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

Primary Purpose

Cystic Fibrosis, Homozygous F508del Mutation

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Nasal brushing
Sputum sample
blood sample
Orkambi
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional other trial for Cystic Fibrosis focused on measuring CYSTIC FIBROSIS, ORKAMBI

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hôpital Necker-Enfants Malades

Outcomes

Primary Outcome Measures

Percentage of FEV1
Absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) from baseline to week 24 of Orkambi®

Secondary Outcome Measures

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
Percentage of FEV1
Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 48
% of FVC
Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48
% of RFC
Absolute change in percent predicted of Functional Residual Capacity (%RFC) from baseline through week 24 and 48
Lung clearance index
Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48
Height
Absolute change in height-for-age-z-score from baseline to week 24 and 48
Weight
Absolute change in weight-for-age-z-score from baseline to week 24 and 48
colony forming unit (CFU)
Absolute change in colony forming unit (CFU) of sputum microorganisms from baseline to week 24 and 48
Number of exacerbations
Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi®
Sweat Cl-
Absolute change in sweat Cl- from baseline to 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
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.
Area under the curve (AUC) of Lumacaftor/Ivacaftor
Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor
Drug concentrations of Lumacaftor/Ivacaftor
Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor

Full Information

First Posted
February 12, 2019
Last Updated
May 20, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT03894657
Brief Title
Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®.
Acronym
PREDICT-CF
Official Title
Validation of Respiratory Epithelial Functional Assessment to Predict Clinical Efficacy of Orkambi®. Pathway to Personalized Therapy in Cystic Fibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
December 18, 2019 (Actual)
Primary Completion Date
November 25, 2021 (Actual)
Study Completion Date
May 12, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis, Homozygous F508del Mutation
Keywords
CYSTIC FIBROSIS, ORKAMBI

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
91 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Diagnostic Test
Intervention Name(s)
Nasal brushing
Intervention Description
Nasal scrapping at visit V0
Intervention Type
Other
Intervention Name(s)
Sputum sample
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
blood sample
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Orkambi
Intervention Description
Study the predictive value for improvement of the respiratory function after 24 weeks of Orkambi treatment. Orkambi treatment is part of usual care.
Primary Outcome Measure Information:
Title
Percentage of FEV1
Description
Absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) from baseline to week 24 of Orkambi®
Time Frame
Baseline, Week 24
Secondary Outcome Measure Information:
Title
Z-score of FEV1
Description
Absolute change in the Z-score of forced expiratory volume in 1 second (FEV1) from baseline to week 24 and to week 48
Time Frame
Baseline, Week 24, week 48
Title
Percentage of FEV1
Description
Absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 48
Time Frame
Week 48
Title
% of FVC
Description
Absolute change in percent predicted of forced vital capacity (%FVC) from baseline through week 24 and 48
Time Frame
Baseline, Week 24 and week 48
Title
% of RFC
Description
Absolute change in percent predicted of Functional Residual Capacity (%RFC) from baseline through week 24 and 48
Time Frame
Baseline, Week 24 and week 48
Title
Lung clearance index
Description
Absolute change in lung clearance index 2.5 (LCI2.5) from baseline through Week 48
Time Frame
Baseline, Week 48
Title
Height
Description
Absolute change in height-for-age-z-score from baseline to week 24 and 48
Time Frame
Baseline, Week 24 and week 48
Title
Weight
Description
Absolute change in weight-for-age-z-score from baseline to week 24 and 48
Time Frame
Baseline, Week 24 and week 48
Title
colony forming unit (CFU)
Description
Absolute change in colony forming unit (CFU) of sputum microorganisms from baseline to week 24 and 48
Time Frame
Baseline, Week 24 and week 48
Title
Number of exacerbations
Description
Number of exacerbations to week 48 in comparison to the year previous treatment with Orkambi®
Time Frame
Baseline, Week 48
Title
Sweat Cl-
Description
Absolute change in sweat Cl- from baseline to week 48
Time Frame
Baseline, Week 48
Title
Level in Forskolin/IBMXdependant Short Circuit Current
Description
Level in Forskolin/IBMXdependant Short Circuit Current change in patient nasal epithelial (HNE) cells incubated with Lumacaftor/Ivacaftor
Time Frame
Baseline
Title
percentage of cells displaying apical staining
Description
Correction of CFTR expression at the apical membrane in HNE cells incubated with Lumacaftor/Ivacaftor, assessed by the percentage of cells displaying apical staining.
Time Frame
baseline
Title
Area under the curve (AUC) of Lumacaftor/Ivacaftor
Description
Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor
Time Frame
Week 24, week 48
Title
Drug concentrations of Lumacaftor/Ivacaftor
Description
Pharmacokinetic parameters of Lumacaftor, M28-lumacaftor, Ivacaftor, M1-ivacaftor, and M6-ivacaftor
Time Frame
Week 24, week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ISABELLE SERMET, PhD
Organizational Affiliation
Hospital Necker Enfants Malades
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Necker-Enfants Malades
City
Paris
State/Province
ILE DE France
ZIP/Postal Code
75015
Country
France

12. IPD Sharing Statement

Learn more about this trial

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

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