Response to CFTR Modulators in CF Patients Under 18 Years

Study Overview
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Brief Summary
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CFTR modulators should improve the prognosis of Cystic Fibrosis. Identifying patients under the age of 18 responding to CFTR modulators as well as detecting possible toxicity is an important medical objective given the potential side effects and the high cost of these molecules. This observational follow-up cohort study is carried out as part of routine care. The main objective is to assess the evolution of pulmonary structural impairment by low-dose CF scan at the end of the first year of CFTR modulator therapy. The secondary objectives are to evaluate structural impairment at low dose scan at 3 years and 5 years of CFTR modulator treatment, the evolution of respiratory functional parameters, growth, puberty, lung infection, sweat test, quality of life and pancreatic function, as well as tolerance of modulators including liver toxicity.

Detailed Description
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Cystic fibrosis (CF) is a deadly disease. This is due to overinfected chronic obstructive pulmonary disease that progresses to end-stage respiratory failure. CFTR modulators should improve the prognosis of CF, as they may slow the progression of patients' lung disease. Assessing their impact in the paediatric population is becoming a major issue. Children and adolescents under the age of 18 are a target cohort because they have a lung disease that is still poorly developed. Early prescription of CFTR modulators is therefore a priority but requires evidence of absence of toxicity. Identifying patients under the age of 18 responding to CFTR modulators as well as detecting possible toxicity, is an important medical objective given the potential side effects and the high cost of these molecules. The outcomes previously used in Phase III studies (FEV1, frequency of exacerbations, nutritional status) are insufficiently sensitive in this population. Other criteria need to be analyzed to identify the response to CFTR modulators in the short and medium term. The investigators hypothesize that the assessment of pulmonary structural impairment by low-dose lung CT-scan as part of routine care could be a much more sensitive criterion for the development of lung disease under CFTR modulators. This observational follow-up cohort study is carried out as part of routine care. It does not involve a specific collection for research. Excess bronchial secretions and blood will be kept instead of being discarded in the event of a possible requalification for research. The main objective is to assess the evolution of pulmonary structural impairment by low-dose CF scan at the end of the first year of CFTR modulator therapy The secondary objectives are to assess following criteria Tolerance of modulators in this age group, including screening for bronchial reactivity at treatment, early liver toxicity Longitudinal evolution of pulmonary structural impairment by low dose scan at 3 years and 5 years of CFTR modulator treatment Evolution of respiratory functional parameters Measurement by spirometry and plethysmography Lung clearance index (if possible) Longitudinal evolution of bacterial colonization, compared to the year prior to modulating treatment Exacerbations: number, duration, days of antibiotics, hospitalizations, return to stable condition Colonization of bronchial secretions Changes in quality of life Evolution of the sweat test Longitudinal evaluation of pancreatic function Longitudinal evaluation of growth and puberty compared to the year prior to CFTR modulator Growth speed, and bone age Bone mineralization, body composition (if possible) Pubertal markers from 9 years in girls and 10 years in boys Evaluation of glycemic dysregulation if present Preservation of samples taken as part of routine care (serum, bronchial secretions) for possible research use

Official Title
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Evaluation of the Response to CFTR Modulators in Patients With Cystic Fibrosis Less Than 18 Years of Age

Conditions
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Cystic Fibrosis in Children

Intervention / Treatment
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* Drug: CFTR Modulators


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children with cystic fibrosis under the age of 18 under CFTR modulator therapy Exclusion Criteria: Patients with cystic fibrosis without indication for CFTR modulator therapy Patients over the age of 18 Pregnant or lactating women

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CF children treated with CFTR modul<br>Cystic fibrosis patients under 18 years treated with CFTR modulators according to french health recommendations observational cohort study | Drug: CFTR Modulators<br>* CFTR modulators as recommended in routine care by the french health authorities<br>* Other names: Orkambi, Kalydeko...;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung Imaging | Lung structural injury assessed by Low Dose CT, as part of routine care | at initiation, as part of national guidelines | 
| Lung Imaging | Lung structural injury assessed by Low Dose CT, as part of routine care | at 1 year, as part of national guidelines | 
| Lung Imaging | Lung structural injury assessed by Low Dose CT, as part of routine care | at 3 years, as part of national guidelines | 
| Lung Imaging | Lung structural injury assessed by Low Dose CT, as part of routine care | at 5 years, as part of national guidelines | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| weight in kilogrammes | weight in kilogrammes (associated with a retrospective collection in the year prior to treatment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| height in meters | height in meters (associated with a retrospective collection in the year prior to treatment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| pubertal evolution | pubertal evolution (associated with a retrospective collection in the year prior to treatment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| bronchial infectious exacerbations | bronchial infectious exacerbations (associated with a retrospective collection in the year prior to treatment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Forced Expiratory Volume in 1 second(FEV1) | Forced Expiratory Volume in 1 second(FEV1) in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Forced Vital Capacity (FVC) | Forced Vital Capacity (FVC) in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Force Expiratory Flow 50 (FEV50) | Force Expiratory Flow 50 (FEV50) in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Forced Expiratory Flow 25-75 (FEV25-75) | Forced Expiratory Flow 25-75 (FEV25-75) in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Residual Volume (RV) | Residual Volume (RV) in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Total Pulmonary Capacity | Total Pulmonary Capacity in liter | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Lung Clearance Index - Lung Clearance Index | Lung clearance of nitrogen | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| colonization of bronchial secretions | bacteria, fungi, mycobacteria | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| quality of life questionnaire | CFQ questionnaire for children above 8 years: worse 0, better 100 | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| ENT quality of life questionnaire | SN-score: better score 1, worse 7 | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| Abdominal quality of life questionnaire | better score: 0, worse: 25 | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| liver ultrasound | liver ultrasound | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| elastometry (data available in centers with the necessary equipment) | elastometry (data available in centers with the necessary equipment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| sweat test | sweat collection | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| serum and fecal pancreatic biological markers | immunoreactive trypsin, lipase, amylase, vitamin A and E, Prothrombin time, and fecal (fecal elastase | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| bone biological markers | 25OHvitD, Ca, P, PTH, Osteocalcin, IgF1, IgF1BP3, CTX | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| bone maturation | Zscore (in relation to height and sex and weight) (data available in centers with the necessary equipment) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| puberty | serum dosage of FSH, LH, Estradiol, testosterone Pelvic ultrasound if puberty initiated in girls | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| intestine inflammation | fecal Calprotectine | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| glycemic regulation | monitoring of glycemic dysregulation ( as routinely done in the centers) | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs | 
| side effects: declarative collection and monitoring | declarative collection and monitoring | longitudinal monitoring of assessments carried out as part of routine care during 5 yrs |