Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®.

Assistance Publique - Hôpitaux de Paris91 enrolled

Overview

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.

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

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Cystic Fibrosis Homozygous F508del Mutation

Interventions

Nasal brushingDIAGNOSTIC_TEST

Nasal scrapping at visit V0

Sputum sampleOTHER

Visit V0 : 1 Aliquot for Sputum biobank Visit V1 : 2 Aliquots * for Sputum biobank * for pharmacokinetic (PK) study Visit V2 : 2 Aliquots * for Sputum biobank * for pharmacokinetic (PK) study

blood sampleOTHER

Visit V0 : Additional 14 mL * 5 mL in ethylenediaminetetraacetic acid (EDTA) tube for DNA Analysis * 3 mL in Dry tube for Serum biobank * 6 mL in acid citrate dextrose (ACD) tube for peripheral blood mononuclear cell (PBMC) biobank Visit V1 : Additional 9 mL * 2x3 mL in dry tube for pharmacokinetic (PK) study * 3 mL in Dry tube for Serum biobank Visit V2 : Additional 6 mL * 3 mL in dry tube for pharmacokinetic (PK) study * 3 mL in Dry tube for Serum biobank

Eligibility

Sex: ALLMin age: 5 Years

Medical Language ↔ Plain English

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

Locations (1)

Hôpital Necker-Enfants Malades

Paris, Île-de-France Region, France

Outcomes

Primary Outcomes

Percentage of FEV1

Absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) from baseline to week 24 of Orkambi®

Time frame: Baseline, Week 24

Secondary Outcomes

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

Time frame: 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

Time frame: Week 48

% of FVC

Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48

Time frame: 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

Time frame: Baseline, Week 24 and week 48

Lung clearance index

Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48

Time frame: Baseline, Week 48

Height

Absolute change in height-for-age-z-score from baseline to week 24 and 48

Time frame: Baseline, Week 24 and week 48

Weight

Absolute change in weight-for-age-z-score from baseline to week 24 and 48

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.