Intestinal Current Measurements (ICM) to Evaluate the Activation of Mutant CFTR in Subjects With Cystic Fibrosis Aged 12 Years and Older, Homozygous for the p.Phe508del-CFTR Mutation, Treated With Lumacaftor in Combination With Ivacaftor
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 104
- 试验地点
- 3
- 主要终点
- ICM Absolute change from baseline of the cumulative chloride secretory ion current response to forskolin/IBMX and carbachol in rectal tissue as a CFTR biomarker
研究概览
简要总结
The academic investigator - initiated trial will evaluate in a postapproval setting whether, and if yes, to what extent and variability, the treatment with lumacaftor in combination with ivacaftor reverses the p.Phe508del CFTR - mediated basic defect in p.Phe508del homozygous subjects with cystic fibrosis under real life conditions.
详细描述
Study design. This academic investigator - initiated trial will resolve the key issue whether, and if yes, to what extent and variability, the treatment with lumacaftor in combination with ivacaftor (Orkambi®) will reverse the p.Phe508del CFTR - mediated basic defect in p.Phe508del homozygous subjects with cystic fibrosis (CF) under real life conditions.
Each p.Phe508del homozygous subject will function as his own control. Baseline measurements will be performed within a 4-week interval prior to the start of oral treatment with lumacaftor + ivacaftor. According to the phase 3 study results by week 4 the gain of FEV1 levels off, drug levels are in steady state and all reversible initial reductions of lung function are resolved. Thus the second assessment will be performed during the initial steady state at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor + ivacaftor. At both days of investigations the basic defect will be assessed by Gibson-Cooke pilocarpine iontophoresis sweat test, nasal transepithelial potential difference measurement (NPD) and intestinal current measurement (ICM). Moreover lung function will be measured by spirometry. The plasma concentrations of lumacaftor, ivacaftor, and their metabolites will be determined and the safety of the oral treatment with Orkambi will be assessed according to the prescribing information.
Study participants will be requested to record the administration of Orkambi® by date and time for 7 days before the scheduled visit to perform functional CFTR assays. Orkambi® should be administered within 30 minutes of consuming fat-containing food according to the FDA-approved patient labeling and the prescribing information. Subjects will be given a diary to record the time and doses of administration of Orkambi® for seven days before the scheduled visit.
Measures against recruitment bias. The local patient databases at the three sites will be searched for all subjects who fulfil the inclusion criteria. After all subjects have been removed from the list who fulfill one or more exclusion criteria, the eligible subjects will be randomly assigned to rank numbers. Subjects will then be contacted in the sequence as they appear in the rank number list.
Statistical analysis. The sample size estimate is based on the absolute change from baseline of the cumulative chloride secretory ion current response to forskolin/Isobutyl methyl xanthine (IBMX) and carbachol in ICM as outcome measure of CFTR function. Assuming a nominal type I error of 0.05 and a power of 0.8, 125 or 33 subjects are needed to demonstrate a treatment effect of 5% or 10%, respectively. Thus even modest changes in the basis defect can be demonstrated in a recruited cohort of 125 subjects and incomplete data sets in up to half of all subjects.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •p.Phe508del homozygous subjects aged 6 years and older with cystic fibrosis
- •FEV1 ≥ 40% of predicted normal for age, gender and height (Knudson standards) or FEV1 > 35% of predicted normal for age, gender and height at baseline, stable lung function during the preceding three months and no acute upper or lower respiratory infection or pulmonary exacerbation during the preceding four weeks
- •Hematology, serum chemistry, coagulation results at baseline with no clinically significant abnormalities that would interfere with the oral treatment with Orkambi® and with the study assessments, as judged by the investigator
- •Able to understand and comply with protocol requirements, restrictions, and instructions and likely to complete the study as planned, as judged by the investigator
- •Willing to remain on a stable medication regimen and administration of Orkambi® according to the FDA-approved patient labeling and the prescribing information for the duration of study participation -
排除标准
- •History of any illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering Orkambi®
- •An acute upper or lower respiratory infection or pulmonary exacerbation at baseline
- •Advanced liver disease as documented by sonography
- •Abnormal liver function at baseline, defined as ≥ 3 upper limit of normal in minimum 3 of the following: serum aspartate transaminase, serum alanine transaminase, gamma-glutamyl transpeptidase, or total bilirubin
- •Abnormal blood creatine phosphokinase at baseline
- •Abnormal renal function at baseline, defined as creatinine clearance < 60 mL/min
- •Co-medication with strong Cytochrome P450, Family 3, subfamily A (CYP3A) inhibitors and inducers
- •Non-congenital lens opacities
- •Haemorrhoids (bleeding risk when taking rectal suction biopsies for ICM)
- •History of nasal surgery that removed the respiratory epithelium
- •Topical treatment of nostrils in the 3 days prior to baseline
- •Disturbing nasal aspects of secretions, erythema, crustae, ulcera, edema at baseline
- •Participation in a clinical study involving administration of a CFTR modulator
- •History of solid organ or haematological transplantation
- •History of alcohol, medication, or illicit drug abuse Exclusion criteria 1, 3, 4, 5, 6, 7 and 8 refer to known risk factors for the treatment with Orkambi®.
结局指标
主要结局
ICM Absolute change from baseline of the cumulative chloride secretory ion current response to forskolin/IBMX and carbachol in rectal tissue as a CFTR biomarker
时间窗: Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor
ICM will be performed according to the Standard Operating Procedure ICM_EU001, version 2.7 (October 2011) 'Ion Transport in Rectal Biopsies for Diagnosis and Clinical Trials in Cystic Fibrosis of the European Cystic Fibrosis Society (ECFS) Diagnostic Working Group \& Clinical Trials Network modified by in-house protocol adjustments at the CF electrophysiology laboratories in Hannover and Heidelberg as described by Graeber et al. (2015) \[39\]. Electronic files of the tracings will be evaluated on-site and at the CF Electrophysiology Laboratory at the University of Heidelberg.
次要结局
- Spirometry Absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1)(Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor)
- NPD Absolute change from baseline of the Sermet score of nasal transepithelial potential difference measurements (NPD) as a CFTR biomarker(Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor)
- Sweat chloride testing Absolute change from baseline of the chloride concentration in Gibson-Cooke pilocarpine iontophoresis sweat test as a CFTR biomarker(Measurement at the baseline visit within a 4-week interval prior to the start of oral treatment with lumacaftor and ivacaftor; second measurement at a day 10 - 14 weeks after the initiation of oral treatment with lumacaftor and ivacaftor)