2 (seated or supine; position should be consistent for a given patient at both visits), defined as any of the following:
- •Systolic blood pressure (B.P) < 90 or ≥ 150 mmHg
- •Diastolic B.P < 45 or ≥ 90 mmHg
- •Pulse rate < 45 or >110 beats/minute
- •Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the Investigator, that may interfere with the interpretation of corrected ECG interval measured from the onset of the QRS complex to the offset of the T wave (QTc) interval changes.
- •QTc prolongation defined as QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 ms.
- •ECG interval measured from the onset of the P wave to the onset of the QRS complex (PR/PQ) interval prolongation (>240 ms), intermittent second or third degree atrioventricular (AV) block, or AV dissociation.
- •Persistent or intermittent complete bundle branch block (BBB) with ECG interval measured from the onset of the QRS complex to the J point (QRS) >120 ms or evidence of pre-excitation.
研究组 & 干预措施
Placebo + AZD5634
Experimental
Subjects were administered single dose of placebo in period 1 and AZD5634 in period 2.
干预措施: Placebo (Drug)
Placebo + AZD5634
Experimental
Subjects were administered single dose of placebo in period 1 and AZD5634 in period 2.
干预措施: AZD5634 (Drug)
AZD5634 + Placebo
Experimental
Subjects were administered single dose of AZD5634 in period 1 and placebo in period 2.
干预措施: Placebo (Drug)
AZD5634 + Placebo
Experimental
Subjects were administered single dose of AZD5634 in period 1 and placebo in period 2.
干预措施: AZD5634 (Drug)
结局指标
主要结局
Percentage of average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
时间窗: 0 to 60 minutes
Assessment of the average whole lung clearance between 0 and 60 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634, (%MCC 0--60, whole) in subjects with cystic fibrosis (CF).
次要结局
- Percentage of average tracheobronchial clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles(0 to 60 minutes)
- Percentage of average whole lung cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles(60 minutes to 90 minutes)
- Percentage of average central clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles(0 to 60 minutes)
- Percentage of particle clearance at 6-hour(6 hours)
- Percentage of average central cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles(60 minutes to 90 minutes)
- Terminal elimination rate constant (λz)(Pre-dose and up to 6 hours post-dose)
- Terminal elimination half-life (t1/2,λz)(Pre-dose and up to 6 hours post-dose)
- Cumulative amount of AZD5634 excreted in urine from time zero to 6 hours (Ae 0-6)(Pre-dose and up to 6 hours post-dose)
- Cumulative percentage of dose excreted unchanged in urine from time zero to 6 hours (fe(0-6)%)(Pre-dose and up to 6 hours post-dose)
- Time of last quantifiable concentration (t last)(Pre-dose and up to 6 hours post-dose)
- Percentage of average peripheral clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles(0 to 60 minutes)
- Observed last quantifiable concentration (C last)(Pre-dose and up to 6 hours post-dose)
- Time to reach maximum plasma concentration (t max)(Pre-dose and up to 6 hours post-dose)
- Percentage of average peripheral cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles(60 minutes to 90 minutes)
- Maximum observed plasma concentration (Cmax)(Pre-dose and up to 6 hours post-dose)
- Area under the concentration-time curve from time zero extrapolated to infinity (AUC)(Pre-dose and up to 6 hours post-dose)
- Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC 0-last)(Pre-dose and up to 6 hours post-dose)
- Area under the plasma concentration-time curve from time zero to 6 hours post-dose (AUC 0-6)(Pre-dose and up to 6 hours post-dose)
- Safety of subjects by evaluating the pulse rate.(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating spirometry results(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating the ECG results(Pre-dose and up to 6 hours post-dose)
- Safety of subjects by the physical examination(From screening (≤28 days) up to 14-21 days post dosing)
- Percentage of average tracheobronchial cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles(60 minutes to 90 minutes)
- Apparent clearance (CL/F)(Pre-dose and up to 6 hours post-dose)
- Apparent volume of distribution at terminal phase (Vz/F)(Pre-dose and up to 6 hours post-dose)
- Safety of subjects by evaluating the incidence of adverse events (AEs)(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating the systolic and diastolic blood pressure(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating the respiratory rate.(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating fractional excretion of potassium (FEK)(Pre-dose and at 0-6 hours post-dose)
- Safety of subjects by evaluating urine sodium/potassium (Na/K) ratio(Pre-dose and at 0-6 hours post-dose)
- Safety of subjects by evaluating the pulse oximetry(From screening (≤28 days) up to 14-21 days post dosing)
- Safety of subjects by evaluating the clinical laboratory test results for biochemistry(From screening (≤28 days) until 14-21 days post dosing)
- Safety of subjects by evaluating the clinical laboratory test results for urinalysis(From screening (≤28 days) until 14-21 days post dosing)
- Safety of subjects by evaluating the clinical laboratory test results for hematology(From screening (≤28 days) until 14-21 days post dosing)
- Renal clearance, estimated by dividing Ae(0-t) (CLR)(Pre-dose and up to 6 hours post-dose)
研究者
研究点 (1)
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