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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Elexacaftor / Ivacaftor / Tezacaftor

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.

• Study Type: Observational
• Enrollment (Anticipated): 130

Contacts and Locations

• Study Contact: Name: Alexander Schnell, Dr. med.; Phone Number: +499131/8533118; Email: alexander.schnell@uk-erlangen.de
• Study Contact Backup: Name: Andre Hörning, PD Dr. med.; Phone Number: +499131/8533118; Email: andre.hoerning@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • University Hospital Erlange, Department of Pediatrics
      • Contact: Alexander Schnell, Dr. med.; Phone Number: +4991318533118; Email: alexander.schnell@uk-erlangen.de
      • Contact: André Hörning, PD Dr. med.; Phone Number: +4991318533118; Email: andre.hoerning@uk-erlangen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2020
• Primary Completion (Anticipated): October 18, 2023
• Study Completion (Anticipated): October 18, 2023

Study Registration Dates

• First Submitted: September 27, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 7, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Immune cell function; Clinical parameters
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor; Elexacaftor
• Other Study ID Numbers: CF-Immuno

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No