Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung disease

C. Martin a,b,c,1, E. Burnet b,c,1, A. Ronayette-Preira d, P. de Carli d, J. Martin e,
L. Delmas f, B. Prieur b,c, P.-R. Burgel a,b,c,∗
a Université de Paris, Institut Cochin, Inserm U1016, Paris, France

b Respiratory Medicine and National Reference Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP–HP), Paris, France

c ERN-Lung CF network
d Vaincre la Mucoviscidose, 75013 Paris, France e Moutier-d’Ahun, France

f Paris, France

a r t i c l e i n f o

Article history:

Received 28 April 2021 Accepted 7 May 2021 Available online 17 May 2021

a b s t r a c t

Backgound. – Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conduc-tance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation.

Methods. – A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10th to August 21th 2020 to French patients aged 12 years and older with advanced CF who were treated with elexacaftor-tezacaftor-ivacaftor. Their responses were summarized as numbers (%), and free-text items were analysed using a grounded theory approach.

Results. – Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28–41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0–5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment.

Conclusion. – After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

1. Introduction

Elexacaftor-tezacaftor-ivacaftor is a cystic fibrosis transmem-brane conductance regulator (CFTR) modulator combination that was recently developed for the treatment of people with cys-tic fibrosis (CF) carrying at least one Phe508del CFTR mutation.

∗ Corresponding author at: French National Reference Center for Cystic Fibrosis, Cochin Hospital, 27, rue du Faubourg Saint Jacques, 75014 Paris, France.

E-mail address: [email protected] (P.-R. Burgel).

1 Equal contribution.


2590-0412/© 2021 SPLF and Elsevier Masson SAS. All rights reserved.

Pivotal clinical trials were conducted in patients aged 12 years and older with a percent-predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. These studies com-pared elexacaftor-tezacaftor-ivacaftor to placebo in patients with a Phe508del/minimal function genotype [1] or to tezacaftor-ivacaftor in patients homozygous for the Phe508del mutation [2]. They showed that elexacaftor-tezacaftor-ivacaftor improved ion transport (as demonstrated by a significant reduction in sweat chlo-ride concentrations), lung function and body mass index (BMI), and reduced the occurrence of pulmonary exacerbations [1–3]. The safety profile has proven favorable with only mild to moderate adverse effects. These findings led to its approval by regulatory

C. Martin, E. Burnet, A. Ronayette-Preira et al. Respir. Med and Res 80 (2021) 100829

agencies in the United States in October 2019 and in Europe in August 2020. A recently published study reported early outcomes of elexacaftor-tezacaftor-ivacaftor in 245 CF patients with advanced lung disease (ppFEV1 ≤ 40%), confirming a dramatic improvement in respiratory function and nutritional status, to such an extent that indication for lung transplantation was suspended in 47 of 53 patients [4].

Clinical trials rely mostly on physician-reported outcomes (usu-ally objective measurements) that are requested by regulatory agencies to demonstrate a drug’s safety and efficacy. Over the past two decades, there has been greater emphasis on documenting patient-reported outcomes (e.g., symptoms and quality of life). In CF, the most widely used questionnaire is the Cystic Fibro-sis Questionnaire–Revised (CFQ-R), which has been validated for assessing patient perceptions on the effects of new CF therapies [5]. Recent clinical trials assessing the effects of elexacaftor-tezacaftor-ivacaftor have used the CFQ-R respiratory domain score and reported important improvements in patient-reported quality of life [1,2]. However, they limited their analysis to the absolute change in the CFQ-R score and did not detail the effects of treat-ment on respiratory symptoms, extrapulmonary effects or general patient functioning. Although it is now widely accepted that CF patients should be involved in research and in drug development [6], prompting regulatory agencies to systematically seek patient opinions when evaluating a new drug [7], the available data on patient experiences with elexacaftor-tezacaftor-ivacaftor remains limited.

At the time of writing (April 2021), elexacaftor-tezacaftor-ivacaftor has not been commercialized in France though it has been available for use in patients with advanced CF lung disease since December 2019 through an early access program. The French CF patient association, Vaincre la Mucoviscidose (Paris, France), was contacted by the national regulatory agency (Commission de Transparence de la Haute Autorité de Santé) that is responsible for drug evaluation, to undertake a survey evaluating the per-ceived impact of triple therapy in patients aged 12 years and older with advanced CF lung disease (ppFEV1 ≤ 40 and/or an indication for lung transplantation) who were treated with elexacaftor-tezacaftor-ivacaftor.

The goal of this study was therefore to collect the perspec-tives of these patients, following treatment initiation, in order to gain a better understanding of their perceived changes in respi-ratory symptoms and systemic manifestations, treatment burden and overall impact on quality of life.

2. Methods

2.1. Survey design and patient population

A 13-item questionnaire was designed by two researchers at Vaincre la Mucoviscidose with the help of a focus group of CF patients and family members, who participated in question formulation and tested the validity of the responses. It included nine closed ques-tions regarding:

• age;

• date of initiation;

• CFTR genetic profile;

• use of lumacaftor-ivacaftor (Orkambi®) prior to initiation of elexacaftor-tezacaftor-ivacaftor;

• overall impression of health status since initiation;

• general wellbeing; and impact of triple therapy on:

◦ social life,

◦ treatment burden and hospitalization time,

◦ emotional health and physical status (several items).

Four open questions invited patients to describe, in their own words, the impact of triple therapy on:

• lung transplant status;

• quality of life;

• occurrence of treatment-related adverse events, and;

• a general conclusion on how triple therapy has impacted their life.

This last question enabled patients to freely describe the impact of treatment on any and all aspects of their lives. An English trans-lation of the questionnaire is available in the Online supplement.

The link to the online questionnaire was distributed to patients from July 10th to August 21th 2020 via the physicians of the French CF Reference Centre Network (which includes all 47 French CF cen-tres) and through a private Facebook group for patients receiving elexacaftor-tezacaftor-ivacaftor. Patients were assured that their individual data and responses would remain strictly confiden-tial and would not be communicated to their healthcare team. Responses were sent to a secure Email address and all identifiers were removed prior to analysis. All patients provided consent for the use of their anonymized data. For patient under 18 years old, additional approval from parents was required. In accordance with French laws, no ethical committee approval was necessary for this anonymous survey. The authors were commissioned by Vaincre la Mucoviscidose to analyze the data and write up the findings. The reg-ulatory agency did not take part in questionnaire development or in the selection of authors, participants, study design, data analysis or writing of the manuscript.

2.2. Data analysis

Responses to open questions pertaining to clinical symptoms and the impact of triple therapy on treatment burden were grouped into categories and presented in histograms (% patients). All answers provided were taken into account; when the patient did not mention a particular symptom it was categorized as “not reported”. Free-text answers to the final open question on how triple therapy has impacted their life were analysed using a grounded theory approach, a systematic methodology that involves the construction of hypotheses and theories through the collection and analysis of qualitative data [8].

Two researchers (CM and EB), working in tandem, coded patient responses and identified concepts and themes. Terms and phrases were categorized using constant comparative analysis and the cat-egories were grouped manually into emerging themes. Themes and categories were refined, broadened or narrowed as needed and until saturation, following an inductive and iterative analysis process. This allowed the construction of a conceptual framework representing the non-quantifiable effects of elexacaftor-tezacaftor-ivacaftor, based solely on patient impressions.

Finally, content analysis of the responses to the concluding free-text question was conducted by an independent researcher (LD). A standardized code was designed to build a word cloud, with a weighted word size based on frequency of occurrence. Only terms with a frequency of three or more were retained. Words or expressions that described the patient’s condition prior to elexacaftor-tezacaftor-ivacaftor initiation were excluded, as were non-relevant words, such as “it, as, so, etc”. Further exclusions were defined through an iterative process to retain only terms that expressed the impressions, both positive and negative, of patients after initiation of elexacaftor-tezacaftor-ivacaftor. The terms were then translated into English, referring to the original text in order to ensure accuracy of meaning. A script was written using the free Python 3.9.1 programming language (Python Software Foundation)


C. Martin, E. Burnet, A. Ronayette-Preira et al. Respir. Med and Res 80 (2021) 100829

Fig. 1. Patient-reported symptoms after initiation of elexacaftor-tezacaftor-ivacaftor. Data are presented as percentage of patients (n = 101) with each response modality.

to generate the word cloud image, which took the shape of an elexacaftor-tezacaftor-ivacaftor pill.

3. Results

3.1. Patients

At the time of questionnaire distribution in July 2020, 245 patients were receiving elexacaftor-tezacaftor-ivacaftor in France. Of these, 101 (41%) responded to the questionnaire. All patients were aged 12 years and older and had advanced CF, as this was a requirement for receiving elexacaftor-tezacaftor-ivacaftor through the French early access program. The median [IQR] age was 35 [28–41] years and duration of treatment with elexacaftor-tezacaftor-ivacaftor was 4.3 [3.0–5.6] months (min 6 days; max 7.3 months). Self-reported patient characteristics are presented in Table 1.

3.2. Impact on symptoms and treatment burden

The impact of triple therapy described in the free-text responses to the open questions of several items of question 9 (i.e. pul-monary and extrapulmonary symptoms, sleep quality) is depicted in Fig. 1A–G. Patients generally reported an improvement in res-piratory symptoms, including cough reduction and a decrease in sputum production, which completely disappeared in at least half of the patients. Most patients remained free from exacerbations since treatment initiation. They also reported an improvement in extrapulmonary symptoms, particularly appetite and sleep qual-ity. However, there was mostly no improvement in gastrointestinal manifestations, with approximately 20% of patients even reporting a worsening of symptoms, presumably related to treatment adverse effects.

The impact on overall treatment burden was evaluated in the free-text responses to the open questions of several items of ques-tion 9 and to the free-text responses of open question 5 regarding lung transplantation candidate status, and is depicted in Fig. 2A–F.


C. Martin, E. Burnet, A. Ronayette-Preira et al. Respir. Med and Res 80 (2021) 100829

Fig. 2. Patient-reported treatment burden after initiation of elexacaftor-tezacaftor-ivacaftor. Data are presented as percentage of patients with each response modality. Note that data on diabetes control and lung transplant discussions were limited to patients that had diabetes and/or lung transplant discussions at initiation of elexacaftor-tezacaftor-ivacaftor.

Table 1

Self-reported characteristics of 101 patients with advanced cystic fibrosis.

Variables All patients, n = 101

12–17 years 3 (3.0%)
18–39 years 67 (66.3%)
40 years and older 31 (30.7%)
CFTR genotype
F508del/F508del 39 (38.6%)
F508del/other 61 (60.4%)
Unreported 1 (1%)
Diabetes 50 (49,5%)
Discussing lung transplantation at initiation of 42 (41.6%)
Time since initiation of
Less than 1 month 9 (8.9%)
1 to 3 months 16 (15.8%)
3 to 6 months 67 (66.3%)
More than 6 months 9 (8.9%)

Data are presented as n (%); CFTR: cystic fibrosis transmembrane conductance reg-ulator.

Most patients reported a decrease in the daily time spent for other treatments, particularly chest physiotherapy, which some patients were able to completely discontinue. There was a decrease in

the need for intravenous antibiotics and in time spent in hospi-tal. Importantly, lung transplantation discussions were suspended in the majority of patients who had been on – or were consid-ered for – the lung transplantation candidate list prior to initiating elexacaftor-tezacaftor-ivacaftor. Finally, in the subset of patients with diabetes, several reported improved glycaemic control, some-times reflected by a decrease in insulin needs.

3.3. Impact on self-esteem and qualitative evaluation

Most patients reported an improvement in physical self-esteem in their answer to item “j” of open question 9 on physical appear-ance (see Fig. 1H). Five broad themes emerged from the qualitative analysis of the free-text responses to question 13 (general con-clusion on how triple therapy has impacted their lives): “prior suffering”, “impact”, “bewilderment”, “pleasure” and “new plans for the future”. Each theme contained four to five categories (see Fig. 3). The emerging framework clearly showed a “before” and an “after” treatment initiation. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation “before” treatment ini-tiation, to renewed and unexpected physical strength, leading to greater self-confidence and autonomy thereafter. The impact of the


C. Martin, E. Burnet, A. Ronayette-Preira et al. Respir. Med and Res 80 (2021) 100829

Fig. 3. Diagram depicting results of free-text analysis, using a grounded theory approach, of responses to the final questions on the overall perceived effects of elexacaftor-tezacaftor-ivacaftor. The analysis of 101 responses using a grounded theory approach allowed the emergence of a theoretical framework, which clearly showed a “before” and an “after” elexacaftor-tezacaftor-ivacaftor (ELX-TEZ-IVA) initiation, contrasting the consequences of advanced disease before initiation to the benefits associated with treatment on physical, psychological and social aspects, leading to the formulation of new life goals and improved quality of life.

physical and psychological changes observed on social roles and on peer and/or family relationships was notable, with a newly found freedom from the guilt of imposing the illness on others.

