Surrogate Markers of Response to New Therapies in Cystic Fibrosis Patients (BIO-CFTR)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Procedure: Nasal swab; rectal biopsy.

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Isabelle Sermet, MD, PhD; Phone Number: 33 1 44 49 48 87; Email: isabelle.sermet@aphp.fr
• Study Contact Backup: Name: Jean-Louis Pérignon, MD, PhD; Email: jean-louis.perignon@aphp.fr

Study Locations

• France
  • Paris, France, 75014
    • Recruiting
    • Necker Hospital
    • Contact: SERMET Isabelle, Professor; Phone Number: 01 44 49 48 87; Email: isabelle.sermet@nck.aphp.fr
    • Contact: LE Bourgeois Muriel, MD; Phone Number: 01 44 49 48 87; Email: isabelle.sermet@nck.aphp.fr
    • Principal Investigator: SERMET Isabelle, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cystic fibrosis, treated; Cystic fibrosis patients treated either by Ivacaftor or by the association Ivacaftor-Lumacaftor	Procedure: 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.
Other: Cystic fibrosis, non treated; Cystic fibrosis patients, non treated by a CFTR modulator	Procedure: 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.
Other: Non-Cystic fibrosis; Patients in whom cystic fibrosis diagnosis has been suspected, but excluded by physiological and genetic investigations	Procedure: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 second	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Vital Capacity	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Forced Expiratory Flow 25-75	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Residual Volume	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
elastase in sputum	elastase activity in UI/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
calprotectin in sputum	calprotectin in µg/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
IL-8 in sputum	IL-8 in µg/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Calprotectin in blood	calprotectin in µg/ml of blood	initiation, 1 month, 3 Months, 6 months and every 6 months
IL-8 in blood	IL-8 in µg/ml of blood	initiation, 1 month, 3 Months, 6 months and every 6 months
tumor necrosis factor in sputum	tumor necrosis factor in µg/g of sputum	initiation, 1 month, 3 Months, 6 months and every 6 months
liver function test in blood	serum glutamate oxaloacetate transaminase in ui/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
liver function test/SGPT in blood	serum glutamate pyruvate transaminase in ui/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
liver function test/bilirubin in blood	Bilirubin in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
liver function test, gammaGT in blood	GammaGT in UI/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
creatine phosphokinase in blood	CPK in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Amylase in blood	amylase in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Impedancemetry	ambulatory measurement of body composition	initiation , 1 month, 3 Months, 6 months and every 6 months
Dynamometry	ambulatory measurement of quadriceps strength	initiation , 1 month, 3 Months, 6 months and every 6 months
Sweat test	chloride concentration in sweat	initiation ,1 month
metabolomics of sweat	measurement of métabolites in sweat	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
proteomics of exhalate	measurement of proteins in exhaled air	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
sputum bronchial microorganism colonization	bacterial, fungi and viral colonization	initiation , 1 month, 3 Months, 6 months and every 6 months
osteodensitometry	Bone mineralization body composition	initiation, 1 year, and every year
glycemic Holter	glycemia monitoring	initiation, 1 year and every year
proton density fat fraction	magnetic resonance Imaging of the Pancreas	treatment initiation, 1 year
CFTR activity in nasal cells/chloride	Chloride transport in primary nasal cell cultures obtained by nasal brushing and study in Ussing chamber (µA/cm2)	initiation of treatment and repeated if cell culture failure
CFTR activity in nasal cells/bicarbonat	Bicarbonate transport in primary nasal cell cultures obtained by nasal brushing and study in Ussing chamber (µA/cm2)	initiation of treatment and repeated if cell culture failure
CFTR activity in intestinal epithelium/chloride	Chloride transport in intestinal primary culture and study in Ussing chamber (µA/cm2)	initiation of treatment and repeated of cell culture failure
CFTR activity in intestinal epithelium/bicarbonate	Bicarbonate transport in intestinal primary culture and study in Ussing chamber (µA/cm2)	initiation of treatment and repeated of cell culture failure
sweat evaporimetry	quantity of sweat produced afer bet-adrenergic stimulation after subcutaneous injection	initiation and 1 month
Elasto MRI	measurement of liver fibrosis by MRI	initiation and 1 year
Lung Clearance Index	Capacity of the lung to washout pure Oxygen,	initiation, 6 months, 1 year and every 6 months
proteomics in blood	measurement of proteins in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
metabolomics in blood	measurement of métabolites in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
proteomic in urine	measurement of proteins in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
Exhaled air composition	Volatile organic compounds in exhaled air	initiation, 7 days, 1 month, 6 months, 1 year and every year
proteomics of sweat	measurement of proteins in sweat	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Lung MRI	Lung Imaging evaluation : number of bronchiectasis, number of mucus plugs	initiation, at 1 year and every year
fecal elastase	elastase feces in µg/g feces	initiation, at 6 months and every year
fecal calprotectin	calprotectin, concentraion in feces in µg/g	initiation, at 6 months and every year
Chest CT scan	Lung Imaging: % versuys normal of lung parenchuma with bronchiectasis, airway wall thickening, mucus plugs, air trapping	initiation, 3 years and 5 years
abdominal ultrasonography	presence of liver hyperechogenicity, fibrosis, as assessed by the radiologist	treatment initiation, 1 year and every year
patient quality of life	Score tolerance of the treatment, perception of respiratory, digestive symptoms, energy, body image as assessed by the "Cystic Fibrosis Questionnaire" score a better quality of life is indicated by an increase in the score value. Minimum value is 0, maximum is 100.	initiation, 1 month, 6 months, 1 year and every 6 months
metabolomics in urine	measurement of métabolites in urine	initiation, 7 days, 1 month, 6 months, 1 year and every year

Collaborators and Investigators

• Sponsor: Hôpital Necker-Enfants Malades
• Collaborators: Association Mucoviscidose-ABCF2; Vaincre la Mucoviscidose
• Investigators: Study Director: Aleksander Edelman, phD, APHP

Publications and helpful links

General Publications

• 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/NEJMoa1409547. Epub 2015 May 17.
• 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.
• 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.
• 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.
• 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.
• 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 2014 Jun 24.
• 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. CFTR biomarkers: time for promotion to surrogate end-point. Eur Respir J. 2013 Jan;41(1):203-16. doi: 10.1183/09031936.00057512. Epub 2012 Aug 9.
• 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.
• Pranke I, Hatton A, Masson A, Flament T, Le Bourgeois M, Chedevergne F, Bailly C, Urbach V, Hinzpeter A, Edelman A, Sermet-Gaudelus I. Might Brushed Nasal Cells Be a Surrogate for CFTR Modulator Clinical Response? Am J Respir Crit Care Med. 2019 Jan 1;199(1):123-126. doi: 10.1164/rccm.201808-1436LE. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: November 11, 2016
• First Submitted That Met QC Criteria: November 11, 2016
• First Posted (Estimated): November 16, 2016

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: ABCF-2016-01; 2016-A00309-42 (Other Identifier: ANSM, French national agency for drug safety)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO