Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. (PREDICT-CF)

• ClinicalTrials.gov Identifier: NCT03894657
• Recruitment Status: Completed
• First Posted: March 28, 2019
• Last Update Posted: May 23, 2022
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis; Homozygous F508del Mutation	Diagnostic Test: Nasal brushing; Other: Sputum sample; Other: blood sample; Drug: Orkambi	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 91 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. Pathway to Personalized Therapy in Cystic Fibrosis
• Actual Study Start Date: December 18, 2019
• Actual Primary Completion Date: November 25, 2021
• Actual Study Completion Date: May 12, 2022

Arms and Interventions

Intervention Details:

• 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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of FEV1 [ Time Frame: 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 :

1. Z-score of FEV1 [ Time Frame: 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
2. Percentage of FEV1 [ Time Frame: Week 48 ]
   Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 48
3. % of FVC [ Time Frame: Baseline, Week 24 and week 48 ]
   Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48
4. % of RFC [ Time Frame: Baseline, Week 24 and week 48 ]
   Absolute change in percent predicted of Functional Residual Capacity (%RFC) from baseline through week 24 and 48
5. Lung clearance index [ Time Frame: Baseline, Week 48 ]
   Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48
6. Height [ Time Frame: Baseline, Week 24 and week 48 ]
   Absolute change in height-for-age-z-score from baseline to week 24 and 48
7. Weight [ Time Frame: Baseline, Week 24 and week 48 ]
   Absolute change in weight-for-age-z-score from baseline to week 24 and 48
8. colony forming unit (CFU) [ Time Frame: Baseline, Week 24 and week 48 ]
   Absolute change in colony forming unit (CFU) of sputum microorganisms from baseline to week 24 and 48
9. Number of exacerbations [ Time Frame: Baseline, Week 48 ]
   Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi®
10. Sweat Cl- [ Time Frame: Baseline, Week 48 ]
    Absolute change in sweat Cl- from baseline to week 48
11. Level in Forskolin/IBMXdependant Short Circuit Current [ Time Frame: Baseline ]
    Level in Forskolin/IBMXdependant Short Circuit Current change in patient nasal epithelial (HNE) cells incubated with Lumacaftor/Ivacaftor
12. percentage of cells displaying apical staining [ Time Frame: 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.
13. Area under the curve (AUC) of Lumacaftor/Ivacaftor [ Time Frame: Week 24, week 48 ]
    Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor
14. Drug concentrations of Lumacaftor/Ivacaftor [ Time Frame: Week 24, week 48 ]
    Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor

Eligibility Criteria

• Ages Eligible for Study: 5 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

France

Hôpital Necker-Enfants Malades

Paris, ILE DE France, France, 75015

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

• Principal Investigator: ISABELLE SERMET, PhD; Hospital Necker Enfants Malades

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03894657
• Other Study ID Numbers: P170907J; 2018-002624-16 ( EudraCT Number )
• First Posted: March 28, 2019
• Last Update Posted: May 23, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

CYSTIC FIBROSIS; ORKAMBI

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases