Clinical trial NCT05576324: Effect of the CFTR-modulating Triple Therapy Elexacaftor - Tezacaftor - Ivacaftor
Official title: Effect of the CFTR-modulating Triple Therapy Elexacaftor - Tezacaftor - Ivacaftor on Numerical Distribution in Peripheral Mononuclear Immune Cells Derived From Patients With Cystic Fibrosis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis
Clinical parameters
Immune cell function
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2022-10-12
Enrollment: 130
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients who are under the care of the CF Center Erlangen at the time of the study and who meet the inclusion criteria will be considered for the patient collective.

Recruitment of healthy subjects will be performed during routine blood sampling in patients with pulmonary disease during outpatient appointments as well as during inpatient stays after prior informed consent has been obtained.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Peripheral Blood Immunograms
timeFrame: prior ETI
measure: Peripheral Blood Immunograms
timeFrame: 6 months ETI
Secondary outcomes:
measure: Shear Wave Velocity (SWV)
timeFrame: prior ETI
measure: Shear Wave Velocity (SWV)
timeFrame: 6 months ETI
measure: Attenuation Coefficient (AC)
timeFrame: prior ETI
measure: Attenuation Coefficient (AC)
timeFrame: 6 months ETI
measure: Serum bile acids
timeFrame: prior ETI
measure: Serum bile acids
timeFrame: 6 months ETI
measure: Respiratory function test (FEV1, FVC)
timeFrame: prior ETI
measure: Respiratory function test (FEV1, FVC)
timeFrame: 6 months ETI
measure: Blood cell count
timeFrame: prior ETI
measure: Blood cell count
timeFrame: 6 months ETI
measure: Erythrocytoid hemoglobin A1c
timeFrame: prior ETI
measure: Erythrocytoid hemoglobin A1c
timeFrame: 6 months ETI
measure: Plasma electrolytes
timeFrame: 6 months ETI
measure: Liver transaminases
timeFrame: prior ETI
measure: Liver transaminases
timeFrame: 6 months ETI
measure: Plasmatic bilirubin
timeFrame: prior ETI
measure: Plasmatic bilirubin
timeFrame: 6 months ETI
measure: Prothrombin time
timeFrame: prior ETI
measure: Prothrombin time
timeFrame: 6 months ETI
measure: Coagulation factors
timeFrame: prior ETI
measure: Coagulation factors
timeFrame: 6 months ETI
measure: Plasmatic albumine
timeFrame: prior ETI
measure: Plasmatic albumine
timeFrame: 6 months ETI
measure: Plasmatic C-reactive proteine
timeFrame: prior ETI
measure: Plasmatic C-reactive proteine
timeFrame: 6 months ETI
measure: Plasmatic cholinesterase
timeFrame: prior ETI
measure: Plasmatic cholinesterase
timeFrame: 6 months ETI
measure: Plasmatic glutamate dehydrogenase
timeFrame: 6 months ETI
measure: Plasmatic creatinin
timeFrame: prior ETI
measure: Plasmatic creatinin
timeFrame: 6 months ETI
measure: Serum immunoglobulins
timeFrame: prior ETI
measure: Serum immunoglobulins
timeFrame: 6 months ETI
measure: Sweat chloride
timeFrame: prior ETI
measure: Sweat chloride
timeFrame: 6 months ETI
measure: BMI
timeFrame: prior ETI
measure: BMI
timeFrame: 6 months ETI
measure: Age
timeFrame: prior ETI
measure: Microbial colonization status
timeFrame: prior ETI
measure: Microbial colonization status
timeFrame: 6 months ETI
measure: Individual concomitant medication regime
timeFrame: prior ETI
measure: Individual concomitant medication regime
timeFrame: 6 months ETI
measure: Functional pulmonary magnetic resonance imaging
timeFrame: prior ETI
measure: Functional pulmonary magnetic resonance imaging
timeFrame: 6 months ETI
measure: Neutrophilic dihydrorhodamine assay
timeFrame: prior ETI
measure: Neutrophilic dihydrorhodamine assay
timeFrame: 6 months ETI
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Hospital Erlange, Department of Pediatrics
state: Bavaria
Study officials:
References:
citation: Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL; VX16-445-001 Study Group. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1612-1620. doi: 10.1056/NEJMoa1807120. Epub 2018 Oct 18.
citation: Zemanick ET, Taylor-Cousar JL, Davies J, Gibson RL, Mall MA, McKone EF, McNally P, Ramsey BW, Rayment JH, Rowe SM, Tullis E, Ahluwalia N, Chu C, Ho T, Moskowitz SM, Noel S, Tian S, Waltz D, Weinstock TG, Xuan F, Wainwright CE, McColley SA. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2021 Jun 15;203(12):1522-1532. doi: 10.1164/rccm.202102-0509OC.
citation: McDonald TV, Nghiem PT, Gardner P, Martens CL. Human lymphocytes transcribe the cystic fibrosis transmembrane conductance regulator gene and exhibit CF-defective cAMP-regulated chloride current. J Biol Chem. 1992 Feb 15;267(5):3242-8.