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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cystic Fibrosis, Homozygous F508del Mutation

Intervention / Treatment
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* Diagnostic Test: Nasal brushing
* Other: Sputum sample
* Other: blood sample
* Drug: Orkambi


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Nasal brushing|Nasal scrapping at visit V0|
|Other: Sputum sample|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|
|Other: blood sample|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|
|Drug: Orkambi|Study the predictive value for improvement of the respiratory function after 24 weeks of Orkambi treatment. Orkambi treatment is part of usual care.|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYSTIC FIBROSIS, ORKAMBI