Surrogate Markers of Response to New Therapies in Cystic Fibrosis Patients

Cystic Fibrosis Clinical Trial

— BIO-CFTR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02965326
• Other study ID #: ABCF-2016-01
• Secondary ID: 2016-A00309-42
• Status: Recruiting
• Phase: N/A
• Start date: May 2016
• Est. completion date: October 2026

Study information

• Verified date: March 2024
• Source: Hôpital Necker-Enfants Malades
• Contact: Isabelle Sermet, MD, PhD
• Phone: 33 1 44 49 48 87
• Email: isabelle.sermet[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: October 2026
• Est. primary completion date: March 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

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.

Locations

Country	Name	City	State
France	Necker Hospital	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Hôpital Necker-Enfants Malades	Association Mucoviscidose-ABCF2, Vaincre la Mucoviscidose

Country where clinical trial is conducted

France, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Forced Expiratory Volume in 1 second	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	Forced Vital Capacity	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	Forced Expiratory Flow 25-75	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	Residual Volume	Respiratory Function test	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	elastase in sputum	elastase activity in UI/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	calprotectin in sputum	calprotectin in µg/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	IL-8 in sputum	IL-8 in µg/g of sputum	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	Calprotectin in blood	calprotectin in µg/ml of blood	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	IL-8 in blood	IL-8 in µg/ml of blood	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	tumor necrosis factor in sputum	tumor necrosis factor in µg/g of sputum	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	liver function test in blood	serum glutamate oxaloacetate transaminase in ui/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	liver function test/SGPT in blood	serum glutamate pyruvate transaminase in ui/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	liver function test/bilirubin in blood	Bilirubin in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	liver function test, gammaGT in blood	GammaGT in UI/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	creatine phosphokinase in blood	CPK in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	Amylase in blood	amylase in mg/ml	initiation, 1 month, 3 Months, 6 months and every 6 months
Secondary	Impedancemetry	ambulatory measurement of body composition	initiation , 1 month, 3 Months, 6 months and every 6 months
Secondary	Dynamometry	ambulatory measurement of quadriceps strength	initiation , 1 month, 3 Months, 6 months and every 6 months
Secondary	Sweat test	chloride concentration in sweat	initiation ,1 month
Secondary	proteomics of sweat	measurement of proteins in sweat	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	metabolomics of sweat	measurement of métabolites in sweat	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	proteomics of exhalate	measurement of proteins in exhaled air	initiation, 7 days, 1 month, 6 months, 1 year and every 6 months
Secondary	sputum bronchial microorganism colonization	bacterial, fungi and viral colonization	initiation , 1 month, 3 Months, 6 months and every 6 months
Secondary	Lung MRI	Lung Imaging evaluation : number of bronchiectasis, number of mucus plugs	initiation, at 1 year and every year
Secondary	osteodensitometry	Bone mineralization body composition	initiation, 1 year, and every year
Secondary	fecal elastase	elastase feces in µg/g feces	initiation, at 6 months and every year
Secondary	fecal calprotectin	calprotectin, concentraion in feces in µg/g	initiation, at 6 months and every year
Secondary	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
Secondary	glycemic Holter	glycemia monitoring	initiation, 1 year and every year
Secondary	abdominal ultrasonography	presence of liver hyperechogenicity, fibrosis, as assessed by the radiologist	treatment initiation, 1 year and every year
Secondary	proton density fat fraction	magnetic resonance Imaging of the Pancreas	treatment initiation, 1 year
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	sweat evaporimetry	quantity of sweat produced afer bet-adrenergic stimulation after subcutaneous injection	initiation and 1 month
Secondary	Elasto MRI	measurement of liver fibrosis by MRI	initiation and 1 year
Secondary	Lung Clearance Index	Capacity of the lung to washout pure Oxygen,	initiation, 6 months, 1 year and every 6 months
Secondary	proteomics in blood	measurement of proteins in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
Secondary	metabolomics in blood	measurement of métabolites in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
Secondary	proteomic in urine	measurement of proteins in blood	initiation, 7 days, 1 month, 6 months, 1 year and every year
Secondary	metabolomics in urine	measurement of métabolites in urine	initiation, 7 days, 1 month, 6 months, 1 year and every year
Secondary	Exhaled air composition	Volatile organic compounds in exhaled air	initiation, 7 days, 1 month, 6 months, 1 year and every year