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

Not Applicable

Completed

• Conditions: Homozygous F508del Mutation; Cystic Fibrosis

• Registration Number: NCT03894657
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

Study Timeline

• Study First Submitted: 2019-02-12
• Study First Submitted QC: 2019-03-27
• Study First Posted: 2019-03-28
• Study Start: 2019-12-18
• Primary Completion: 2021-11-25
• Status Verified: 2022-05
• Study Completion: 2022-05-12
• Last Update Submitted: 2022-05-20
• Last Update Posted: 2022-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 91

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
Lung clearance index	Baseline, Week 48	Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48
Area under the curve (AUC) of Lumacaftor/Ivacaftor	Week 24, week 48	Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor
% 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
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
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 FEV1	Week 48	Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) 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
Sweat Cl-	Baseline, Week 48	Absolute change in sweat Cl- from baseline to 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
Weight	Baseline, Week 24 and week 48	Absolute change in weight-for-age-z-score from baseline to week 24 and 48
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.
Number of exacerbations	Baseline, Week 48	Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi®
Drug concentrations of Lumacaftor/Ivacaftor	Week 24, week 48	Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor

Trial Locations

Locations (1)

Hôpital Necker-Enfants Malades; 🇫🇷 Paris, ILE DE France, France