Combined Effect of CFTR Protein Modulator Drugs and Exercise in Cystic Fibrosis

Study Overview
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Brief Summary
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This study aims to assess the effects of programmed exercise combined with CFTR protein modulator drugs in the cardiorespiratory fitness, strength, functional capacity and agility in a group of young patients with Cystic Fibrosis.

Detailed Description
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The present study is a new clinical trial that extends our previous work intended to assess the effect of programmed exercise with or without electrical stimulation on cardiorespiratory fitness, strength, functional capacity and agility in a group of young patients with Cystic Fibrosis (ECOMIRIN) registered at ClinicalTrials.gov (Identifier: NCT04153669). After finishing the study, a subset of the participants was treated with either TEZ/IVA or LUM/IVA per standard of care, as they were considered candidates according to the AEMPS (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-000833-37/ES). Those patients are expected to complete five months of pharmacological treatment without exercise by June 2020. Primary Objective To evaluate the effect of an exercise program on physical fitness in cystic fibrosis patients after 5 months of administration of LUM/IVA or TEZ/IVA in comparison to the effect produced by the same exercise program before administration of the drug. Secondary Objectives Other specific objectives include comparing the beneficial effects of exercise and LUM/IVA or TEZ/IVA on: 1) cardiorespiratory function and muscle strength; 2) the concentration of chlorine in sweat; and 3) quality of life.

Official Title
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Combined Effect of CFTR Protein Modulator Drugs and Exercise on Pulmonary Function, Fitness, Sweat Test and Quality of Life in Children With Cystic Fibrosis

Conditions
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Cystic Fibrosis in Children

Intervention / Treatment
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* Behavioral: Exercise
* Behavioral: Unsupervised exercise
* Drug: CFTR Modulators


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be included, patients must have participated in the ECOMIRIN clinical trial (ClinicalTrials.gov Identifier: NCT04153669). They must have a previous CF diagnosis, defined as: sweat chlorine ≥ 60 mEq/L and/or carry two variants of the CFTR gene characterized as pathogenic. Age 6-18 years; eligible to receive treatment with TEZ/IVA or LUM/IVA according to the AEMPS (LUM/IVA for 6-11 year-old children homozygous for the F508del mutation; TEZ/IVA for ≥ 12 year-old children homozygous for the Phe508del mutation, as well as heterozygous for the F508 mutation plus one of the following mutations: P67L, R117C, L206W, R352Q, A455E, D579G, 711 + 3A G, S945L, S977F, R1070W, D1152H, 2789 + 5G A, 3272-26A G, and 3849 + 10kbC T); Agreement to collaborate in performing static and dynamic pulmonary function tests. Consent of children and/or parents or legal guardians to participate in the study after having read and understood the informed consent form. Exclusion Criteria: CF patients not consenting to participate in the study at any time after reading and understanding the informed consent form will be excluded. CF patients who are not eligible to receive treatment with TEZ/IVA or LUM/IVA according to the AEMPS during the course of the study will be excluded. Study participants will be excluded if they test positive for any contagious viral infection that may affect the outcomes (e.g. SARS-CoV-2).

Ages Eligible for Study
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Minimum Age: 6 Years
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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-group non-randomized, prospective. Within-subject multitreatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multitreatment<br>Pharmacological treatment per standard of care (whole study length, starting on week 1). Supervised exercise protocol (phase 1, 8 weeks starting on week 9). Unsupervised exercise protocol (phase 2, 8 weeks starting on week 17). | Behavioral: Exercise<br>* Surpervised exercise program: Includes a concurrent exercise intervention (strength training and aerobic training), 3 days a week, 60 minutes sessions.<br>Behavioral: Unsupervised exercise<br>* Unsupervised exercise program: The same exercise program learned during the supervised phase will be practiced at home.<br>Drug: CFTR Modulators<br>* Standard of care: Lumacaftor with Ivacaftor or Tezacaftor combined with Ivacaftor. For children between 6 and 11 years of age, Lumacaftor 400 mg combined with Ivacaftor 500 mg in total per day, divided into 2 doses per day; for those over 11 years of age, Tezacaftor 100 mg combined with Ivacaftor 150 mg in the morning, adding a dose of Ivacaftor 150 mg at night. https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-000833-37/ES<br>* Other names: EudraCT Number 2019-000833-37;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Strength | Changes in strength will be measured using a five repetition maximum test (5RM) | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Change in Cardiorespiratory Fitness | Changes in cardiorespiratory fitness will be measured using a cardiopulmonary exercise test (CPET) | Four assessment points throughout the study: baseline and after each 8-week intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Forced expiratory volume in 1 second (FEV1) | Changes in FEV1 will be measured using Spirometry (z-score based on Global Lung Function Initiative reference DOI: 10.1016/j.arbres.2017.07.019) | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Changes in Forced vital capacity (FVC) | Changes in FVC will be measured using Spirometry (z-score based on Global Lung Function Initiative reference DOI: 10.1016/j.arbres.2017.07.019) | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Changes in FEV1/FVC ratio (FEV1%) | Changes in FEV1/FVC ratio (FEV1%) will be measured using Spirometry (z-score based on Global Lung Function Initiative reference DOI: 10.1016/j.arbres.2017.07.019) | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Changes in Forced expiratory flow (FEF) | Changes in FEF will be measured using Spirometry (z-score based on Global Lung Function Initiative reference DOI: 10.1016/j.arbres.2017.07.019) | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Changes in Physical Activity Questionnaire (PAQ) for children and adolescents | Changes in physical activity levels will be measured using PAQ-C for children under 14 years of age and PAQ-A for adolescents over 14 years of age. Items 1 to 9 will be used in the physical activity composite score, and means will be calculated to obtain the final PAQ-C activity summary score. Items 1 to 8 will be used in the physical activity composite score, and means will be calculated to obtain the final PAQ-A activity summary score. A score of 1 indicates low physical activity, whereas a score of 5 indicates high physical activity. | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Change in quality of life: Cystic Fibrosis-Questionnaire-Revised (CFQ-R) | Changes in quality of life will be measures with the Cystic Fibrosis-Questionnaire-Revised (CFQ-R). Scores for each health related quality of life domain are calculated; after recoding, each item is summed to generate a domain score and standardized. Scores range from 0 to 100, with higher scores indicating better health. | Four assessment points throughout the study: baseline and after each 8-week intervention | 
| Sweat chloride level | Chloride concentration in sweat (mEq/L) will be measured in the laboratory using an MK II Chloride Analyzer 926S | Four assessment points throughout the study: baseline and after each 8-week intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Electrostimulation, Combined Training, Physical Fitness