Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis

Silva Filho, Luiz Vicente Ribeiro Ferreira da; Athanazio, Rodrigo Abensur; Tonon, Carolina Rodrigues; Ferreira, Juliana Carvalho; Tanni, Suzana Erico

doi:10.36416/1806-3756/e20230187

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SYSTEMATIC REVIEW AND META-ANALYSIS • J. bras. pneumol. 49 (6) • 2023 • https://doi.org/10.36416/1806-3756/e20230187 linkcopy

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis.

Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV₁% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, −0.16; 95% CI, −0.28 to −0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m²; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, −0.03; 95% CI, −0.08 to 0.01), and none of the studies reported deaths.

Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Keywords: Cystic fibrosis/therapy; Cystic fibrosis transmembrane conductance regulator; Membrane transport modulators

Study	Design	Population	Intervention (N)	Comparator (N)	Outcome	Duration
Barry et al.²³ (NCT04058353) North America, Europe, and Australia	Phase 3 double-blind RCT with active control arm	≥ 12-year-olds with CF and F508del-gating or F508del-residual function genotypes	ETI E: 200 mg once daily; I: 150 mg every 12 h; T: 100 mg once daily (N = 132)	TI or I I: 150 mg every 12 h; T: 100 mg once daily (N = 126)	FEV₁%, sweat chloride concentration, score on CFQ respiratory domain, adverse events	8 weeks
Heijerman et al.¹⁴ (NCT03525548) Belgium, Netherlands, UK, and USA (NCT03525574-extension)	Phase 3 double-blind RCT with active control arm Open label extension	≥ 12-year-olds with CF and homozygous for F508del mutation, FEV₁ 40-90%, stable CF	ETI E: 200 mg once daily; I: 150 mg every 12 h; T: 100 mg once daily (N = 55)	TI T: 100 mg once daily; I: 150 mg, every 12 h (N = 52)	FEV₁%, sweat chloride concentration, score on CFQ respiratory domain, adverse events	4 weeks 96-week extension
Keating et al.¹² (NCT03227471) USA, Netherlands, Belgium, and Australia	Phase 2 double-blind RCT with active control arm or placebo	≥ 18-year-olds with CF F508del-MF genotype patients were randomized to receive triple therapy or a triple placebo control Patients homozygous for the F508del mutation genotype were randomized to receive triple therapy or active control arm	F508del-MF genotype: ETI E: 50,100, or 200 mg once daily); I: 150 mg every 12 h; T: 100 mg once daily (n = 53) or VX-445 in triple combination with T and VX-561 (n = 22) Homozygous for F508del: ETI E: 200 mg/day p.o.; T: 100 mg/day; I: 150 mg every 12 h (n = 21) [64 patients received E 200 mg per day p.o.] (N = 96)	F508del-MF genotype: placebo (n = 12) or VX-445 in triple combination (n = 8) Homozygous for F508del: TI I: 150 mg every 12 h; T: 100 mg once daily (n = 7) (N = 27)	FEV₁%, score on CFQ respiratory domain, adverse events	4 weeks
Mall et al.¹⁶ (NCT04353817) Australia, Canada, Denmark, France, Germany, Israel, Netherlands, Spain, Switzerland, and UK	Phase 3 double-blind placebo-controlled RCT	6-12-year-olds with CF and F508del-MF genotypes, FEV₁ 40-90%, stable CF	Children < 30 kg: E: 100 mg once daily; T: 50 mg once daily; I: 75 every 12 h Children ≥ 30 kg: E: 200 mg once daily; T: 100 mg once daily; I: 150 every 12 h (N = 60)	Placebo (N = 61)	FEV₁%, lung clearance index, sweat chloride concentration, score on CFQ respiratory domain, adverse events	24 weeks
Middleton et al.¹³ (NCT03525444) USA, Europe, and Australia Extension (NCT03525574)	Phase 3 double-blind placebo-controlled RCT Open label-extension	≥ 12-year-olds with CF and heterozygous for the F508del-MF genotype, FEV₁ 40-90%, stable CF	ETI E: 200 mg once daily; I: 150 mg every 12 h; T: 100 mg once daily (N = 201)	Placebo (N = 204)	FEV₁%, exacerbations, BMI, sweat chloride concentration, score on CFQ respiratory domain, adverse events	24 weeks 96-week extension
Sutharsan et al.¹⁵ (NCT04105972) Australia, Belgium, Germany, and UK	Phase 3 double-blind RCT with active control arm	≥ 12-year-olds with CF and homozygous for F508del, FEV₁ 40-90%, stable CF	ETI E: 200 mg once daily; I: 150 mg every 12 h; T: 100 mg once daily (N = 87)	TI I: 150 mg every 12 h; T: 100 mg once daily (N = 88)	FEV₁%, sweat chloride concentration, score on CFQ respiratory domain, adverse events	24 weeks

Study	Randomization	Allocation	Double blind	Observer	Losses	Characteristic Prognosis	Outcome	ITT	Sample size calculation	Early stop trial
Barry et al.²³
Heijerman et al.¹⁴
Keating et al.¹²
Mall et al.¹⁶
Middleton et al.¹³
Sutharsan et al.¹⁵

Certainty assessment							No of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Elexacaftor +tezacaftor + ivacaftor	Placebo or active control	Relative (95% CI)	Absolute (95% CI)
Mortality
6	randomized trials	serious^a	not serious	not serious	not serious	none	0/577 (0.0%)	0/550 (0.0%)	not estimable	0 fewer per 1000 (from 0 fewer to 0 more)	𑁣𑁣𑁣𐊫 Moderate	CRÍTICAL
Adverse events
6	randomized trials	serious^a	not serious	not serious	not serious	none	470/577 (81.5%)	464/550 (84.4%)	not estimable	0 fewer per 1000 (from 0 fewer to 0 more)	𑁣𑁣𑁣𐊫 Moderate	CRÍTICAL
Quality of life
6	randomized trials	serious^a	serious^b	not serious	serious^c	none	577	550	-	mean 14.93 points higher (9.98 higher to 19.89 higher)	𑁣𐊫𐊫𐊫 Very low	CRÍTICAL
Pulmonary exacerbations
6	randomized trials	serious^a	serious^b	not serious	not serious	none	65/577 (11.3%)	165/550 (30.0%)	not estimable	0 fewer per 1000 (from 0 fewer to 0 fewer)	𑁣𑁣𐊫𐊫 Low	IMPORTANT
FEV₁
6	randomized trials	serious^a	serious^b	not serious	serious^c	none	577	550	-	mean 10.47 pp higher (6.88 higher to 14.06 higher)	𑁣𐊫𐊫𐊫 Very low	IMPORTANT
BMI
3	randomized trials	serious^a	serious^b	not serious	serious^c	none	343	344	-	mean 1.07 kg/m² higher (0.9 lower to 1.25 higher)	𑁣𐊫𐊫𐊫 Very low	IMPORTANT

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Sociedade Brasileira de Pneumologia e Tisiologia SCS Quadra 1, Bl. K salas 203/204, 70398-900 - Brasília - DF - Brasil, Fone/Fax: 0800 61 6218 ramal 211, (55 61)3245-1030/6218 ramal 211 - São Paulo - SP - Brazil
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[TFN1] RCT: randomized controlled trial; CF: cystic fibrosis; E: elexacaftor; T: tezacaftor; I: ivacaftor; CFQ: Cystic Fibrosis Questionnaire; and MF: minimal function.