Cystic Fibrosis, Homozygous F508del Mutation
Conditions
Keywords
CYSTIC FIBROSIS, ORKAMBI
Brief summary
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
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.
Interventions
DIAGNOSTIC_TESTNasal brushing
Nasal scrapping at visit V0
OTHERSputum 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
OTHERblood 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
DRUGOrkambi
Study the predictive value for improvement of the respiratory function after 24 weeks of Orkambi treatment. Orkambi treatment is part of usual care.
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of FEV1 | Baseline, Week 24 | Absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) from baseline to week 24 of Orkambi® |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Z-score of FEV1 | Baseline, Week 24, week 48 | Absolute change in the Z-score of forced expiratory volume in 1 second (FEV1) from baseline to week 24 and to week 48 |
| Percentage of FEV1 | Week 48 | Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 48 |
| % of FVC | Baseline, Week 24 and week 48 | Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48 |
| % of RFC | Baseline, Week 24 and week 48 | Absolute change in percent predicted of Functional Residual Capacity (%RFC) from baseline through week 24 and 48 |
| Lung clearance index | Baseline, Week 48 | Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48 |
| Height | Baseline, Week 24 and week 48 | Absolute change in height-for-age-z-score from baseline to week 24 and 48 |
| Weight | Baseline, Week 24 and week 48 | Absolute change in weight-for-age-z-score from baseline to week 24 and 48 |
| colony forming unit (CFU) | Baseline, Week 24 and week 48 | Absolute change in colony forming unit (CFU) of sputum microorganisms from baseline to week 24 and 48 |
| Number of exacerbations | Baseline, Week 48 | Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi® |
| Sweat Cl- | Baseline, Week 48 | Absolute change in sweat Cl- from baseline to week 48 |
| Level in Forskolin/IBMXdependant Short Circuit Current | Baseline | Level in Forskolin/IBMXdependant Short Circuit Current change in patient nasal epithelial (HNE) cells incubated with Lumacaftor/Ivacaftor |
| percentage of cells displaying apical staining | baseline | Correction of CFTR expression at the apical membrane in HNE cells incubated with Lumacaftor/Ivacaftor, assessed by the percentage of cells displaying apical staining. |
| Area under the curve (AUC) of Lumacaftor/Ivacaftor | Week 24, week 48 | Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor |
| Drug concentrations of Lumacaftor/Ivacaftor | Week 24, week 48 | Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORISABELLE SERMET, PhD
Hospital Necker Enfants Malades
Outcome results
None listed