Effect of the CFTR-modulating Triple Therapy Elexacaftor - Tezacaftor - Ivacaftor

Study Overview
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Brief Summary
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The aim of this study is to investigate the frequency distribution, cytokine profile and function of peripheral, mononuclear leukocyte populations (monocytes, NK cells, T/B lymphocytes) and their correlation to clinical and biochemical parameters in patients with cystic fibrosis receiving CFTR modulatory triple therapy consisting of elexacaftor, tezacaftor and ivacaftor and to compare it with patients without CFTR modulatory therapy and healthy control subjects.

Detailed Description
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The therapy of cystic fibrosis usually consists of an inhalative therapy with hy-pertonic saline and other mucolytics (e.g. dornase alpha) for secretolysis as well as a pancreatic enzyme replacement therapy. In recent years, however, the introduction of novel drugs, the so-called CFTR modulators, has revolutionized the previous treatment concept of a symptom-oriented therapy. Ivacaftor, which was approved by the FDA in 2012 for the treatment of patients with G551D mutation, causes a prolongation of the opening probability of the CFTR channel (CFTR potentiator) and was able to show a significant improvement in lung function in studies. By combining ivacaftor with the CFTR corrector lumacaftor, which improves the processing of the CFTR channel in the endoplasmic reticulum as well as its incorporation into the cell membrane, this therapeutic strategy has also been successfully tested for use in patients with F508del homozygous mutation. Also, the combination of ivacaftor with another CFTR corrector, tezacaftor, was approved for the treatment of patients with F508del heterozygous mutations in which the second mutation was classified as a mutation with residual activity and was able to show an increase in FEV1. The efficacy of this therapeutic approach was further enhanced by the combination of ivacaftor as a CFTR potentiator with tezacaftor and a next-generation CFTR corrector, elexacaftor; in the pivotal study, an improvement in FEV1 of an average of 14 points in untreated patients and 11 points in ivacaftor/tezacaftor-pretreated patients was demonstrated, as well as a significant decrease in hospitalizations due to pulmonary exacerbation. Since September 2020 in the European Union, this combination has been approved under the trade name Kaftrio® for the treatment of patients with F508del homozygous mutation or F508del heterozygous mutation and minimal function mutation. This form of therapy is based on a concept that comes closest to a causal therapy. In April 2021, the EMA granted approval for the drug for all patients older than 12 years and with evidence of at least one F508del mutation. In addition, the manufacturer applied for an extension of the approval in the EU for children aged 6-11 years based on the also very positive study results and received a positive decision from the European Medicines Agency (EMA) in November 2021. However, in addition to the clear role of the CFTR channel in epithelial tissues, it has been increasingly shown in recent years that the CFTR channel is also expressed by a variety of immune cells of the innate as well as the acquired immune system, such as neutrophils, macrophages, monocytes, and B and T lymphocytes. Its absence or dysfunction in cystic fibrosis seems to trigger a disturbed regulation or an exaggerated reaction of various immune responses.

Official Title
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Effect of the CFTR-modulating Triple Therapy Elexacaftor - Tezacaftor - Ivacaftor on Numerical Distribution in Peripheral Mononuclear Immune Cells Derived From Patients With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Elexacaftor / Ivacaftor / Tezacaftor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (m/f/d) with molecularly genetically confirmed cystic fibrosis aged 6 years and older. Do not meet any of the exclusion criteria Written informed consent For study arm Kaftrio® ongoing: Kaftrio® therapy for at least 6 months For study arm Kaftrio® longitudinal: no Kaftrio® therapy started yet Exclusion Criteria: Use of inhaled or systemic glucocorticoids as part of a permanent medication regimen Pregnancy

