Cystic fibrosis (CF) is an inherited genetic disease leading to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR is involved in active excretion of chloride at the apical membrane of the epithelial cells (1–4). Among more than 2,000 mutations of the CFTR gene, the homozygous F508del represents the most frequent in France with a prevalence of up to 41% of patients (5). This mutation leads to a processing and trafficking defect of the CFTR protein resulting in an early degradation or a dysfunctional protein expressed into the apical membrane of the cells (1, 4, 6). As a consequence, epithelial mucus secretion is dehydrated, promoting pulmonary infection (7) and organ injury (e.g., pancreatic insufficiency), leading to impaired lung function, growth, and nutritional outcomes (8–10). Therapeutic approaches over the last 20 years based on symptomatic treatments (physiotherapy, fluidifiers, and pancreatic enzymes, etc.) (11, 12) slowed down the progression of CF and enhanced life expectancy (4, 10). Nevertheless, CF remains a severe disease, in which pulmonary exacerbations and poor nutritional status contribute to progressive lung function decline and death in young adults (4, 8, 10). The highest decline in lung function occurs during adolescence which is thus a pivotal period in the management of the disease (13).

In this context, therapeutic approaches have been developed to improved cell chloride secretion by targeting the defect in F508del-CFTR folding using in association: the CFTR corrector lumacaftor (LUM) (enhances trafficking and processing), and the CFTR potentiator ivacaftor (IVA) (increases the channel opening probability) (1, 4). Phase III studies have demonstrated good tolerance of the lumacaftor/ivacaftor association (LUM/IVA) and significant potential benefits in young children aged 2–5 years old (14) and 6–11 years (15, 16) [e.g., improved body mass index (BMI)], and in adolescents over 12 years of age and adults [i.e., improvement in BMI and lung function, assessed by the percentage of predicted forced expiratory volume in 1 s (ppFEV1), and decrease in the number of exacerbations usually defined by clinical deterioration treated with IV antibiotics] (17). The positive effect of LUM/IVA on lung function decline and BMI has been confirmed in patients over 12 years by the 96 weeks follow-up PROGRESS study (8) and more recently, in France, in the real-life study performed by Burgel et al. (18). However, the PROGRESS study mostly included CF adults (8), and the study performed by Burgel et al. followed CF adolescents only for a year after LUM/IVA initiation.

Thus, real-life studies are needed to confirm the ability of LUM/IVA to change the course of the disease and to evaluate its long-term effects, particularly in adolescents, who are at a critical stage of their development.

Thus, we conducted a pediatric prospective real-life cohort study including F508del homozygote adolescents followed-up within the French South-Western network (MUCOSUD) to assess the evolution of the ppFEV1 before and after the LUM/IVA initiation. The secondary objectives were to assess (i) the evolution of clinical [i.e., anthropometric parameters (weight, height, and BMI expressed as Z-scores) and number of pulmonary exacerbation, antibiotic use], biological (i.e., sweat chloride concentration), and radiological (i.e., the Bhalla CT-scan score with the percentage high attenuation volume (%HAV) mucus secretions sub-score) parameters; (ii) to identify parameters associated with response to treatment; and (iii) to assess the tolerance to treatment.

The study was conducted prospectively between February 2016 and December 2018 within the French South-West network of pediatric CF centers (tertiary-care university hospitals in Bordeaux, Toulouse, and Limoges) and the included CF adolescents (12–18 years old) eligible for LUM/IVA treatment (F508del homozygotes aged 12 years and older) not included in other CFTR modulator protocols study. Patients having stopped LUM/IVA within 3 months after initiation of treatment were excluded from the analyses. It was a non-interventional study. Indeed, LUM/IVA has been approved by the Food and Drug Administration and the European Medicines Agency, and labeled in France since 2015 for CF patients with F508del homozygous CFTR mutation over 12 years of age. Thus, at the time of the patient follow-up period, LUM/IVA was prescribed as part of the routine care of a patient. In addition, the use of the data collected and analyzed for the study were exclusively extracted from the medical records of the patients (MUCODOMEOS, https://www.vaincrelamuco.org/2019/05/09/mucodomeos-un-logiciel-adapte-aux-besoins-des-crcm-2684) after having obtained their informed consent. In this context and according to the French law in force, the approval of an ethics committee was not required.

This real-life study highlights the long-term effectiveness and safety of LUM/IVA on lung function and nutritional outcomes in CF adolescents in real life. We found a significant improvement in the ppFEV1, from worsening in the 2 years preceding treatment to a significant increase during the 2 years of the LUM/IVA therapy, particularly in patients with ppFEV1 < 80% or BMI Z-score < 0 at the LUM/IVA initiation and a concomitant improvement in BMI Z-score and sweat chloride concentration after the LUM/IVA treatment.

The impact of LUM/IVA on ppFEV1 appears to be greater in the adolescents in the present study compared with that reported in the pivotal phase III randomized controlled trials, TRANSPORT (+2% to 4% after 24 weeks of LUM/IVA) (17) and PROGRESS (+0.5% at 96 weeks) (8). In the long term, the PROGRESS study demonstrated a slowing down of lung function decline in treated compared with paired non-treated patients from the US registry, but with the persistence of a declining trend in ppFEV1 (8). In comparison, in our study, we showed an increase in ppFEV1 in treated patients. Both the TRANSPORT and PROGRESS studies mainly involved CF adults (8, 17), whereas we focused on CF adolescents only. Our results are consistent with the slowing down of lung function decline after a year of LUM/IVA treatment in adolescents with CF included in the French real-life cohort (18), and with another study performed by Loukou et al. (29). In our study, we confirmed the short term effect at 6 months of LUM/IVA treatment with a proportion of good responders close to a previous report (20). Moreover, we demonstrated both a sustained long-term effect up to 2 years after the LUM/IVA initiation and a significant number of late responders. We also demonstrated that in some patients who were not good responders, ppFEV1 stability was observed, and this represents a satisfactory response since adolescence is the period of greatest decline in lung function. In addition, we demonstrated some benefits in adolescents with impaired lung function or BMI Z-score < 0, and at a lesser extent in those with normal ppFEV1 or BMI Z-score > 0 at the start of the treatment (i.e., ≈50% of good responders). Patients with impaired lung function or BMI Z-score < 0 had also the worst sweat chloride which may be related to a poorer nutritional status or greater CFTR dysfunction. Thus, it was not surprising that restoring CFTR function and/or nutritional status with LUM/IVA has a better effect in these patients. Moreover, we highlighted an inverse correlation between the age at the LUM/IVA initiation and improvement in ppFEV1 after 2 years of treatment. This suggests that early initiation of the treatment at a younger age regardless of pulmonary function or growth parameters may be more beneficial. This was in accordance with the improvement in lung clearance index at 24 weeks of treatment in younger patients (9.1 ± 1.5 years old) with normal lung function as previously described in a 6–11 year phase III study (15).

Interestingly, we observed significant improvement in growth parameters (i.e., weight and BMI Z-score), particularly in adolescents with poor BMI Z-scores at the start of LUM/IVA as demonstrated in younger patients included in the LUM/IVA phase III (14) or in CF adults (8).

As previously described in an industry-sponsored and larger real-life studies (8, 14, 15, 17–20), we confirmed the improvement induced by LUM/IVA regarding CFTR function, with a significant decrease in sweat chloride concentration, particularly in the most severe patients (low ppFEV1 or BMI). However, we did not find any difference in sweat chloride concentration improvement between responders and non-responders, nor any association between this parameter and ppFEV1 or BMI Z-score improvement as previously demonstrated (15, 17, 19, 21).

