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

Обзор

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.

Вмешательства

• Препарат Elexacaftor, Tezacaftor, Ivacaftor
  Patients with CF, of any age, about to start Elexacaftor, Tezacaftor, Ivacaftor therapy

Первичные конечные точки

• Difference in DNA methylation level before and after the start of therapy [Срок оценки: baseline, 3, 6, 9, 12, 24 months post-Elexacaftor, Tezacaftor, Ivacaftor]

Вторичные конечные точки (2)

• Difference in serum levels of fatty acids, amino acids, sugars and cytokines. [Срок оценки: 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) [Срок оценки: baseline, 3, 6, 9, 12, 24 months post-Elexacaftor, Tezacaftor, Ivacaftor]

Критерии участия

Критерии включения

• 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.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Италия · 6 центров

• Centro per la Fibrosi Cistica, Azienda Universitaria Ospedaliera Consorziale Policlinico — Bari
• Dipartimento di Pediatria, Centro Fibrosi Cistica, Fondazione IRCCS Ca' Granda Ospedale Ma — Milan
• Unità Pediatrica, Dipartimento di Scienze Mediche Traslazionali, Centro di Riferimento Reg — Naples
• Ospedale pediatrico Bambino Gesù, IRCCS, Dipartimento Pediatrico Universitario Ospedaliero — Roma
• Centro per la Fibrosi Cistica, Ospedale Infantile Regina Margherita — Torino
• Azienda Ospedaliera Universitaria Meyer Istituto di Ricovero e Cura a Carattere Scientific — Florence

Идентификаторы

NCT: NCT07363304 · MEM-ETI

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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