The physical, psychological and social impacts of treatment were found to have two main consequences: increased pleasure in life/improved quality of life and new life goals (long-term plan-ning). Surprise at the magnitude of the effects was a ubiquitous theme. Many wrote of a “miracle”, a “revolution” and “magic”, with terms like “resurrection”, “new life”, “rebirth”, and “second chance” occurring frequently. The improvement in quality of life was felt in terms of appreciation at having the time -and being physically able- to participate in certain activities, socially in particular, and in terms of newfound pleasures such as unimpeded eating and laugh-ing. Long-term planning contrasted with the perception of a closed future prior to elexacaftor-tezacaftor-ivacaftor initiation, described as leading to transplantation or death. Many spoke of being able to make plans for future, and of having new goals, such as marriage, parenthood and professional or educational prospects.

Few patients expressed any reservations regarding the effects of treatment. Some perceived their weight gain and/or the change in their appearance negatively. Only one patient wrote of being concerned about the effects potentially tapering off and expressed disappointment. A few others wrote of limited quantifiable effects but noticeable improvement on breathing quality and energy, which may have been due to treatment being available too late in the course of their decline. Emotional ambiguity was also expressed with regards to a new dependence towards the drug. Nonetheless, overall, the perception of treatment effectiveness on all aspects of health and life was overwhelmingly positive and encouraging. This was also clearly apparent in the content analysis demonstrating the frequency with which terms were used (see word cloud depicted in Fig. 4).

4. Discussion

Patient perspectives on the effects of elexacaftor-tezacaftor-ivacaftor were obtained from 101 patients with advanced CF using a questionnaire combining both closed and free-text questions.

Initiation of elexacaftor-tezacaftor-ivacaftor was associated with a significant improvement in respiratory symptoms, sleep quality and physical self-esteem, and with a reduction in treatment burden. Furthermore, grounded theory analysis of the free-text responses to the concluding question showed that initiation of elexacaftor-tezacaftor-ivacaftor had positive physical, psychological and social effects, which translated into improved quality of life and the for-mulation of new life goals and an overwhelmingly positive impact on general well-being.

To our knowledge, the present study is the first to seek patient perspectives following the initiation of elexacaftor-tezacaftor-ivacaftor in patients with advanced pulmonary disease. Previous studies have described the improvement in patient-reported qual-ity of life with regards to respiratory symptoms following initiation of elexacaftor-tezacaftor-ivacaftor in patients aged 12 years and older with ppFEV1 between 40 and 90, and reported a large numerical increase in the CFQ-R respiratory domain score that exceeded the minimum for a clinically important difference [1–3]. Our study confirms these previous reports and extends the find-ings by giving voice to patient perceptions of the changes in pulmonary symptoms, extrapulmonary manifestations and treat-ment burden in those with advanced disease. Interestingly, patients did not report any improvement in gastro-intestinal symptoms, which may require further investigation to determine whether this was due to treatment adverse effects or to other factors unrelated to CFTR function. Nonetheless, these patient-reported outcomes suggest that elexacaftor-tezacaftor-ivacaftor contributes to remarkable improvement in multiple aspects of patient quality of life across the range of disease severity.

One strength of our study was the use of the grounded theory approach to analyse open free-text responses and explore patient impressions of this novel treatment, about which little is known at this time. While open questions allow patients to choose to empha-size certain topics and give more strength to the answers provided, grounded theory is a rigorous methodology that involves the con-struction of hypotheses and theories through the collection and analysis of free-text data and has been widely applied to qualitative research in the social sciences. To our knowledge, it has not been


C. Martin, E. Burnet, A. Ronayette-Preira et al. Respir. Med and Res 80 (2021) 100829

Fig. 4. Word cloud analysis of free-text answers. Diagram produced with weighted word size based on frequency of occurrence (see Methods). Larger words are those that were found more frequently.

used previously to evaluate the perspectives of CF patients regard-ing treatments and quality of life. Our sample of 101 responses was considered sufficient to allow a structured analysis and the emergence of a theoretical framework. Importantly, the framework identified through grounded theory analysis was largely substanti-ated by the content analysis examining the word frequency, which strengthened our findings.

A relatively large number of patients with advanced CF treated with elexacaftor-tezacaftor-ivacaftor (n = 101)–41% of all patients treated in France at the time of the survey–agreed to participate. The true response rate remains unclear, as there is no way to know how many of the 245 patients treated at that time actually received the questionnaire, and a longer time frame could have yielded more responses. Indeed, patients were asked to complete the survey over only six weeks during the summer and the study could not been extended as the goal was to provide timely data for the French reg-ulatory agency. The sample of patients and the responses provided may therefore not be representative of the population of CF patients with advanced disease as a whole and those with positive outcomes may have been more likely to respond, thus introducing responder bias.

Although responder bias cannot be excluded, the relative homo-geneity of responses reinforces confidence in our findings. All answers were taken into account in the analysis, and when a particular symptom was not mentioned in the patient’s response (whether worsened, unchanged or improved) it was categorized as “not reported”. Even though it appears very unlikely, we can-not exclude that the patient omitted to declare a worsening of symptoms rather than the absence of symptoms. Yet patients who experienced negative outcomes would have been equally moti-vated to participate in the study and to respond truthfully to the open questions, which were worded so as to illicit both positive and negative responses.

Indeed, we sought to explore patient perspectives through their own words. The mixed methods design and the use of grounded theory should therefore be seen as hypothesis-generating rather than solid evidence. For example, over two thirds of diabetic patients reported an improvement in glycaemic control, which will need confirmation in further research, as only limited effects were observed with previous CFTR modulators (e.g., lumacaftor-ivacaftor) [9,10]. Furthermore, the CFQ-R questionnaire, which is commonly used to evaluate quality of life in clinical trials on CFTR modulator therapy, was not used the present study. We therefore cannot draw any comparisons between our findings and those reported in clinical trials. However, our study population was

limited to patients with advanced lung disease, which were excluded from clinical trials, and our findings cannot be gener-alized to the CF population as a whole. Finally, this survey was conducted relatively early after treatment initiation, with a median time of 4.3 months. Longer-term data may yield different findings.

Data on patient perspectives after the initiation of elexacaftor-tezacaftor-ivacaftor are a useful adjunct to results obtained in randomized clinical trials and in real-world observational stud-ies. Although safety and efficacy must be evaluated in randomized control trials, real-world studies assess the effectiveness of novel therapies in less selective populations [11,12], thus providing com-plementary evidence. Going further, seeking patient perspectives may provide useful insight into their experience and expecta-tions of novel drugs, which regulatory agencies are increasingly interested in. Researchers have therefore started conducting sur-veys in both patients and caregivers to guide research priorities [6,13] and future studies [14]. There is little doubt that such an approach should be further developed in future years as collabora-tion between researchers and patients appears essential.

In conclusion, the results of a survey seeking the perspectives of patients with advanced CF within the few months after elexacaftor-tezacaftor-ivacaftor initiation provided interesting insights into the benefits associated with highly effective CFTR modulators in the short term. These insights were communicated to the French regulatory agency and likely contributed to the recognition that elexacaftor-tezacaftor-ivacaftor has incremental value in compar-ison with previous CFTR modulators. Long-term evaluation will be necessary to confirm these trends.



Author contributions

Data acquisition: AR, PdC.

Data analysis: all authors.

Manuscript drafting: CM, EB, PRB.

Manuscript revision, editing, approval: all authors.

Disclosure of interest

EB, AR, PdC, JM, LD, BP declare that they have no competing interest.


C. Martin, E. Burnet, A. Ronayette-Preira et al.

CM declares personal fees from Chiesi, Vertex and Zambon for lecturing and/or participating to advisory board outside of this work.

PRB declares personal fees from Astra-Zeneca, Boehringer Ingel-heim, Chiesi, GSK, Novartis, Pfizer, Teva, Vertex and Zambon for lecturing and/or participating to advisory board and grants from GSK and Vertex, all outside of this work.


The authors thank the patients and families that took time to answer the survey and doctors and nurses working in the French Cystic Fibrosis Reference Center Network who helped disseminat-ing the questionnaire to the patients.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/ j.resmer.2021.100829.


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