Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis
Author Contributions
PRB, AM, ID, ISG, HC, and DH were responsible for the design of the study. Data collection was performed by PRB, AM, ID, RC, LM, AP, MME, MP, MA, PR, CM, JM, SB, ISG, HC, JDS, and DH. Data management and analysis were conducted by PRB, JDS, LL, CD, and JLP. Statistical analysis was carried out by JLP. The initial draft of the manuscript was written by PRB and JDS, and all authors contributed to revisions, approved the final version, and agreed on its intellectual content.
Funding
The study received financial support through grants from Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Legs Pascal Bonnet.
Descriptor Number
9.17 Cystic Fibrosis: Translational and Clinical Studies
Manuscript Word Count
3802 words
Abstract Word Count
249 words
Notation of Prior Abstract Presentation
Some data from this study were previously presented at the European Cystic Fibrosis Society Conference held in Liverpool, United Kingdom, in June 2019.
Online Data Supplement
An online data supplement is available and can be accessed through the issue’s table of contents at [www.atsjournals.org](http://www.atsjournals.org).
Abstract
Rationale: Lumacaftor-ivacaftor is a CFTR modulator approved for patients with cystic fibrosis who are homozygous for the Phe508del mutation.
Objectives: To assess the safety and effectiveness of lumacaftor-ivacaftor in adolescents aged 12 years or older and adults aged 18 years or older under real-world conditions after market approval.
Methods: The study was conducted across 47 cystic fibrosis reference centers in France. All patients initiating lumacaftor-ivacaftor therapy between January 1 and December 31, 2016, were eligible. Safety and effectiveness were monitored for one year following initiation, as per recommendations from the French CF learning society.
Main Results: A total of 845 patients (292 adolescents, 553 adults) began lumacaftor-ivacaftor therapy. Of these, 18.2% (154 patients) discontinued treatment, primarily due to respiratory (48.1%) or non-respiratory (27.9%) adverse events. Logistic regression analysis indicated that being in the adult age group, having ppFEV1 below 40%, and requiring multiple intravenous antibiotic courses in the year before treatment were associated with a higher likelihood of discontinuation. Among patients who remained on therapy, improvements were observed in ppFEV1 (+3.67%), BMI (+0.73 kg/m²), and a 35% reduction in intravenous antibiotic courses. In contrast, patients who discontinued therapy experienced a decline in ppFEV1 and showed no gains in BMI or reductions in antibiotic use.
Conclusions: In patients who tolerated it, lumacaftor-ivacaftor was associated with improvements in pulmonary function and nutritional status. Discontinuation, more frequent in adults, was linked to a higher risk of clinical decline, underlining the importance of monitoring and individualizing therapy.
Introduction
Cystic fibrosis is a genetic disorder caused by mutations in the CFTR gene, which encodes a protein critical for chloride and bicarbonate ion transport across epithelial surfaces. Disrupted ion transport contributes to multi-organ involvement, with pulmonary complications and malnutrition being major determinants of prognosis. Advances in symptomatic management—including antibiotics, nutritional interventions, and care at specialized centers—have significantly improved patient outcomes. More recently, the development of small-molecule therapies targeting defective CFTR proteins has introduced mutation-specific treatment options capable of partially restoring ion channel function.
The Phe508del mutation is the most prevalent CFTR mutation, found in approximately 70% of cystic fibrosis patients, with 40–50% being homozygous. Lumacaftor-ivacaftor has shown safety and efficacy in phase 3 trials for individuals homozygous for Phe508del who are aged 12 years and older. These studies demonstrated modest gains in lung function, a reduction in exacerbations, and slight improvements in BMI, leading to approval in the United States in February 2015 and in Europe in November 2015. However, the modest improvements in ppFEV1 and nutritional status, along with limited reductions in exacerbation frequency, have raised questions about the broader clinical utility of the drug, particularly in light of its cost and lack of approval in some countries.
A recent real-world study of 41 patients, including adolescents and young adults, further emphasized the variability in treatment response over a six-month period. Although the phase 3 and extension trials suggested a tolerable safety profile, smaller real-world studies have identified respiratory adverse events as a potential cause of early discontinuation, particularly in patients with ppFEV1 below 40%, who were excluded from earlier trials. Given these concerns, a large-scale, real-world evaluation of lumacaftor-ivacaftor in an unselected patient population is needed to better understand its clinical impact.
