Impact of Elexacaftor-Tezacaftor-Ivacaftor Treatment on Metabolic, Epigenetic and Fecal Microbiota Profiles in People With Cystic Fibrosis.

Cystic Fibrosis (CF) is a genetic disease that affects multiple organs and systems. In recent years, the marketing of CFTR protein modulator drugs, such as the Elexacaftor-Tezacaftor-Ivacaftor (ETI) combination, has significantly improved patients' quality of life and prognosis. ETI, currently prescribed in Italy for CF patients over six years of age with at least one F508del mutation, has shown improvements in lung function, nutritional status, and a reduction in pulmonary exacerbations. In the coming months, ETI will be prescribable for patients aged $\ge$ 2 years with at least one F508del mutation; furthermore, the EMA recently approved its use in all patients aged $\ge$ 2 years, including those with mutations other than F508del (excluding patients with homozygous Class I mutations).Recent studies also highlight an impact on systemic metabolism, with an increase in blood cholesterol levels, blood pressure, and nutritional status, leading to a marked increase in patients with obesity. This could result in an increased long-term cardiovascular risk, especially in children with CF. Additionally, early data show that ETI also induces changes in the gut microbiota and epigenetic modifications by altering DNA methylation, particularly in genes crucial for the onset of CF-related complications, such as diabetes.The gut microbiota of CF patients differs from that of healthy controls, and ETI appears to improve microbial diversity while reducing intestinal inflammation and antibiotic resistance genes. Although ETI-related adverse events are mostly mild and similar to typical respiratory exacerbation symptoms (cough, headache, pharyngodynia, or transient bronchospasm), concerning side effects such as neuropsychiatric effects, intracranial hypertension, or liver failure have also been reported. Currently, it is not possible to predict which patients are at a higher risk of adverse events, but it is known that some of these are related to the blood levels of ETI's individual components. Therefore, monitoring these levels could be useful for dose optimization and reducing the risk of adverse events.Despite the publication of numerous real-world studies on the efficacy and safety of ETI and the sharing of recent standards of care for CF patients on modulator therapy, prospective studies are desirable, especially in the pediatric population. These are needed to monitor metabolic and epigenetic parameters, as well as changes in the fecal microbiota, correlating them with the blood levels of individual ETI components.

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis (CF)
• Intervention / Treatment: Drug: Elexacaftor, Tezacaftor, Ivacaftor

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Vito Terlizzi, Medical Doctor; Phone Number: +39 055 566 2474; Email: vito.terlizzi@meyer.it
• Study Contact Backup: Name: Cristina Fevola, Ph.D.; Phone Number: +39 055 566 2780; Email: cristina.fevola@meyer.it

Study Locations

• Italy
  • Florence, Italy, 5016
    • Recruiting
    • Azienda Ospedaliera Universitaria Meyer Istituto di Ricovero e Cura a Carattere Scientifico
    • Contact: Vito Terlizzi, MD; Phone Number: +39 055 566 2474; Email: vito.terlizzi@meyer.it
  • Bari
    • Bari, Bari, Italy
      • Not yet recruiting
      • Centro per la Fibrosi Cistica, Azienda Universitaria Ospedaliera Consorziale Policlinico
      • Contact: Giuseppina Leonetti; Phone Number: +39 080 5593552; Email: susy.leonetti@virgilio.it
  • Milano
    • Milan, Milano, Italy
      • Not yet recruiting
      • Dipartimento di Pediatria, Centro Fibrosi Cistica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
      • Contact: Valeria Daccò; Phone Number: +39 02 55032456; Email: valeria.dacco@policlinico.mi.it
  • Napoli
    • Napoli, Napoli, Italy
      • Not yet recruiting
      • Unità Pediatrica, Dipartimento di Scienze Mediche Traslazionali, Centro di Riferimento Regionale per la Fibrosi Cistica, Università degli Studi di Napoli Federico II
      • Contact: Angela Sepe; Phone Number: +39 081 746 3273; Email: ornellasepe@hotmail.com
  • Roma
    • Roma, Roma, Italy
      • Not yet recruiting
      • Ospedale pediatrico Bambino Gesù, IRCCS, Dipartimento Pediatrico Universitario Ospedaliero, UOC Pneumologia e Fibrosi Cistica
      • Contact: Federico Alghisi; Phone Number: +39 06 68592749; Email: federico.alghisi@opbg.net
  • Torino
    • Torino, Torino, Italy
      • Not yet recruiting
      • Centro per la Fibrosi Cistica, Ospedale Infantile Regina Margherita
      • Contact: Irene Esposito; Phone Number: +39 3402373611; Email: espirene75@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll patients with CF pre and post ETI therapy, followed up at included Italian CF centers.

Description

Inclusion Criteria:

• Patients with CF, of any age, about to start ETI therapy, in accordance with marketing authorization Italian legislative directives, followed at the participating CF centers.
• Obtaining informed consent.

Exclusion Criteria:

• CF patients not in ETI therapy and CF patients already in ETI therapy.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in DNA methylation level before and after the start of therapy	baseline, 3, 6, 9, 12, 24 months post-Elexacaftor, Tezacaftor, Ivacaftor

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference in serum levels of fatty acids, amino acids, sugars and cytokines.	baseline, 3, 6, 9, 12, 24 months post-Elexacaftor, Tezacaftor, Ivacaftor
Correlation between serum levels of fatty acids, amino acids, sugars and cytokines and plasma levels of individual components of the triple modulator therapy (Elexacaftor, Tezacaftor, Ivacaftor)	baseline, 3, 6, 9, 12, 24 months post-Elexacaftor, Tezacaftor, Ivacaftor

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2025
• Primary Completion (Estimated): November 30, 2028
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: January 15, 2026
• First Submitted That Met QC Criteria: January 15, 2026
• First Posted (Actual): January 23, 2026

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 23, 2026
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cystic Fibrosis; elexacaftor, ivacaftor, tezacaftor drug combination
• Other Study ID Numbers: MEM-ETI

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes