Behavioural and sleep issues after initiation of elexacaftor–tezacaftor–ivacaftor in preschool-age children with cystic fibrosis

The introduction of triple combination therapy with elexacaftor–tezacaftor–ivacaftor (ETI), a highly effective CFTR modulator drug, has revolutionised the prognosis for people with cystic fibrosis carrying at least one p.Phe508del (F508del) allele.1 ETI restores chloride transport through the F508de...

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Published in:	The Lancet (British edition) Vol. 404; no. 10448; pp. 117 - 120
Main Authors:	Sermet-Gaudelus, I, Benaboud, Sihem, Bui, Stéphanie, Bihouée, Tiphaine, Gautier, Sophie, Barboura, Mahassen, Barzic, Audrey, Benhalla, Lilia, Bennour, Khadidja, Bessaci, Katia, Bessou, Antoine, Bihouee, Thiphaine, Bonnel, Anne-Sophie, Bouleghem, Nesrine, Chedevergne, Frédérique, Corvol, Harriet, Cosson, Laure, Couderc, Laure, Dalphin, Marie-Laure, De carli, Paola, Deneuville, Eric, Foucaud, Pierre, Gabsi, Asma, Gachelin, Elsa, Hassani, Fatiha, Houdouin, Veronique, Huet, Frédéric, Jamin, Marie, Kaba, Kadiatou, Labbe, Guillaume, Languepin, Jane, Laurans, Muriel, Lerena, Cathy, Letierce, Alexia, Livrozet, Clotilde, Marguet, Christophe, Mely, Laurent, Messaoudi, Rania, Mittaine, Marie, Perisson, Caroline, Piccini-bailly, Carole, Reix, Philippe, Remus, Natascha, Ronayette, Anna, Sahki, Djouher, Scalbert, Manuela, Sermet-Gaudelus, Isabelle, Socchi, Floriane, Stremler, Nathalie, Tatopoulos, Aurélie, Thouvenin, Guillaume, Troussier, Françoise, Weiss, Laurence, Wizla, Nathalie
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 13-07-2024 Elsevier Limited Elsevier
Subjects:	Adolescents Adverse events Age Anxiety Asymptomatic Attention deficit hyperactivity disorder Children Chloride Chloride transport Chlorides Clinical trials Cystic fibrosis Fluoxetine Life Sciences Literature reviews Locomotor activity Lungs Nocebos Patients Pediatrics Placebos Plasma Questionnaires Respiratory function Sleep Subgroups Suicidal behavior Suicidal ideation Suicide Suicides & suicide attempts Sweat Teenagers France
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Summary:	The introduction of triple combination therapy with elexacaftor–tezacaftor–ivacaftor (ETI), a highly effective CFTR modulator drug, has revolutionised the prognosis for people with cystic fibrosis carrying at least one p.Phe508del (F508del) allele.1 ETI restores chloride transport through the F508del-CFTR channel, which is associated with significant improvement in lung function and sweat chloride concentration in patients older than 6 years.2 A placebo-controlled study showed that ETI improves lung clearance, bodyweight, and sweat chloride concentration after 6 months of treatment in children with cystic fibrosis aged 2–6 years, with an overall acceptable safety profile.3 In France, children with cystic fibrosis (age ≥2 years) have had access to ETI since December, 2023.4 In this context, 197 preschool-age children (ie, aged 2–5 years) were enrolled from 34 paediatric cystic fibrosis referral centres across France in the real-world study MODUL-CF (NCT04301856) and underwent an evaluation at baseline and at follow-up visits at 1 month and 3 months. In an in-vivo murine depression model, ivacaftor resulted in improvement in locomotor activity, similar to fluoxetine, and a non-controlled study showed a decreased prevalence of depression in patients treated with ivacaftor.11 In 14 randomised controlled trials in individuals older than 6 years, mainly in adolescents and adults, no alarming adverse events have been observed.6 Ramsey and colleagues6 reported a similar exposure-adjusted rate of depression-related adverse events in a pooled group of patients aged 6 years and older treated with ETI (3·32 per 100 person-years; 1711 patients) compared with the placebo group (3·24 per 100 person-years; 1369 patients), as well as for suicidal ideation (0·23 per 100 person-years in the ETI group vs 0·28 per 100 person-years in the placebo group) and suicide attempt (0·08 per 100 person-years vs 0·14 per 100 person-years).6 We searched the literature for depression or depression-related events in phase 4 or real-world post-marketing studies of ETI that used validated instruments to evaluate depression symptoms, such as the Patient Health Questionnaire, and we did not identify any studies reporting an increase in depression events with ETI, apart from in specific subgroups (the search strategy for literature review and results are in the appendix [pp 2–3, 5, 7–9]).6 Patients who undergo successful treatment for cystic fibrosis might have difficulties adapting to their new life paradigm, in terms of the shift from a status of patient to that of asymptomatic healthy individual. In addition to this shift, some behavioural issues might also be discovered that were not previously recognised or not considered while they had symptomatic cystic fibrosis. [...]the patients who are aware of the potential adverse events of ETI might experience a so-called nocebo effect. [...]our observations, the first to our knowledge in preschool-age children, raise the possibility of an iatrogenic effect.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Correspondence-1 ObjectType-Feature-3 content type line 23
ISSN:	0140-6736 1474-547X 1474-547X
DOI:	10.1016/S0140-6736(24)01134-6