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| longitudinal<br>Inclusion of patients with diagnosed CF prior ETI therapy, follow-up visit after 6 months | Drug: Elexacaftor / Ivacaftor / Tezacaftor<br>* Elexacaftor / Ivacaftor / Tezacaftor is a triple drug therapy that modulates CFTR availability at (apical) cell membranes and increases opening probability.<br>* Other names: ETI, Kaftrio®;|
| under ETI<br>Patients with diagnosed CF already receiving ETI therapy for 6 months | Drug: Elexacaftor / Ivacaftor / Tezacaftor<br>* Elexacaftor / Ivacaftor / Tezacaftor is a triple drug therapy that modulates CFTR availability at (apical) cell membranes and increases opening probability.<br>* Other names: ETI, Kaftrio®;|
| no ETI<br>Patients with diagnosed CF that have refused an ETI treatment or are not eligible for ETI therapy | |
| Healthy Individuals<br>Healthy, age- and gender-matched probands | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral Blood Immunograms | Relative and absolute peripheral blood immune cell count as determined by multicolor flow cytometry | prior ETI | 
| Peripheral Blood Immunograms | Relative and absolute peripheral blood immune cell count as determined by multicolor flow cytometry | 6 months ETI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shear Wave Velocity (SWV) | Difference of mean/median SWV in treated vs. untreated patients as measured by Acoustic Radiation Force Impulse Imaging (ARFI) | prior ETI | 
| Shear Wave Velocity (SWV) | Difference of mean/median SWV in treated vs. untreated patients as measured by Acoustic Radiation Force Impulse Imaging (ARFI) | 6 months ETI | 
| Attenuation Coefficient (AC) | Difference of mean/median AC in treated vs. untreated pediatric patients (6-11 yrs) as measured by Ultrasound-guided attenuation parameter (UGAP) | prior ETI | 
| Attenuation Coefficient (AC) | Difference of mean/median AC in treated vs. untreated pediatric patients (6-11 yrs) as measured by Ultrasound-guided attenuation parameter (UGAP) | 6 months ETI | 
| Serum bile acids | Level of serum bile acids as measured by mass spectrometry | prior ETI | 
| Serum bile acids | Level of serum bile acids as measured by mass spectrometry | 6 months ETI | 
| Respiratory function test (FEV1, FVC) | Respiratory function test (FEV1, FVC) as measured by bodyplethysmography | prior ETI | 
| Respiratory function test (FEV1, FVC) | Respiratory function test (FEV1, FVC) as measured by bodyplethysmography | 6 months ETI | 
| Blood cell count | Blood cell count as defined in x10^3/µl | prior ETI | 
| Blood cell count | Blood cell count as defined in x10^3/µl | 6 months ETI | 
| Erythrocytoid hemoglobin A1c | Erythrocytoid hemoglobin A1c in % | prior ETI | 
| Erythrocytoid hemoglobin A1c | Erythrocytoid hemoglobin A1c in % | 6 months ETI | 
| Plasma electrolytes | Plasma electrolytes (Na, Cl) as defined by mmol/l | 6 months ETI | 
| Liver transaminases | Aspartate/Alanine aminotransferase (AST, ALt) as defined in U/l | prior ETI | 
| Liver transaminases | Aspartate/Alanine aminotransferase (AST, ALt) as defined in U/l | 6 months ETI | 
| Plasmatic bilirubin | Total and direct plasmatic bilirubin as defined in mg/dl | prior ETI | 
| Plasmatic bilirubin | Total and direct plasmatic bilirubin as defined in mg/dl | 6 months ETI | 
| Prothrombin time | Prothrombin time as defined by Quick percent | prior ETI | 
| Prothrombin time | Prothrombin time as defined by Quick percent | 6 months ETI | 
| Coagulation factors | Vitamin K- dependent coagulation factors (II, VII, IX, X) as measured in % | prior ETI | 
| Coagulation factors | Vitamin K- dependent coagulation factors (II, VII, IX, X) as measured in % | 6 months ETI | 
| Plasmatic albumine | Plasma levels of albumine (defined in g/dl) | prior ETI | 
| Plasmatic albumine | Plasma levels of albumine (defined in g/dl) | 6 months ETI | 
| Plasmatic C-reactive proteine | Plasmatic C-reactive proteine (defined in mg/l) | prior ETI | 
| Plasmatic C-reactive proteine | Plasmatic C-reactive proteine (defined in mg/l) | 6 months ETI | 
| Plasmatic cholinesterase | Plasmatic cholinesterase (defined in U/l) | prior ETI | 
| Plasmatic cholinesterase | Plasmatic cholinesterase (defined in U/l) | 6 months ETI | 
| Plasmatic glutamate dehydrogenase | Plasmatic glutamate dehydrogenase (defined in U/l) | 6 months ETI | 
| Plasmatic creatinin | Plasmatic creatinin (defined in mg/dl) | prior ETI | 
| Plasmatic creatinin | Plasmatic creatinin (defined in mg/dl) | 6 months ETI | 
| Serum immunoglobulins | Serum immunoglobulins G, A, M, E (defined in g/l) | prior ETI | 
| Serum immunoglobulins | Serum immunoglobulins G, A, M, E (defined in g/l) | 6 months ETI | 
| Sweat chloride | Sweat chloride level (defined in mmol/l) | prior ETI | 
| Sweat chloride | Sweat chloride level (defined in mmol/l) | 6 months ETI | 
| BMI | BMI in kg/m^2 | prior ETI | 
| BMI | BMI in kg/m^2 | 6 months ETI | 
| Age | Patients' age in years | prior ETI | 
| Microbial colonization status | Microbial colonization status as defined by microbiological reports | prior ETI | 
| Microbial colonization status | Microbial colonization status as defined by microbiological reports | 6 months ETI | 
| Individual concomitant medication regime | Individual concomitant medication regime | prior ETI | 
| Individual concomitant medication regime | Individual concomitant medication regime | 6 months ETI | 
| Functional pulmonary magnetic resonance imaging | Ventilation defect, perfusion defect, combined defects in longitudinal pediatric cohort (6-11 yrs) | prior ETI | 
| Functional pulmonary magnetic resonance imaging | Ventilation defect, perfusion defect, combined defects in longitudinal pediatric cohort (6-11 yrs) | 6 months ETI | 
| Neutrophilic dihydrorhodamine assay | Assay for determination of neutrophilic reactive oxygen species (measured as stimulation index) | prior ETI | 
| Neutrophilic dihydrorhodamine assay | Assay for determination of neutrophilic reactive oxygen species (measured as stimulation index) | 6 months ETI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic fibrosis, Clinical parameters, Immune cell function