Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. (PREDICT-CF)

Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. Pathway to Personalized Therapy in Cystic Fibrosis

The purpose of the study is to investigate whether the correction of CFTR function by Lumacaftor/Ivacaftor in a patient-derived primary nasal cell model is a surrogate biomarker for respiratory improvement in Orkambi® treated patients.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Homozygous F508del Mutation
• Intervention / Treatment: Diagnostic test: Nasal brushing; Other: Sputum sample; Other: blood sample; Drug: Orkambi

Detailed Description

Orkambi® is a combination of Ivacaftor (a CFTR channel potentiator) and Lumacaftor (a corrector partially rescuing the traffic of mutated CFTR). This treatment is now marketed in France for patients homozygotes for the mutation p.Phe508del, aged 12 and above. Systematic use of this product is a concern due to the lack of predictive markers of efficacy, the highly variable respiratory improvement in patients and potential serious side effects.

The purpose of this study is to investigate the predictive value for improvement of the respiratory function after 24 weeks of Orkambi treatment of an in vitro test. This test quantifies the correction of CFTR activity as assessed by the change of cyclic AMP (cAMP) dependant chloride (Cl-) secretion in patient derived Human Nasal Epithelial (HNE) derived primary culture after Lumacaftor/Ivacaftor 48 hours incubation.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Hôpital Necker-Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Homozygous F508del patient aged 5 years or older
• Patient with an indication for Orkambi® treatment according to the marketing authorization application
• Patient never received Orkambi® in the past
• Patient able to perform FEV1
• Signed Informed consent form by the patient (if aged ≥ 18 years), or by parents / legal guardian and patient's agreement (if aged < 18 years) Patient affiliated to the health insurance system

Exclusion Criteria:

• Homozygous F508del patients who do not meet the treatment indications according to the marketing authorization application
• Patients refusing Orkambi®
• CF patients not homozygous for the p.Phe508del mutation
• Active smoker
• Severe nasal mucosa disrepair
• Contraindications to xylocaine anesthesia,
• Participation with another interventional study with drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of FEV1	Absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) from baseline to week 24 of Orkambi®	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Z-score of FEV1	Absolute change in the Z-score of forced expiratory volume in 1 second (FEV1) from baseline to week 24 and to week 48	Baseline, Week 24, week 48
Percentage of FEV1	Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 48	Week 48
% of FVC	Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48	Baseline, Week 24 and week 48
% of RFC	Absolute change in percent predicted of Functional Residual Capacity (%RFC) from baseline through week 24 and 48	Baseline, Week 24 and week 48
Lung clearance index	Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48	Baseline, Week 48
Height	Absolute change in height-for-age-z-score from baseline to week 24 and 48	Baseline, Week 24 and week 48
Weight	Absolute change in weight-for-age-z-score from baseline to week 24 and 48	Baseline, Week 24 and week 48
colony forming unit (CFU)	Absolute change in colony forming unit (CFU) of sputum microorganisms from baseline to week 24 and 48	Baseline, Week 24 and week 48
Number of exacerbations	Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi®	Baseline, Week 48
Sweat Cl-	Absolute change in sweat Cl- from baseline to week 48	Baseline, Week 48
Level in Forskolin/IBMXdependant Short Circuit Current	Level in Forskolin/IBMXdependant Short Circuit Current change in patient nasal epithelial (HNE) cells incubated with Lumacaftor/Ivacaftor	Baseline
percentage of cells displaying apical staining	Correction of CFTR expression at the apical membrane in HNE cells incubated with Lumacaftor/Ivacaftor, assessed by the percentage of cells displaying apical staining.	baseline
Area under the curve (AUC) of Lumacaftor/Ivacaftor	Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor	Week 24, week 48
Drug concentrations of Lumacaftor/Ivacaftor	Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor	Week 24, week 48

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: ISABELLE SERMET, PhD, Hôspital Necker Enfants Malades

Publications and helpful links

General Publications

• Bouazza N, Urien S, Foissac F, Choupeaux L, Lui G, Froelicher Bournaud L, Rouillon S, Zheng Y, Bardin E, Stremler N, Bessaci K, Bihouee T, Coirier-Duet E, Marguet C, Deneuville E, Laurans M, Reix P, Gerardin M, Mittaine M, Epaud R, Thumerelle C, Weiss L, Berthaud R, Semeraro M, Treluyer JM, Benaboud S, Sermet-Gaudelus I. Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy. Clin Pharmacokinet. 2024 Mar;63(3):333-342. doi: 10.1007/s40262-023-01342-3. Epub 2024 Feb 4.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2019
• Primary Completion (Actual): November 25, 2021
• Study Completion (Actual): May 12, 2022

Study Registration Dates

• First Submitted: February 12, 2019
• First Submitted That Met QC Criteria: March 27, 2019
• First Posted (Actual): March 28, 2019

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: CYSTIC FIBROSIS; ORKAMBI
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cystic Fibrosis; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection; lumacaftor, ivacaftor drug combination
• Other Study ID Numbers: P170907J; 2018-002624-16 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No