Surrogate Markers of Response to New Therapies in Cystic Fibrosis Patients

Официальное название

Personalized Therapy of Cystic Fibrosis: Set-up of Response Markers

Обзор

The purpose of this study is to determine which biological marker, or association of biological markers, best predict clinical response of cystic fibrosis patients to CFTR modulators.

Подробное описание

This study is based upon the hypothesis that clinical response of cystic fibrosis patients to CFTR modulators is correlated to in vitro responses to these drugs of epithelial cells derived from the patients, as assessed by CFTR-dependent Chloride secretion. Epithelial cells will be derived either from nasal or rectal epithelia, and consist both of cultured cells and organoids. The drugs tested will be Ivacaftor, or Lumacaftor/Ivacaftor, according to patient's treatment. Results of these assays will be compared with response to treatment at 6 and 12 months, assessed by clinical response and in vivo assay of CFTR function.

Вмешательства

• Процедура Nasal swab; rectal biopsy.
  Nasal epithelial cells will be obtained by nasal swabs from patients of the three arms; intestinal epithelial cells will be obtained, by rectal biopsy, only from patients treated by CFTR modulators.

Первичные конечные точки

• Forced Expiratory Volume in 1 second [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]

Вторичные конечные точки (12)

• Forced Vital Capacity [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• Forced Expiratory Flow 25-75 [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• Residual Volume [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• elastase in sputum [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• calprotectin in sputum [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• IL-8 in sputum [Срок оценки: initiation, 7 days, 1 month, 6 months, 1 year and every 6 months]
• Calprotectin in blood [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]
• IL-8 in blood [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]
• tumor necrosis factor in sputum [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]
• liver function test in blood [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]
• liver function test/SGPT in blood [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]
• liver function test/bilirubin in blood [Срок оценки: initiation, 1 month, 3 Months, 6 months and every 6 months]

Критерии участия

Критерии включения

• Cystic fibrosis patients treated by CFTR modulators (Ivacaftor or the association Ivacaftor-Lumacaftor)
• Cystic fibrosis patients non treated by CFTR modulators
• Patients in whom cystic fibrosis diagnosis has been suspected, but excluded by physiological and genetic investigations

Критерии исключения

• pregnant or lactating women
• contraindication to nasal swab
• contraindication to rectal biopsy

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Франция · 1 центр

• Necker Hospital — Paris

Публикации

• Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185. PMID 22047557
• Graeber SY, Hug MJ, Sommerburg O, Hirtz S, Hentschel J, Heinzmann A, Dopfer C, Schulz A, Mainz JG, Tummler B, Mall MA. Intestinal Current Measurements Detect Activation of Mutant CFTR in Patients with Cystic Fibrosis with the G551D Mutation Treated with Ivacaftor. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1252-5. doi: 10.1164/rccm.201507-1271LE. No abstract available. PMID 26568242
• Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, Vera-Llonch M. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015 Jul 2;13:93. doi: 10.1186/s12955-015-0293-6. PMID 26135562
• De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014 Dec;13(6):674-80. doi: 10.1016/j.jcf.2014.09.005. Epub 2014 Sep 26. PMID 25266159
• Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D; VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014 Jul;2(7):527-38. doi: 10.1016/S2213-2600(14)70132-8. Epub 2 PMID 24973281
• Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa14095 PMID 25981758
• De Boeck K, Kent L, Davies J, Derichs N, Amaral M, Rowe SM, Middleton P, de Jonge H, Bronsveld I, Wilschanski M, Melotti P, Danner-Boucher I, Boerner S, Fajac I, Southern K, de Nooijer RA, Bot A, de Rijke Y, de Wachter E, Leal T, Vermeulen F, Hug MJ, Rault G, Nguyen-Khoa T, Barreto C, Proesmans M, Sermet-Gaudelus I; European Cystic Fibrosis Society Clinical Trial Network Standardisation Committee. PMID 22878883
• Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NW, Bijvelds MJ, Scholte BJ, Nieuwenhuis EE, van den Brink S, Clevers H, van der Ent CK, Middendorp S, Beekman JM. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013 Jul;19(7):939-45. doi: 10.1038/nm.3201. Epub 2013 Jun 2. PMID 23727931

Идентификаторы

NCT: NCT02965326 · ABCF-2016-01 · 2016-A00309-42

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