This study was conducted to evaluate the safety and effectiveness of lumacaftor-ivacaftor over a one-year period in a broad population of adolescents and adults homozygous for Phe508del in France. Data were collected from the 47 centers in the French CF reference network following the drug’s release in December 2015. Some findings from this research have previously been presented in abstract form.
Methods
Study Design
This was a nationwide, observational, multicenter study conducted at 47 cystic fibrosis reference centers in France. The study protocol was registered and approved by the French Society for Respiratory Medicine. In accordance with French legal guidelines, all participants received information about the study, but written consent was not required.
Patients who began lumacaftor-ivacaftor therapy in 2016 were followed for 12 months. Clinical evaluations, including pulmonary function tests and physical assessments, were conducted at baseline and at follow-up visits scheduled at 1, 3, 6, and 12 months. Respiratory and non-respiratory adverse events were recorded prospectively in patient medical records by attending clinicians. Collected data included height, weight, BMI, ppFEV1, and the number and duration of intravenous antibiotic courses administered in the year prior to and following treatment initiation. Standard laboratory monitoring included liver function tests at each visit and creatine phosphokinase measurements at baseline, one month, and twelve months.
Statistical Analysis
Data were expressed as percentages, medians with interquartile ranges, or means with standard deviations. Differences in treatment discontinuation rates among various subgroups, such as age groups, ppFEV1 thresholds, and prior use of antibiotics, were assessed using Kaplan-Meier survival analyses and log-rank tests. Clinical changes, including weight, BMI, and ppFEV1 from baseline to one year, were evaluated using the Wilcoxon paired test. Comparisons of the best ppFEV1 values before and after treatment, along with the number of intravenous antibiotic courses, were analyzed using paired McNemar’s tests and paired t-tests. Logistic regression was used to identify baseline characteristics linked to a higher likelihood of discontinuing treatment due to any cause or respiratory-related adverse events. Variables with a p-value below 0.10 in univariate analyses were included in the multivariable models. A p-value under 0.05 was considered statistically significant. All statistical analyses were conducted using SAS version 9.4.
Results
Patient Population
From January 1 to December 31, 2016, 845 individuals began lumacaftor-ivacaftor therapy across 47 centers within the French CF Reference Network. The cohort consisted of 292 adolescents and 553 adults. At the start of treatment, 88 percent of patients were prescribed the full recommended dose of lumacaftor (400 mg) and ivacaftor (250 mg) twice daily. The remaining 12 percent received a reduced dosage, primarily due to anticipated drug interactions or specific clinical concerns.
Treatment Discontinuation
In the year following initiation of lumacaftor-ivacaftor therapy, 641 patients (75.6 percent) remained on continuous treatment, 39 patients (4.6 percent) had intermittent treatment characterized by temporary discontinuation and reintroduction, and 154 patients (18.2 percent) permanently discontinued treatment. Follow-up information was unavailable for 11 patients (1.3 percent).
Among those who began treatment at full dose, 17.3 percent (129 of 745) discontinued without resuming, compared to 25 percent (25 of 100) of those who started at a reduced dose. Median follow-up times were similar across treatment groups: 369 days for continuous, 370 days for intermittent, and 363 days for those who discontinued. Median time under treatment was significantly shorter for patients who discontinued (90 days) and those with intermittent treatment (322 days) compared to continuous treatment patients (369 days).
The primary causes of treatment discontinuation among the 154 patients were respiratory adverse events (48.1 percent) and non-respiratory adverse events (27.9 percent). Median time to discontinuation due to respiratory issues was 42 days, significantly shorter than the 127 days observed for discontinuation due to other causes.
Discontinuation rates were higher in adults compared to adolescents (23.5 percent versus 8.2 percent), in patients with ppFEV1 below 40 percent compared to those at or above 40 percent (28.2 percent versus 16.3 percent), and in patients with multiple intravenous antibiotic courses in the previous year. Logistic regression identified baseline characteristics associated with increased discontinuation risk, although the presence of preexisting CF liver disease did not increase this risk.
Temporary discontinuation and subsequent reintroduction of lumacaftor-ivacaftor occurred in patients due to respiratory adverse events (16 individuals), non-respiratory adverse events (8 individuals), and other reasons (11 individuals), including pregnancy, fertility procedures, and drug interactions. Of the 90 patients who discontinued treatment for respiratory reasons, 32 attempted to resume. Sixteen successfully resumed treatment and were included in the intermittent group, while the other 16 were reclassified as discontinued.
Adverse Events
Adverse events potentially linked to lumacaftor-ivacaftor therapy were reported in 59.4 percent of patients. The most common adverse events were respiratory (38 percent), digestive (21.8 percent), menstrual irregularities (6.4 percent), fatigue (4.4 percent), and headache (3.3 percent). These adverse events were most frequent in the early months of treatment and declined over time, partly due to treatment discontinuation. However, a decline in adverse events was also seen among patients who remained on treatment for a full year. Adverse events occurred more often in individuals with diabetes (65.4 percent versus 56.8 percent).
Liver enzyme elevations exceeding three times the upper limit of normal were observed in five patients. Four of these had preexisting CF-related liver disease. Two patients, one with a history of cirrhosis and portal hypertension, discontinued treatment due to elevations exceeding six times the upper limit. Creatine phosphokinase levels exceeding five times the normal limit were reported in twenty patients. Two of them discontinued treatment due to levels more than ten times normal and the presence of muscle pain.
Effectiveness
Lung Function
An increase in ppFEV1 was observed within one month of starting lumacaftor-ivacaftor and remained over a 12-month period. At the one-year mark, the mean absolute increase in ppFEV1 across all patients was 2.7 percent. Those on continuous treatment saw an average increase of 3.67 percent, while patients with intermittent treatment had a 2.36 percent increase. Patients who discontinued treatment experienced a decline of 1.36 percent in ppFEV1.
Further analysis focusing only on those who remained on continuous treatment for a year revealed that adolescents had a larger improvement in ppFEV1 (4.76 percent) compared to adults (2.91 percent). Clinically meaningful increases in ppFEV1 were also observed: approximately 40 percent of patients had at least a 5 percent improvement, and 20 percent had at least a 10 percent improvement.
Weight and Body Mass Index
The cohort experienced an average weight gain of 2.1 kg and a BMI increase of 0.5 kg/m² over the year following treatment initiation. In patients with continuous treatment, these gains were consistent and gradual. In those with intermittent treatment, gains were delayed. No weight or BMI increases were observed in patients who discontinued treatment. Weight and BMI gains occurred across all adolescent subgroups, and among adults who maintained continuous or intermittent treatment, but not in those who discontinued.
Intravenous Antibiotic Courses
Of the 845 patients, data on intravenous antibiotic use before and after treatment was available for 797 individuals. In patients with continuous exposure to lumacaftor-ivacaftor, the average number of courses dropped from 1.18 to 0.77, representing a 35 percent reduction. For those with intermittent exposure, the number of courses remained virtually unchanged. Patients who discontinued treatment saw no meaningful change in the frequency of antibiotic use.
Vitamins and HbA1C
A comparison of serum levels of vitamin A, vitamin D (25OHD), and vitamin E before and after one year of treatment revealed no overall increase in vitamin concentrations. Notably, patients undergoing continuous lumacaftor-ivacaftor treatment demonstrated a significant decline in 25OHD levels. Among individuals with diabetes, no reduction in HbA1C levels was observed during the treatment period.
Discussion
This study assessed the one-year safety and effectiveness of lumacaftor-ivacaftor in a large national cohort of adolescents and adults with cystic fibrosis who are homozygous for the Phe508del CFTR mutation. Discontinuation of lumacaftor-ivacaftor occurred in 18.2 percent of patients, primarily due to respiratory adverse events and, to a lesser extent, non-respiratory adverse events. Patients who remained on treatment (continuously or intermittently) experienced significant improvements in ppFEV1, body weight, BMI, and a reduction in the number of intravenous antibiotic courses. In contrast, patients who discontinued therapy showed a decline in ppFEV1, no gain in weight or BMI, and no reduction in antibiotic use.
The discontinuation rate of 18.2 percent observed in this real-world study was considerably higher than in earlier pivotal clinical trials, where fewer than 5 percent of participants discontinued therapy. This discrepancy likely stems from the inclusion of more severely ill patients in the current cohort, including those with ppFEV1 below 40 percent and frequent prior exacerbations requiring intravenous antibiotics. Among these patients, the discontinuation rate was 28.2 percent. The association between low ppFEV1 and treatment discontinuation confirmed prior findings. Interestingly, even among patients with ppFEV1 equal to or above 40 percent, the discontinuation rate of 16.3 percent remained substantially higher than in the phase 3 trials. The study further identified that repeated respiratory exacerbations treated with intravenous antibiotics during the year prior to therapy initiation were independently associated with a higher risk of discontinuation.
Discontinuation rates were significantly higher in adults than in adolescents, regardless of lung function or exacerbation history. This suggests that other age-related factors, such as comorbidities more common in adults, may have influenced treatment tolerance. Supporting this, adverse events and treatment discontinuation were more frequent in patients with diabetes. Additionally, a 25 percent discontinuation rate was noted among patients whose treatment was initiated at a reduced dosage. While previous findings suggested that initiating lumacaftor-ivacaftor at a lower dose might reduce adverse events in high-risk patients, this study indicates that such a strategy may not sufficiently prevent discontinuation.
The study also highlighted the favorable liver safety profile of lumacaftor-ivacaftor, even in the subset of patients with preexisting CF-related liver disease. Only five patients developed severe liver enzyme elevations, and just two required treatment cessation due to liver-related adverse effects. These outcomes suggest that lumacaftor-ivacaftor may generally be well tolerated in individuals with liver disease, though decisions to initiate therapy should still weigh the risks.
Patients who received 12 months of lumacaftor-ivacaftor treatment exhibited notable clinical improvements, including increases in lung function, body weight, and BMI, and a reduced number of exacerbations requiring intravenous antibiotics. These results support and extend the findings of pivotal trials. Approximately 40 percent of patients experienced at least a 5 percent improvement in ppFEV1, and 20 percent had a 10 percent or greater improvement. This study also provided extended follow-up over 12 months, allowing for more comprehensive assessment of exacerbation frequency and intravenous antibiotic use than prior 6-month trial evaluations.
No significant changes were observed in serum levels of vitamins A, 25OHD, or E. Similarly, HbA1C levels remained stable in patients with diabetes. These findings indicate that while lumacaftor-ivacaftor leads to meaningful respiratory and nutritional benefits for patients able to tolerate it, it does not appear to affect vitamin levels or glycemic control.
Treatment led to a modest improvement in ppFEV1 and a 35 percent reduction in the number of pulmonary exacerbations. Fewer patients experienced frequent exacerbations after treatment. Since frequent exacerbations are associated with faster lung function decline and an increased risk of mortality or lung transplantation, this reduction is clinically significant. Recent analyses of phase 3 trial data have also indicated that reductions in exacerbation rates may occur independently of early changes in lung function, suggesting the importance of using multiple outcome measures when evaluating CFTR modulator effectiveness.
This study was conducted through the French CF Reference Center network, comprising 47 centers across France, and was funded independently of the drug manufacturer. The use of standardized procedures for adverse event documentation and treatment effectiveness assessments led to a robust dataset with minimal missing information. Nonetheless, some limitations must be acknowledged. Although respiratory adverse events were the leading cause of treatment discontinuation, limited data were available on the use of supportive treatments such as long-acting bronchodilators, which may help mitigate respiratory side effects. Compared to phase 3 trials, this cohort had lower usage rates of bronchodilators (75.7 percent vs. 92.2 percent) and hypertonic saline (12.5 percent vs. 59.9 percent), which may have influenced treatment outcomes. Additionally, exacerbations treated with oral antibiotics were not documented, given the challenges of accurately capturing these events in multicenter observational studies. The observed lower rate of liver enzyme elevation compared to randomized trials might be explained by less frequent laboratory monitoring and inherent variability in liver enzymes among patients with CF.
While the study categorized patients based on treatment exposure (continuous, intermittent, discontinued), no formal comparisons between these groups were conducted due to non-randomized group allocation, baseline differences, and likely distinct disease trajectories. Long-term follow-up of lung function decline is warranted once additional data become available.
The findings confirmed lower discontinuation rates in adolescents compared to adults and suggested a more pronounced improvement in lung function among adolescents. Notably, the adolescent group in this study was larger, both in absolute numbers and relative proportion, than in phase 3 clinical trials. These observations support the idea that early initiation of CFTR modulators could yield more favorable outcomes. Recent trials have demonstrated the safety of lumacaftor-ivacaftor in children aged 6 to 11 years and even 2 to 5 years, but real-world post-marketing studies are needed to confirm these results and assess treatment effectiveness.
Among adult patients who discontinued lumacaftor-ivacaftor, often due to respiratory adverse events, a consistent pattern was observed. These individuals typically experienced a decline in lung function, a reduction in body mass index, and frequent pulmonary exacerbations. At baseline, they exhibited more severe disease, indicating a need for personalized clinical strategies aimed at maintaining pulmonary function and nutritional health. For these patients, alternative therapies such as tezacaftor-ivacaftor may provide a more favorable safety profile, particularly with fewer respiratory-related adverse effects. Current research is underway to assess the efficacy and safety of tezacaftor-ivacaftor in those who are unable to tolerate lumacaftor-ivacaftor. Furthermore, data emerging from trials involving triple CFTR modulator combinations suggest that these new treatments may result in significantly better clinical outcomes. It is therefore essential to ensure that patients with advanced disease who cannot tolerate lumacaftor-ivacaftor have timely access to these alternative therapeutic options, including tezacaftor-ivacaftor and triple combination therapies as they become available.
Conclusion
This study demonstrated that a 12-month course of lumacaftor-ivacaftor treatment led to significant improvements in lung function and nutritional status, as well as a reduction in the number of courses of intravenous antibiotics among adolescents and adults with cystic fibrosis who are homozygous for the Phe508del mutation and are able to tolerate the treatment. The findings underscore the importance of large-scale real-life studies in evaluating the safety and effectiveness of new therapies, particularly because patients enrolled in post-marketing studies often present with more advanced disease, lower lung function, and increased exacerbation rates compared to those included in controlled clinical trials. These observations emphasize that the benefits and risks identified in clinical trials may not always be generalizable to patients excluded from such studies. The expected availability of new CFTR modulator combinations, along with the expansion of treatment indications to younger age groups, necessitates the initiation of further real-world studies as soon as these drugs become accessible to the appropriate populations.
Acknowledgement
The authors express their gratitude to URC-CIC Paris Descartes Necker Cochin for their role in the implementation of the study. Appreciation is also extended to the French Cystic Fibrosis Registry for their assistance with data management.
Participating Investigators of the French Cystic Fibrosis Reference Network Study Group
Julie Mounard, Claire Poulet, Cinthia Rames (Amiens); Christine Person, Françoise Troussier, Thierry Urban (Angers); Marie-Laure Dalphin, Jean-Claude Dalphin, Didier Pernet, Bénédicte Richaud-Thiriez (Besançon); Stéphanie Bui, Mickael Fayon, Julie Macey-Caro (Bordeaux); Karine Campbell, Muriel Laurans (Caen); Corinne Borderon, Marie-Christine Heraud, André Labbé, Sylvie Montcouquiol (Clermont-Ferrand); Laurence Bassinet, Natascha Remus (Créteil); Annlyse Fanton, Anne Houzel-Charavel, Frédéric Huet, Stéphanie Perez-Martin (Dijon); Amale Boldron-Ghaddar, Manuela Scalbert (Dunkerque); Laurent Mely (Giens); Boubou Camara, Catherine Llerena, Isabelle Pin, Sébastien Quétant (Grenoble); Aurélie Cottereau, Antoine Deschildre, Alice Gicquello, Thierry Perez, Lidwine Stervinou-Wemeau, Caroline Thumerelle, Benoit Wallaert, Nathalie Wizla (Lille); Jane Languepin, Céline Ménétrey, Magalie Dupuy-Grasset (Limoges); Lucie Bazus, Clelia Buchs, Virginie Jubin, Marie-Christine Werck-Gallois, Catherine Mainguy, Thomas Perrin, Philippe Reix, Agnès Toutain-Rigolet (Lyon Pediatrics); Isabelle Durieu, Stéphane Durupt, Quitterie Reynaud, Raphaele Nove-Josserand (Lyon Adults); Melisande Baravalle-Einaudi, Bérangère Coltey, Nadine Dufeu, Jean-Christophe Dubus, Nathalie Stremler (Marseille); Davide Caimmi, Raphaël Chiron (Montpellier); Yves Billon, Jocelyne Derelle, Sébastien Kieffer, Anne-Sophie Pichon, Cyril Schweitzer, Aurélie Tatopoulos (Nancy); Sarah Abbes, Tiphaine Bihouée, Isabelle Danner-Boucher, Valérie David, Alain Haloun, Adrien Tissot (Nantes); Sylvie Leroy, Carole Bailly-Piccini (Nice); Annick Clément, Harriet Corvol, Aline Tamalet (Paris Trousseau); Pierre-Régis Burgel, Isabelle Honoré, Dominique Hubert, Reem Kanaan, Clémence Martin (Paris Cochin); Cécile Bailly, Frédérique Chédevergne, Jacques De Blic, Brigitte Fauroux, Murielle Le Bourgeois, Isabelle Sermet-Gaudelus (Paris Necker); Bertrand Delaisi, Michèle Gérardin, Anne Munck (Paris Robert Debré); Michel Abély, Bruno Ravoninjatovo (Reims); Chantal Belleguic, Benoit Desrues, Graziella Brinchault (Rennes); Michel Dagorne, Eric Deneuville, Sylvaine Lefeuvre (Rennes-Saint Brieuc); Anne Dirou, Jean Le Bihan, Sophie Ramel (Roscoff); Stéphane Dominique, Christophe Marguet (Rouen); Annabelle Payet (La Réunion); Romain Kessler, Michele Porzio, Vincent Rosner, Laurence Weiss (Strasbourg); Sandra de Miranda, Dominique Grenet, Abdoul Hamid, Clément Picard (Suresnes); François Brémont, Alain Didier, Géraldine Labouret, Marie Mittaine, Marlène Murris-Espin, Laurent Têtu (Toulouse); Laure Cosson, Charlotte Giraut, Anne-Cécile Henriet, Julie Mankikian, Sophie Marchand (Tours); Sandrine Hugé, Véronique Storni (Vannes); Emmanuelle Coirier-Duet (Versailles).
Study Population
Physicians were requested to recruit all patients with cystic fibrosis aged 12 years and older who were homozygous for the F508del CFTR mutation and began lumacaftor-ivacaftor treatment between January 1st and December 31st, 2016, outside the context of interventional research. This led to the inclusion of 853 patients. Of these, 5 patients were excluded due to insufficient data, one patient was under 12 years of age, and 2 had unknown treatment initiation dates. As a result, 845 patients were retained for the final analysis.
Due to the integration of this study within the French Cystic Fibrosis Registry database, a comprehensive overview of lumacaftor-ivacaftor use in France by the end of 2016 was achieved. Among 1635 eligible patients (homozygous F508del, aged 12 or older, and not living with lung transplant), 928 patients (57%) received lumacaftor-ivacaftor during 2016. The study included 853 patients, representing 92% of those treated. The remaining 75 patients were not included, with at least 27 participating in clinical trials. For the remaining 48, registry data could not confirm whether the treatment occurred in trials or as real-world prescriptions.
Adverse Effects
Adverse events potentially linked to lumacaftor-ivacaftor, as reported by treating physicians, included respiratory, digestive, and general events. These events were recorded both in the entire study population and among patients who continued treatment for the full 12 months.
Reasons for Discontinuation
Among 154 patients who discontinued lumacaftor-ivacaftor, 48.1% experienced respiratory adverse events. These included abnormal respiration such as chest tightness or dyspnea (24.7%), bronchospasm (15.6%), increased cough and sputum (5.8%), hemoptysis (1.3%), and pneumothorax (0.7%). Non-respiratory adverse events accounted for 27.9%, including gastrointestinal symptoms (11.7%), myalgia with significant CPK elevation (3.2%), fatigue (3.2%), headache (2.6%), depression (2.6%), metrorrhagia (1.9%), elevated liver function tests (1.3%), tachycardia (0.7%), and rash (0.7%). Additional reasons included non-adherence (4.6%), perceived lack of effectiveness (4.6%), reproductive considerations (3.9%), lung transplantation (3.3%), miscellaneous (2.6%), unknown reasons (1.9%), drug interaction (1.9%), and death (1.3%).
Multivariable Analysis of Discontinuation
Logistic regression analysis showed that being an adult compared to an adolescent increased the odds of discontinuation due to any cause (odds ratio 2.65), and this was statistically significant. Additional variables associated with increased risk included lower baseline ppFEV1 (odds ratio 1.13 per 10% decrease) and the number of IV antibiotic courses received in the previous year (odds ratio 1.13 per course).
For discontinuation due to respiratory events, adults had higher odds (odds ratio 4.36). Other associated factors included presence of diabetes (odds ratio 1.71), lower ppFEV1 (odds ratio 1.32), lower BMI (odds ratio 1.11 per unit decrease), while the number of prior IV antibiotic courses showed a borderline association.
Baseline Characteristics and Treatment Profile
The final study group of 845 patients included 292 adolescents and 553 adults. The median age was 22 years, with adolescents averaging 15 years and adults 27.3 years. Female patients represented 44.6% overall. Median baseline ppFEV1 was 65%, with adolescents at 70% and adults at 60%. A ppFEV1 below 40% was recorded in 14.8% of the overall group, with higher prevalence among adults. The average body mass index was lower in adolescents than in adults.
Microbiological data revealed that 39% had no Pseudomonas aeruginosa infection, 12% had intermittent infection, and 48.5% had chronic infection. Methicillin-sensitive Staphylococcus aureus was found in 67.1% of patients, while 15.7% had methicillin-resistant strains. Other pathogens such as Burkholderia cepacia and Haemophilus influenzae were less common.
Diabetes mellitus was more frequent among adults (35.1%) than adolescents (15.8%). Cirrhosis, elevated liver enzymes, and history of IV antibiotic use were also more prevalent in adults. The majority of patients were on maintenance pulmonary treatments at baseline, including azithromycin, inhaled antibiotics, dornase alfa, and hypertonic saline.
Summary
This national observational study investigates the real-world use of lumacaftor-ivacaftor in French patients with cystic fibrosis who are homozygous for the F508del mutation. The study describes patterns related to the initiation and discontinuation of treatment, the occurrence of adverse events, and baseline patient characteristics. Key risk factors associated with treatment discontinuation include being an adult, having poorer lung function, the presence of diabetes, and prior use of antibiotics. The results provide meaningful insights into patient outcomes and can inform future treatment approaches for similar populations.
Effectiveness
The study explored the changes in pulmonary function, as measured by ppFEV1, over a 12-month period following the start of lumacaftor-ivacaftor treatment in a broad group of patients, including separate analyses for adults and adolescents. Patients demonstrated varying degrees of improvement in lung function, with a notable proportion achieving increases in ppFEV1 of at least 5% or 10% compared to their best values in the year before treatment.
Weight and body mass index (BMI) were monitored throughout the 12-month period following treatment initiation. The findings suggest that changes in these measures varied based on whether the treatment was continued, intermittently used, or discontinued, with differences observed between adults and adolescents.
Liver Function and Related Conditions
The study assessed the prevalence of cirrhosis, portal hypertension, and elevated liver enzymes based on treatment patterns. Similar rates of cirrhosis and elevated liver enzymes were observed between patients who maintained continuous or intermittent treatment and those who discontinued. A subgroup of five patients experienced elevated liver enzymes greater than three times the upper normal limit at any time during the study. Among these, two patients discontinued treatment due to the severity of these abnormalities. Liver function indicators fluctuated over the course of the study, with varying patterns observed between those continuing and those discontinuing treatment.
Adverse Events and Diabetes
The occurrence of adverse events was examined in relation to diabetes status at the beginning of the study. Patients with diabetes experienced a higher rate of overall adverse events compared to those without diabetes. However, there were no statistically significant differences between the two groups in the rates of respiratory or digestive adverse events, suggesting that diabetes may be linked more to general adverse reactions rather than specific system-related effects.
Changes in Vitamin Levels and HbA1C
The study also evaluated differences in serum levels of vitamins A, D, and E, as well as HbA1C, from baseline to 12 months after initiating lumacaftor-ivacaftor treatment.
For Vitamin A, patients showed an overall increase in levels across all treatment groups, with statistically significant gains in those with continuous treatment. Intermittent treatment and treatment discontinuation groups showed less pronounced or non-significant changes.
Vitamin D levels generally decreased over the study period, particularly in the continuous treatment group. Those with intermittent or discontinued treatment showed smaller changes, and these were not statistically significant.
Vitamin E levels also decreased overall, especially in patients receiving continuous treatment. Intermittent and discontinued groups had smaller reductions.
Regarding HbA1C, measured only in patients with diabetes at baseline, no significant changes were observed over the 12-month period across all treatment patterns. The results suggest stable glycemic control in this subgroup throughout the study.