Assessment of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Oral Doses of the Combination of GLPG2451 and GLPG2222, With or Without GLPG2737, in Adult Subjects With Cystic Fibrosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Galapagos NV
- 入组人数
- 10
- 试验地点
- 20
- 主要终点
- Change from baseline in sweat chloride concentration.
研究概览
简要总结
This is a Phase Ib, multi-center, open-label, nonrandomized multiple cohorts study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of a combination treatment of GLPG2451 and GLPG2222, with and without GLPG2737, in adult subjects with Cystic Fibrosis.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Female or male subject ≥18 years of age, on the day of signing the Informed Consent Form (ICF)
- •Confirmed clinical diagnosis of cystic fibrosis (CF) (documented in the subject's medical record).
- •Eligible cystic fibrosis transmembrane conductance regulator (CFTR) genotype at screening:
- •Cohort A: Homozygous for the F508del CFTR mutation
- •Cohort B: Heterozygous for the F508del CFTR mutation with a potentiator non-responsive mutation on the second allele
- •Cohort C: Homozygous for the F508del CFTR mutation
- •A body weight of ≥40 kg at screening.
- •Stable concomitant medication for pulmonary health for CF for at least 4 weeks prior to the first study drug administration and planned continuation of the same concomitant medication for the duration of the dosing period of the study. Subjects with diabetes mellitus and/or pancreatic insufficiency are eligible for the study provided they are on stable treatment (e.g. medication, diet, pancreatic enzyme replacement therapy) for at least 4 weeks prior to the first study drug administration in the opinion of the investigator.
- •Forced expiratory volume in 1 second (FEV1): 40% ≤ FEV1 ≤ 90% of predicted normal for age, sex, and height at screening (pre- or post bronchodilator) at screening.
- •Sweat chloride concentration ≥60 mmol/L at screening.
- •Non-smoker and non-user of any nicotine and or cannabis containing products. A non-smoker is defined as an individual who has abstained from smoking for at least 1 year prior to the screening. A non-user is defined as an individual who has abstained from any nicotine containing products for at least 1 year prior to the screening.
排除标准
- •History of or ongoing allergic bronchopulmonary aspergillosis.
- •Medical history of cataract (or lens opacity) and/or glaucoma.
- •Cataract (or lens opacity) and/or glaucoma determined by an ophthalmologist during the screening period.
- •Unstable pulmonary status or respiratory tract infection (including rhinosinusitis) requiring a change in therapy within 4 weeks prior to the first study drug administration.
- •History of clinically meaningful unstable or uncontrolled chronic disease that makes the subject unsuitable for inclusion in the study in the opinion of the investigator.
- •Need for supplemental oxygen during the day, and >2 L/minute while sleeping.
- •History of hepatic cirrhosis with portal hypertension (e.g., signs/symptoms of splenomegaly, esophageal varices).
- •History of malignancy within the past 5 years (except for basal cell carcinoma of the skin with no evidence of recurrence and/or carcinoma in situ of the cervix that has been treated with no evidence of recurrence).
- •Use of any moderate and strong inhibitor(s) or inducer(s) of CYP3A4 within 4 weeks prior to the first study drug administration (e.g., clarithromycin, itraconazole, ketoconazole, telithromycin, rifampin, carbamazepine).
- •Use of CFTR modulator therapy (e.g., lumacaftor and/or ivacaftor) within 4 weeks prior to the first study drug administration.
- •Use of any oral corticosteroid within 3 months of screening; or history of oral corticosteroid use for ≥30 days (cumulative) within 2 years of screening.
- •Abnormal liver function test at screening; defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/or alkaline phosphatase and/or gamma-glutamyl transferase (GGT) ≥3× the upper limit of normal (ULN); and/or total bilirubin ≥1.5× the ULN.
研究组 & 干预措施
Cohort A - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods.( Study Part I)
干预措施: GLPG2451 dose regimen A (Drug)
Cohort A - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods.( Study Part I)
干预措施: GLPG2222 (Drug)
Cohort A - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods.( Study Part I)
干预措施: GLPG2737 (Drug)
Cohort B - F508del heterozygous/potentiator nonresponsive
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (study Part II)
干预措施: GLPG2451 dose regimen B (Drug)
Cohort B - F508del heterozygous/potentiator nonresponsive
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (study Part II)
干预措施: GLPG2222 (Drug)
Cohort B - F508del heterozygous/potentiator nonresponsive
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (study Part II)
干预措施: GLPG2737 (Drug)
Cohort C - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (Study Part II)
干预措施: GLPG2451 dose regimen B (Drug)
Cohort C - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (Study Part II)
干预措施: GLPG2222 (Drug)
Cohort C - F508del homozygous
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days, followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14 days, without washout in between the sequential treatment periods. (Study Part II)
干预措施: GLPG2737 (Drug)
结局指标
主要结局
Change from baseline in sweat chloride concentration.
时间窗: Between Day 1 pre-dose and Day 28
To assess changes in sweat chloride concentration after administration of the combination of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part II).
Trough plasma concentration observed at the end of the dosing interval (24 hours post-dose) (Ctrough).
时间窗: Between Day 2 and Day 28
To characterize the PK of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part I and Part II).
Maximum observed plasma concentration (Cmax).
时间窗: Day 28
To characterize the PK of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part I).
Area under the plasma concentration-time curve from time zero until 24 hours (AUC0-24h).
时间窗: Day 28
To characterize the PK of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part I).
Change from baseline in percent predicted FEV1.
时间窗: Between Day 1 pre-dose and Day 28
To assess changes in percent predicted FEV1 after administration of the combination of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part II).
Number of subjects with adverse events.
时间窗: Up to 24 weeks after the last dose
To assess safety and tolerability of doses of GLPG2451 and GLPG2222 with or without GLPG2737 (Study Part I and Part II).
次要结局
- Change from baseline in sweat chloride concentration.(Between Day 1 pre-dose and Day 28)
- Change from baseline in percent predicted FEV1.(Between Day 1 pre-dose and Day 28)