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

Cystic Fibrosis Clinical Trial

— PREDICT-CF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03894657
• Other study ID #: P170907J
• Secondary ID: 2018-002624-16
• Status: Completed
• Phase: N/A
• Start date: December 18, 2019
• Est. completion date: May 12, 2022

Study information

• Verified date: May 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: May 12, 2022
• Est. primary completion date: November 25, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Homozygous F508del Mutation

Intervention

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
• 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.

Locations

Country	Name	City	State
France	Hôpital Necker-Enfants Malades	Paris	ILE DE France

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

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