A retrospective analysis of clinical parameters, safety and tolerability of Elexacaftor/Tezacaftor/Ivacaftor in a cohort of patients aged 6-17 years with cystic fibrosis

Background Elexacaftor/Tezacaftor/Ivacaftor (ETI) improved clinical outcomes in patients with cystic fibrosis having at least one copy of the Phe508del CFTR mutation [1]. However, ETI safety and efficacy in pediatric setting is poorly documented. Methods A retrospective, single-center study of 27 patients, aged 6-17 years, followed for at least 6 months between October 2022 and March 2024, was performed. The primary outcome was to evaluate the change of lung function (ppFEV1 and ppFVC) at 6 and 12 months after the initiation of ETI. Secondary outcomes included the number of pulmonary exacerbations, nutritional status (BMI, z-score-weight and z-score-height), sweat chloride concentration (SwCl), CFQ-R score and adverse events. Results After 12 months of treatment, ETI improved the ppFEV1 from basal mean of 88 to 103 (p=0,013) and ppFVC absolute change of 6% after six months with value stabilization at subsequent follow-up. BMI z-score-weight and z-score-height improved over the 12-month treatment period when compared to the pretreatment baseline. SwCl decreased rapidly through week 24, with a mean treatment difference of −44 mmol/L compared to mean baseline value (p<0.001). PEx rate decreased by 27,6 % after 12 months of treatment. CFQ-R score increased by 14 points from baseline (p<0,001). AEs occurred in 14.8% (n=4) of patients. All adverse events were reversible and mild to moderate in severity and they disappeared with dosage reduction. Conclusions ETI therapy improved lung function, nutritional status and quality of life in pediatric patients. ETI resulted in an acceptable adverse event and tolerability profile with no permanent treatment discontinuations. A retrospective analysis of clinical parameters, safety and tolerability of Elexacaftor/Tezacaftor/Ivacaftor in a cohort of patients aged 6-17 years with cystic fibrosis Nicola Perrotta 1,2 *, Luigi Angelo Fiorito 1,2, Rossella Gentile 1,2, Roberta Vescovo 2, Alfonso Piciocchi 4, Roberto Poscia 5,6, Giuseppe Cimino 3 Affiliations: 1 Department of Physiology and Pharmacology ”V. Erspamer”, Sapienza University, 00161 Rome, Italy 2 Pharmacy Unit, AOU Policlinico Umberto I- Sapienza University, 00161 Rome, Italy 3 Cystic Fibrosis Center, AOU Policlinico Umberto I - Sapienza University, 00161 Rome, Italy 4 Biostatistics Unit, GIMEMA Foundation, 00182 Rome, Italy 5 Clinical Research Unit, AOU Policlinico Umberto I- Sapienza University, 00161 Rome, Italy 6 Interdepartmental Center for Rare Diseases, AOU Policlinico Umberto I- Sapienza University, 00161 Rome, Italy *Correspondence to: Dr. Nicola Perrotta. E-mail: [email protected]. Tel.: +39-0649971. https://orcid.org/0000-0002-0809-5118

Elexacaftor/Tezacaftor/Ivacaftor (ETI) improved clinical outcomes in patients with cystic fibrosis having at least one copy of the Phe508del CFTR mutation [1]. However, ETI safety and efficacy in pediatric setting is poorly documented.

A retrospective, single-center study of 27 patients, aged 6-17 years, followed for at least 6 months between October 2022 and March 2024, was performed. The primary outcome was to evaluate the change of lung function (ppFEV1 and ppFVC) at 6 and 12 months after the initiation of ETI. Secondary outcomes included the number of pulmonary exacerbations, nutritional status (BMI, z-score-weight and z-score-height), sweat chloride concentration (SwCl), CFQ-R score and adverse events.

After 12 months of treatment, ETI improved the ppFEV1 from basal mean of 88 to 103 (p=0,013) and ppFVC absolute change of 6% after six months with value stabilization at subsequent follow-up. BMI z-score-weight and z-score-height improved over the 12-month treatment period when compared to the pretreatment baseline. SwCl decreased rapidly through week 24, with a mean treatment difference of −44 mmol/L compared to mean baseline value (p<0.001). PEx rate decreased by 27,6 % after 12 months of treatment. CFQ-R score increased by 14 points from baseline (p<0,001). AEs occurred in 14.8% (n=4) of patients. All adverse events were reversible and mild to moderate in severity and they disappeared with dosage reduction.

ETI therapy improved lung function, nutritional status and quality of life in pediatric patients. ETI resulted in an acceptable adverse event and tolerability profile with no permanent treatment discontinuations.

Elexacaftor-Tezacaftor-Ivacaftor; cystic fibrosis; pediatric setting; effectiveness; safety;

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is involved in the regulation of chloride and bicarbonate across the apical membrane of epithelial cells [2]. Defective CFTR protein results in a reduction in chloride secretion and an increase in sodium absorption, followed by an osmotic uptake of water, leading to the production of thick fluid secretions. Besides, pulmonary inflammation leads to the development of pathogens, as Staphylococcus Aureus and Pseudomonas Aeruginosa that can increase respiratory infections [3]. However, CF is a multisystem disease that affects various organs, resulting in pancreatic insufficiency, biliary and gut obstruction, and male infertility [4]. Until recently, the medical treatment of cystic fibrosis was mainly restricted to improve the symptoms of the disease. A triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ETI), was approved in June 2021 by Italian Medicines Agency (AIFA) for the treatment of people with CF (PwCF) carrying one or two copies of the Phe508del CFTR mutation [5]. In phase 3 randomized clinical trials, ETI was found to be safe and effective, improving the pulmonary function and nutritional status [6-7] Furthermore, ETI has demonstrated unprecedented clinical benefit including improvements in lung function, respiratory symptoms and nutritional outcomes in children through an open-label phase 3 study and a randomized, placebo-controlled trial, respectively [8-9]. Consequently, in September 2022 AIFA approved the use of ETI in children aged six and older who have at least one copy of the Phe508del mutation [10]. Nevertheless, further real-world data are required to define the efficacy and safety of ETI in a larger and heterogeneous population and to provide a better understanding of the disease in the real clinical context. This is particularly useful in the case of children with severe pulmonary function, who are generally excluded from clinical trials.

Study design and objectives This study is a retrospective, single-center, observational cohort investigation conducted at the CF Regional Reference Centre, Umberto I University Hospital, Rome, Italy, between October 2022 and March 2024. It aimed to evaluate the effects of ETI therapy in pediatric patients with CF aged 6-17 years who were followed for a minimum of six months. The patients were divided into two age groups: 6-11 years and 12-17 years at the baseline. ETI treatment was administered to all eligible patients according to national guidelines based on body weight. Children weighing less than 30 kg received Elexacaftor 100 mg once daily, Tezacaftor 50 mg once daily, and Ivacaftor 75 mg twice daily. For those weighing 30 kg or more, the doses were increased to Elexacaftor 200 mg once daily, Tezacaftor 100 mg once daily, and Ivacaftor 150 mg twice daily. The primary focus of the study was to assess the absolute changes in lung function in accordance with the international standards [11], specifically the percent predicted forced expiratory volume in one second (ppFEV1) and percent predicted forced vital capacity (ppFVC), measured at six- and twelve-months post-therapy initiation. The study also examined pulmonary exacerbation rates (PEx), defined as hospitalizations or the need for intravenous antibiotics due to exacerbation of the disease. PEx data were collected for 12 months before and after starting treatment. Baseline lung function was obtained from the last spirometric measurement taken before the start of therapy. The study also analyzed improvements in lung function among individuals with different degrees of lung impairment, including severe impairment (ppFEV1 < 40%), moderate impairment (40 < ppFEV1 < 70) and normal lung function. Secondary outcomes included changes in nutritional status [body mass index (BMI), weight z-score and height z-score], sweat chloride levels (SwCl), and quality of life as assessed through the Cystic Fibrosis Questionnaire-Revised (CFQ-R), administered at baseline, six months, and twelve months. Data on adverse events, microbial colonization, mortality, and the rate of lung transplantation were also collected as secondary endpoints. Participants The inclusion criteria for participants were specific to subjects aged 6-17 years with confirmed CF and homozygosity or heterozygosity for the Phe508del CFTR mutation. Exclusion criteria included patients under the age of six, those requiring mechanical ventilation, those with severe hepatic impairment, or those with a history of organ transplantation. Clinical and analytical data such as lung function tests (ppFEV1, ppFVC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase, and bilirubin levels were collected from electronic medical records, along with details on the CFTR mutation genotype, treatment regimens, and complications related to CF, such as bronchial bacterial colonization and hospitalizations. The study was approved by the local ethics committee (reference number 7096) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents or legal guardians of each participant, and the children were asked to provide assent to participate according to national legislation. Statistical Analysis Descriptive analysis of the data was performed. The Shapiro-Wilk test was conducted to assess normality, given the small sample size. ANOVA (Analysis of Variance) was employed to evaluate the variance of ppFEV1, ppFVC, BMI, SwCl and CFQ-R. To support the analysis, scatter plots, boxplots and bubble chart were performed for each variable mentioned, allowing for a visual assessment of the relationships and distributions. All tests were 2-sided, accepting p<0.05 as statistically significant and confidence intervals were calculated at 95% level. All analyses were performed using R software (R Core Team 2022) [12].

From October 2022 to March 2024, 27 patients were observed over a period of 6 and 12 months from baseline. The median age was 12 years (11.0, 16.0). Patients were divided into two age groups: 6-11 years (n=10) and 12-17 years (n=17). The majority of patients (88.9%) were in homozygosity for the CFTR Phe508del mutation, while comorbidities accounted for 96% of the entire cohort. Pancreatic insufficiency was evident in all patients, with one male patient (aged 16 years) displaying signs of infertility. No cases of diabetes or hepatopathy were observed. The baseline characteristics of the study population are presented in Table 1. Pulmonary function ETI demonstrated a rapid and sustained increase in absolute change in ppFEV1 of 11 percentage points at 6 months and 15% at 12 months follow-up compared to baseline (p = 0.013) (Table 2). There was no statistically significant difference between the age groups at six months (p=0.96) and at subsequent follow-up (p=0.73) (Table 3). Both patient cohorts started from similar baseline ppFEV1 values (87±26 for children and 89±17 for adolescents) and reached the same value at T6 (ppFEV1=99). A further increase was observed at T12, with final absolute changes from baseline of 18% and 14% for the 6-11- and 12-17-years groups, respectively. Only one patient had a severe lung impairment (ppFEV1=30) at baseline. This value has increased by 15% and 19% after 6 and 12 months, respectively. Furthermore, PwCF with baseline ppFEV1 between 40 and 70 showed a marked and progressive increase in ppFEV1 of 35% (99±3) and 46% (110±3) at 6 and 12 months. The absolute change in this cohort of patients was significantly higher than in patients with a baseline ppFEV1>70 (p=0.005) (Table 3). PwCF with ppFEV1>70 exhibited a mean increase of 7% at six months, with an 8% increase observed at 12 months respect to the baseline. Although the absolute change in mean ppFVC wasn’t statistically significant (p=0.30), an increase of 8% was observed after six months of ETI compared to baseline, with values stabilizing at 114±15 after 12 months (Table 2). Nutritional status Although ETI therapy resulted in a progressive improvement in BMI (+0.8 kg/m2 and +2.4 kg/m2 at 6 and 12 months, respectively), the absolute change in total BMI (p=0.16), weight z-score (p=0.63) and height z-score (p=0.72) was not statistically significant (Tab.2). The distribution of the z-score for weight and height from baseline at each study visit, stratified by age group, is shown in Figure 3. Pulmonary exacerbation rate In the 12 months prior to ETI treatment, 46.1% (n=13) of patients required hospitalization or intravenous antibiotics, including 5 patients with at least one episode, 3 with at least two episodes, 2 with at least three episodes and 2 with at least five episodes. However, 12 months after the initiation of ETI therapy, the frequency of infectious exacerbations had significantly decreased to 18.5% of PwCF (n=5), with four patients experiencing more than two episodes per year 12 months after initiating ETI treatment. Sweat chloride concentration test Total sweat chloride concentrations decreased rapidly through week 24, with a mean treatment difference of −44 mmol/L compared to mean baseline value (p<0.001) (Table 2). This statistically significant improvement was maintained at 12 months after starting treatment, with values fluctuating up to 46 (±25) mmol/L. No statistically significant differences were observed among age groups (p= 0.87). Microbial colonization The prevalence of the most common chronic infections among pediatric patients was reported in Figure 1 (n=27). The figure illustrates the percentage of bacterial colonization from 12 months prior to treatment to 12 months post-ETI, with a three-month interval between each follow-up. All the pathogens analyzed demonstrated a significant reduction in the number of infections following the initiation of ETI treatment, particularly after six months of treatment. The percentage of infections decreased 12 months after ETI, from 11.4% to 4.2% for S. aureus, from 12.6% to 3.2% for rugose P. aeruginosa, and from 6.5% to 1.2% for K. pneumoniae (Fig. 1). A bubble chart showed the rates of chronic infections, stratified according to the age groups (Fig.2). CFQ-R respiratory domain scores The CFQ-R scores increased significantly from 76 (±4) to 90 (±2) through six months, with a mean treatment difference of 14 points from the baseline score (Tab.2). This result was maintained at 12 months (95% CI, p<0.001). Safety AEs occurred in 14.8% (n=4) of patients, all of which were reversible and mild to moderate in severity. The majority of patients who experienced AEs were effectively managed with dose modifications, which resulted in the resolution of symptoms. However, a skin rash was reported in a child following the administration of ETI. This patient discontinued treatment due to toxicity. He was treated with antihistamines and saline, and subsequently continued ETI with a reduced dosage. Two cases of elevated transaminase levels (AST/ALT: 100/110 U/L) were observed in adolescents after 3 and 6 months of treatment with ETI, respectively. When the dose was reduced by 50% and Ivacaftor administration was discontinued at night, transaminase levels decreased to within the normal range. Furthermore, one adolescent exhibited elevated serum creatine phosphokinase (CPK) levels of 550 U/L. Subsequent to a reduction in dosage, these levels returned to a value slightly above the normal range.

The significant benefits on lung function, global clinical parameters, microbiological and nutritional status have led to results never seen before with other CFTR modulators, as evidenced by the findings of several studies [13,7,14,15]. Nevertheless, there is a notable absence of evidence in the existing literature regarding the long-term use of ETI in pediatric population, especially on safety data. ETI therapy was well tolerated, overall safe with an acceptable side-effect profile, and effective in improving lung parameters in our cohort of children and adolescents with CF. All measured parameters exhibited notable enhancements in lung function, BMI, SwCl, PEx and CFQ-R scores within the initial six-month period of therapy. Moreover, a positive trend was observed during the 12-month follow-up period following ETI treatment. The overall increase in ppFEV1 in the entire study cohort (6-17 years) after 24 weeks with ETI was 11%, with a further increase in values at 12 months (+15%); additionally, ppFVC showed no significant changes (p = 0.30) and remained relatively stable over time, likely due to high baseline values. Our results are in line with a similar retrospective observational study [16] who observed an improvement of absolute change in ppFEV1 of 11.4 points after 3 months of ETI (95% CI: 8.0-14-9, n=45, p<0.0001). This effect was maintained at 6 months with a mean increase in ppFEV1 of 12.8%. In addition, the mean absolute change from baseline in lung function tests was not significantly different between our two groups (6-11 and 12-17 years), supporting the hypothesis that the clinical benefit of ETI is independent of age. The pulmonary improvement observed in our group of PwCF aged 6-11 years was comparable to the results of two-phase III clinical trials in pediatric patients. In the first study[8], authors found a 10.2% increase in ppFEV1 compared to baseline in children carrying at least one Phe508del mutation; in the second study[9], treatment with ETI resulted in a mean change in ppFEV1 of 9.5 percentage points (95% CI, 6.6-12.4). Our data from the 12-17 year old group were consistent to the pivotal trial [7], which included patients aged 12 years or older with Phe508del-minimal function genotypes; ETI resulted in a ppFEV1 that was 14.3 points higher through 24 weeks. A subgroup analysis stratified by lung disease severity revealed that subjects with ppFEV1 less than 70% and greater than 40% at baseline showed the most marked improvements, with significant absolute changes during the entire study period (+46%; p<0.001). However, despite the results align with the hypotheses proposed by certain authors [16,17], we suggest considering the possibility of bias due to the limited sample size of these subjects. Therefore, the results must be cautiously interpreted and confirmed on a larger population. The data presented here are comparable to those reported in another study [18], which analyzed patients older than 12 years with advanced lung disease. According to the authors, the efficacy of ETI in patients with severe lung impairment can be assessed within a few weeks of treatment initiation. Indeed, patients with low lung function at baseline and a high frequency of PEx in the year prior to starting ETI therapy demonstrated a significant increase in lung function. These results suggest the efficacy of ETI in this subgroup of PwCF, in contrast to the moderate clinical improvements observed with other CFTR modulators [19-20]. Furthermore, ETI demonstrated positive effects in reducing the number of pulmonary exacerbations (-27.6%), improving respiratory symptoms. Similar results were also recorded in a recent study including 34 children aged 6‐11 years [21]. We agree with the authors that recurrent respiratory infections, which affect up to 25% of children in the first years of life, are generally self-limiting and not CF-dependent [21,22]. Although PEx is an important indicator of disease severity in adults, it may be less reliable as a prognostic factor and indicator of disease progression in the pediatric population. The progressive increase in BMI suggests a potential improvement in growth parameters and nutritional status, independent of age group, which is also supported by the gradual increase in weight z-scores at 6 months (0.28 ± 0.96) and 12 months (0.33 ± 0.91), compared to baseline (0.09 ± 0.99). Although these changes are positive, they were not statistically significant (p=0.63). However, the height z-score showed minimal changes from baseline (-0.14 ± 1.01) to 6 months (-0.32 ± 0.90) and 12 months (-0.33 ± 0.87), with slight improvements observed only in the 6-11 years cohort. Similar results are consistent with a Phase III study [8]. It is important to consider the potential individual variations in response to treatment, as children with CF often experience growth delays that may be more challenging to correct in the short term with treatment. Different studies have demonstrated that patients with CF exhibit low levels of insulin-like growth factor-1 (IGF-1) [23], which is involved in the function of growth hormone (GH), thereby modulating the GH/IGF-1 axis. A modification of this axis has the potential to interfere with the normal growth process [24]. Therefore, as shown in mouse models, mutations in the CFTR gene may result in altered GH secretion and action [25]. These observations suggest a more complex mechanism that still requires further understanding. The mean sweat chloride concentration in the overall population decreased significantly after six months (-44 mmol/L; p<0.001), with values stabilizing at subsequent follow-up, in line with clinical trials [7,8,9]. In both age groups, mean SwCl concentrations fell below the diagnostic threshold for CF of 60 mmol/L by six months. This marked reduction in sweat chloride levels suggests that ETI treatment has a strong effect on correcting the underlying CFTR dysfunction. The rapid and sustained improvement in ppFEV1 was reflected in an increase in the CFQ-R score, which increased by 14 points to a final score of 90±2 (p<0.001) at 12 months in the overall population. Both groups showed a significant change in the CFQ-R score after starting treatment with ETI. These results highlight the key role of ETI in the recovery of respiratory function and thereby improving quality of life. No patients aged 6-17 years reported serious adverse events, demonstrating the good tolerability and safety profile of ETI in this patient cohort. Our findings reported in children were similar to that observed in a Phase III study[8]. There were no deaths or patients placed on the lung transplant waiting list during the study period analyzed. A total of 14.8% of patients experienced adverse events, most of which resolved quickly with a reduction in the daily dose. Toxicity was usually manageable, through transient interruption, or dose reduction. One child developed a skin rash immediately after administration of ETI, requiring discontinuation of therapy and administration of antihistamines and saline. The rechallenge with half dosage was well tolerated and no AEs were reported during the study. Two adolescents showed transaminase elevations, with values doubled from baseline at 3 and 6 months, respectively, after starting ETI treatment. In both cases, the levels decreased after the dose of ETI was reduced. Another adolescent had elevated serum CPK levels (550 U/L). These values returned to levels slightly above the normal range after the dose was reduced. Elevation of liver enzymes and CPK are well-known side effects of CFTR modulators therapy [7,8,9] that affect a small percentage of PwCF, resolving in most cases with a reduced dose. However, careful monitoring of ETI plasma concentrations is required, especially in pediatric patients with a different pharmacokinetic profile that could lead to increased ETI blood concentrations [26]. Therefore, the safety data are still immature, and longer follow-up is needed to draw more definitive conclusions about the impact of ETI on the toxicity profile in a real-world pediatric population. It should be noted that this study is not without limitations. Potential study limitations are the small sample size, the retrospective design and the lack of a control group, which limits the precision of the ETI treatment effect estimates. However, we attempted to overcome this bias by comparing two pediatric populations despite having different respiratory function characteristics at baseline. A strength of our study is the focus on microbiological analysis of sputum before and after ETI treatment, stratified by age group and across the entire population. Significant reductions in P. aeruginosa and S. aureus positivity were observed in the overall setting after 12 months of ETI treatment, in agreement with some studies [27, 28] (Fig. 1). The prevalence of common CF pathogens in respiratory cultures varied over time according to age (Fig. 2). A higher colonization of S. aureus, H. influenzae, rugose and mucoid P. aeruginosa was observed in the 12-17 years cohort compared to the 6-11 years group. Overall, our findings demonstrated a reduction in all bacteria analyzed after ETI treatment, with no significant change observed in H. influenzae in either group (Fig.2). The discovery of this triple therapy, combined with increasingly early neonatal screening, has resulted in a substantial enhancement in the survival rates of PwCF [29]. These improvements have a positive impact on both the symptomatological (in terms of improved lung function, increased energy levels and weight gain) and psychological well-being of pediatric patients, with an improved quality of life and a consequent increase in life expectancy. In fact, the reduction in pulmonary exacerbations, resulting in fewer hospitalizations or the need for intravenous antibiotics, has enabled the children to attend school regularly and to be fully integrated into social life on a par with their peers. Furthermore, subjects with impaired lung function or at high risk of developing impairment showed a greater increase in ppFEV1 than patients with less critical clinical conditions at baseline in some clinical studies [16,17]. In this subset of patients, early initiation of ETI may have significant benefits in terms of rapid recovery of respiratory function and improvement in overall clinical status. It is also conceivable that early use of ETI in subjects homozygous for the Phe508del CFTR, who are at high risk of developing severe clinical manifestations, could prevent the onset of pancreatic insufficiency. A study states that initiating ETI in the first years of life may facilitate the prevention or reversal of complications such as pancreatic insufficiency. There is a possibility that these drugs may also prevent the development of bronchiectasis, diabetes and other complications [30]. However, despite the therapeutic effects of ETI in slowing or, in some cases, halting disease progression in the study population, it is not possible to evaluate the clinical benefit in patients with severe pulmonary impairment as a form of stabilization of the disease. ETI cannot change the clinical condition of patients with pre-existing lung damage. Therefore, this subgroup of subjects should be evaluated very carefully, trying to start therapy early before the respiratory condition becomes irreversible. In addition, in newly diagnosed pediatric patients with acceptable clinical conditions, absence of bronchiectasis and microbial colonization (e.g. Pseudomonas A.) or high number of PEx events/year, especially in PwCF Phe508del with minimal function, we recommend careful case-by-case evaluation of ETI before initiating therapy due to potential side effects mainly in the liver [7,8,9,31]. Therefore, given the limited current evidence, further real-world studies with larger datasets and longer follow-up are required to validate these findings, considering the time of onset of any ETI-related adverse event. This will allow an accurate assessment of the early or late onset of ADRs-ETI related in order to improve the selection of patients eligible for treatment. Prospective studies with the addition of pharmacogenomic assessments would help to clarify the impact of ETI on liver toxicity.

ETI therapy improved lung function, nutritional status and quality of life in pediatric patients, providing further evidence of the clinical relevance of this novel combination in a real-world setting. The therapeutic effects were more pronounced in patients with more impaired lung function at baseline, whereas a stabilization of clinical parameters was observed in subjects with higher baseline ppFEV1. These improvements in both groups in response to ETI therapy reflect enhanced CFTR function and may predict potential long-term clinical benefits. Safety data showed an acceptable adverse event and tolerability profile with no permanent treatment discontinuations. Additionally, a sustained reduction in microorganisms was observed for up to 12 months. Overall, ETI therapy positively impacts both clinical and psychological aspects of the disease, potentially improving life expectancy in PwCF. CRediT authorship contribution statement Nicola Perrotta: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Luigi Angelo Fiorito: Writing – original draft, Visualization, Methodology, Investigation, Conceptualization. Rossella Gentile: Software, Methodology, Formal analysis, Data curation, Conceptualization. Roberta Vescovo: Software, Resources, Methodology, Formal analysis, Data curation, Conceptualization. Alfonso Piciocchi: Software, Methodology, Formal analysis, Data curation, Conceptualization. Roberto Poscia: Validation, Supervision. Giuseppe Cimino: Visualization, Validation, Supervision, Methodology, Investigation, Conceptualization. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical aspects This study was reviewed and approved by Ethics Committee of Sapienza, University of Rome, with the approval number: 7096, dated 6th April 2023. All patients provided written informed consent to participate in the study and for their data to be published. All data collected was treated in accordance with current privacy regulations and Good Clinical Practice (GCP). Data were collected anonymously; each patient was assigned an identification code. Declaration of Conflicting Interests All authors report no conflicts of interest relevant to this article. Data availability statement The data that support the findings of this study are available on request from the corresponding author and are not publicly available due to privacy or ethical restrictions.

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Authors Metrics & Citations Metrics Article Usage 265views 153downloads Citations Download citation Nicola Perrotta, Luigi Angelo Fiorito, Rossella Gentile, et al. A retrospective analysis of clinical parameters, safety and tolerability of Elexacaftor/Tezacaftor/Ivacaftor in a cohort of patients aged 6-17 years with cystic fibrosis. Authorea. 15 January 2025. DOI: https://doi.org/10.22541/au.173697416.66632785/v1 DOI: https://doi.org/10.22541/au.173697416.66632785/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.