In contrast, we could not confirm the decrease in pulmonary exacerbation rates and antibiotics consumption in real life in CF adolescents treated with LUM/IVA as found in placebo-controlled and long-term industry sponsored studies (i.e., decrease in exacerbation rates by 30% to 39%) (8, 17) or in a previous real-life study (i.e., decrease in exacerbation rates by 54%) (30). However, in this last study, patients were older (31 ± 11.6 years old) (8, 14, 26) and/or had worse lung function (ppFEV1: 37.4 ± 11.3 %) (30) and/or had a higher rate of exacerbations treated by intravenous antibiotics (3.4 ± 2.4/year) at the time of initiation of LUM/IVA (30) compared with our patients. Moreover, adolescents in our cohort had <2 exacerbations per year, and <1 intravenous antibiotic course per year, thus, the effect of LUM/IVA is more difficult to demonstrate. In agreement with our results, in young adults with F508 homozygous mutations, Tessel et al. found no difference in the annualized rate of exacerbations (31).

We did not find difference in Bhalla (24) scores or HAV (25) scores after a year of treatment as demonstrated in CF adults with advanced disease only (25). However, such results have not been demonstrated in CF children who have a lower level of disease severity. Indeed, CT scans were not included in the industry-sponsored clinical trials of LUM/IVA involving CF children (8, 9, 14–19). In addition, our results are in agreement with the lack of modification in the visual Eichinger score previously demonstrated in CF before and after treatment despite lung clearance index improvement (32). However, a possible lack of sensitivity in the imaging scores may have impacted these results, as the visual scores may not detect a variation of <50% in lung injury due to their scoring systems (32). Nevertheless, it does not reduce the usefulness of treating young patients before irreversible lesions are established. To note, this lack of improvement in imaging scores could also be the consequence of scans performed too early, since the results on ppFEV1 or BMI were only significant after 2 years of treatment in our population.

In our study, the side effects of the treatment were consistent with those observed in the industry-sponsored studies (8, 15, 17) or real-life cohorts (18, 29), and in favor of good tolerability and patient adherence. Interestingly, we observed psychological side effects such as increased anxiety and depression in one patient leading to an early cessation of treatment as previously described in real life (33) but not in the industry-sponsored studies (8, 15, 17).

Our study had several limitations. First, the number of patients included is low compared with other real-life studies and there is no control-group. However, these patients accounted for 84% of our patients eligible for the LUM/IVA treatment in our centers. Second, spirometric tests performed 2 years and 1 year before and after T0 were selected to match the best ppFEV1 obtained at ±1 month from the chosen time point. We use this method to avoid the transient effect of exacerbation on ppFEV1. Third, pre-treatment data were assessed retrospectively. However, such data included standard items, which were uniformly and prospectively recorded during routine follow-up using the same software in the entire South-West network. This data is also channeled to the national registry, decreasing the risk of bias due to missing data. Fourth, only exacerbations requiring antibiotics have been considered, in contrast to less severe pediatric exacerbations due in most instances to viral infections. However, compared with previous clinical trials we assessed exacerbation requiring IV and/or oral antibiotics and not only those requiring IV courses which represent only a subset of antibiotic-treated exacerbations especially in adolescents. Fifth, the adherence to treatment was assessed at each visit but was based on the reports of children or their parents, and this represents an important limit of real-life studies.

We confirm that in real life, adolescents given long-term LUM/IVA improve their ppFEV1 and BMI Z-score, which have been associated with survival in cystic fibrosis. Adolescents with impaired lung function had a greater treatment benefit on lung function, but early introduction appeared to promote better response to the treatment, with good tolerance. In the era of CFTR modulators, real-life studies help the clinicians understand what type of results are really to be expected according to specific age groups.

This real-life study showed short- and long-term benefits of lumacaftor/ivacafor association in adolescents with cystic fibrosis, particularly in the youngest ones, by changing trajectories and improving lung function and nutritional parameters.

This study focuses on the long-term safety and efficacy of lumacaftor/ivacaftor in children with cystic fibrosis in real-life.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

SB designed and supervised the study, with contributions from AM and MM. SB, AM, LR, FG, CC, RE, JL, MM, GD, MF, and EM included and followed the patients. The statistical analysis was performed by SB, FB, and RE. SB, MM, and AM were major contributors in writing the manuscript and contributed equally to the manuscript. All authors have approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

SB, FG, CC, RE, FB, and MF conducted clinical trials with Vertex pharmacological agents, on behalf of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) and within the scope of ECFS-CTN activities. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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