A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Parallel, Group Study of N91115 to Evaluate Safety and Pharmacokinetics in Patients With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 19
- 主要终点
- Safety assessments based on clinical evaluations, laboratory assessments, and adverse events.
研究概览
简要总结
This Phase 1b study in F508del-CFTR homozygous CF patients is being conducted to assess the safety of N91115 as the sole cystic fibrosis transmembrane conductance regulator (CFTR) modulator at doses near the expected therapeutic exposure level in preparation for Phase 2 studies of N91115 added to the CFTR modulator combination lumacaftor/ivacaftor when launched.
详细描述
Study procedures, frequency and timing are provided in the attached study schema. Adverse events and concomitant medication will be monitored throughout the study from informed consent signing until end of study participation. A Data Monitoring Committee (DMC) will also review unblinded safety data on a monthly basis throughout the study. Limitations on bronchodilators for pulmonary assessments prior to study drug dosing are described below except in emergent situations.
- Short acting β-agonists and anticholinergics will be held for at least 4 hours
- Long acting β-agonists dosed twice daily will be held for at least 12 hours
- Long acting β-agonists dosed once daily and long acting anticholinergics will be held for at least 24 hours
Screening (Day -28 to Day -3):
Patients will sign the informed consent and undergo procedures to determine eligibility including pregnancy testing, demographic information, medical history, and genotype by historical confirmation or blood sample confirmation (as applicable), height and weight, 12-Lead electrocardiogram (ECG), 48-hour Holter monitoring, chemistry, hematology, full physical examination, sweat chloride, smoking and alcohol history, spirometry, sputum microbiology, urinalysis and vital signs.
Day 1 Predose (Day -2 to -1) Patients will return to the clinic to reconfirm eligibility and assess any changes in medical history and pregnancy status. An abbreviated physical examination focusing on cardiovascular, pulmonary and gastrointestinal systems plus an assessment of weight will be conducted. The following will be obtained: 12-lead ECG, abbreviated physical exam, blood for DNA (optional), blood for leukocyte messenger ribonucleic acid (mRNA), blood inflammatory biomarkers, cystic fibrosis questionnaire-revised (CFQ-R), O2 Sat, patient global impression of change (PGIC), safety labs, serum pharmacokinetics (PK), spirometry, sputum microbiology, sweat chloride (SC) (if more than 2 weeks since the screening value was obtained), and vital signs. Sites may choose to perform any of these assessments on Day -2, Day -1 or Day 1 predose except for serum PK that starts Day 1 predose and vital signs that are done Day 1 predose.
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)
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
- •Male or female, age ≥ 18 years with confirmed diagnosis of CF, homozygous for the F508del-CFTR mutation based on historical results generated by Ambry Genetics within the past two years or if unavailable, confirmed by testing done within the past 28 days
- •Sweat chloride ≥ 60 (milliequivalents) mEq/L, by quantitative pilocarpine iontophoresis test (QPIT) at screening
- •Weight ≥ 40 kg at screening
- •Forced expiratory volume (FEV1) ≥ 40% of predicted normal for age, gender, and height (Hankinson standards) pre- or post-bronchodilator value, at screening
- •Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening
- •Hematology, clinical chemistry and urinalysis results with no clinically significant abnormalities that would interfere with the study assessments at screening
排除标准
- •Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment or hospitalization within 2 weeks of Study Day 1
- •Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, Pulmozyme®, hypertonic saline, Azithromycin, Tobi®, Cayston®) within 4 weeks of Study Day 1
- •Blood hemoglobin < 10 g/dL at screening
- •Serum albumin < 2.5 g/dL at screening
- •Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) in 3 or more of the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT), g-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total bilirubin at screening
- •History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) within a year of screening
- •History, including the screening assessment, of ventricular tachycardia or other ventricular arrhythmias
- •History, including the screening assessment, of prolonged cardiac QT interval and/or QTcF (QT with Fridericia's correction) interval (> 450 msec)
- •History of solid organ or hematological transplantation
- •History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening
- •Use of continuous (24 hr/day) or nocturnal supplemental oxygen
研究组 & 干预措施
Group 1 - 50 mg
Every 12 hour oral dosing of N91115 for 28 days
干预措施: N91115 (Drug)
Group 2 - 100 mg
Every 12 hour oral dosing of N91115 for 28 days
干预措施: N91115 (Drug)
Group 3 - 200 mg
Every 12 hour oral dosing of N91115 for 28 days
干预措施: N91115 (Drug)
Group 4 - Placebo
Every 12 hour oral dosing of placebo comparator for 28 days
干预措施: N91115 (Drug)
结局指标
主要结局
Safety assessments based on clinical evaluations, laboratory assessments, and adverse events.
时间窗: 28 Days
次要结局
- Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma(28 Days)