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

University of Erlangen-Nürnberg Medical School130 enrolled

Overview

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.

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.

Study Type

OBSERVATIONAL

Enrollment

130

Conditions

Cystic Fibrosis

Interventions

Elexacaftor / Ivacaftor / TezacaftorDRUG

Elexacaftor / Ivacaftor / Tezacaftor is a triple drug therapy that modulates CFTR availability at (apical) cell membranes and increases opening probability.

Eligibility

Sex: ALLMin age: 6 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

University Hospital Erlange, Department of Pediatrics

Erlangen, Bavaria, Germany

RECRUITING

Outcomes

Primary Outcomes

Peripheral Blood Immunograms

Relative and absolute peripheral blood immune cell count as determined by multicolor flow cytometry

Time frame: prior ETI

Peripheral Blood Immunograms

Relative and absolute peripheral blood immune cell count as determined by multicolor flow cytometry

Time frame: 6 months ETI

Secondary Outcomes

Shear Wave Velocity (SWV)

Difference of mean/median SWV in treated vs. untreated patients as measured by Acoustic Radiation Force Impulse Imaging (ARFI)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 6 months ETI

Serum bile acids

Level of serum bile acids as measured by mass spectrometry

Time frame: prior ETI

Serum bile acids

Central Contacts

Alexander Schnell, Dr. med.

CONTACT

+499131/8533118 alexander.schnell@uk-erlangen.de

Andre Hörning, PD Dr. med.

CONTACT

+499131/8533118 andre.hoerning@uk-erlangen.de

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.