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Cited by 2,225Cystic Fibrosis Research AdvancesInhalation and Respiratory Drug DeliveryGenetic and Kidney Cyst Diseases

Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Open access
Middleton, Peter G., Mall, Marcus A., Dřevínek, Pavel, Lands, Larry C., McKone, Edward F., Polineni, Deepika, Ramsey, Bonnie W., Taylor-Cousar, Jennifer L. +13 more·2019·New England Journal of Medicine
DOI 10.1056/nejmoa1908639PMC PMC7282384
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Abstract

BACKGROUNDCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation.In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimalfunction mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODSWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes.Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks.The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV 1 ) at week 4. RESULTSA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo.Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV 1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001for all comparisons).Elexacaftortezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile.Most patients had adverse events that were mild or moderate.Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONSElexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective.(Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.govnumber, NCT03525444.

AI snapshot

Written from the paper’s full text.

TL;DR

In a phase 3, randomized, double-blind, placebo-controlled trial, elexacaftor–tezacaftor–ivacaftor improved lung function, pulmonary exacerbation rate, respiratory symptoms, sweat chloride, and BMI in patients with cystic fibrosis and Phe508del–minimal function genotypes. The regimen was generally safe, with adverse events mostly mild or moderate.

Key findings

  • Elexacaftor–tezacaftor–ivacaftor increased percentage of predicted FEV1 by 13.8 points at week 4 and 14.3 points through week 24 relative to placebo (P<0.001 for both).
  • The annualized rate of pulmonary exacerbations was 63% lower with active treatment than placebo (rate ratio, 0.37; 95% CI, 0.25 to 0.55; P<0.001).
  • CFQ-R respiratory domain score improved by 20.2 points and sweat chloride concentration decreased by 41.8 mmol per liter relative to placebo through week 24 (P<0.001 for both); BMI improved by 1.04 (P<0.001).
  • Adverse events occurred in 93.1% of the elexacaftor–tezacaftor–ivacaftor group and 96.0% of the placebo group; 1% of active-treatment patients discontinued because of adverse events, and there were no deaths.

Methods

  • Phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 115 sites in 13 countries; 405 patients underwent randomization and 403 received at least one dose (200 active, 203 placebo).
  • Eligible patients were 12 years of age or older with cystic fibrosis and Phe508del–minimal function genotypes, screening ppFEV1 40 to 90%, and stable disease during a 28-day screening period; patients were randomly assigned 1:1 to elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks.
  • The primary end point was absolute change from baseline in ppFEV1 at week 4, analyzed with a mixed-effects model for repeated measures; pulmonary exacerbations were analyzed with negative binomial regression.

Limitations

  • The paper does not include a formal limitations section.
  • Evident from the text: the intervention period was 24 weeks, so long-term durability and safety beyond 24 weeks are not established; patients could enroll in an ongoing 96-week open-label extension.
  • Evident from the text: eligibility was restricted to patients 12 years or older with Phe508del–minimal function genotypes and screening ppFEV1 40 to 90%, limiting generalizability to younger children, other CFTR genotypes, or patients outside that lung-function range.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1056/nejmoa1908639

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

19 of 38 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    For persons homozygous for the Phe508del CFTR mutation, the combination of a single corrector, either lumacaftor or tezacaftor, with the potentiator ivacaftor improves clinical outcomes, including lung function and the rate of pulmonary exacerbations.

    “For persons with cystic fibrosis who are homozygous for the Phe508del CFTR mutation, the combination of a single corrector, either lumacaftor or tezacaftor, with the potentiator ivacaftor improves clinical outcomes, including lung function and the rate of pulmonary exacerbations.9,11”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] Wainwright CE, Elborn JS, Ramsey BW, Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; 373: 220– 31. 25981758 PMC4764353 source
    • cites [11] Taylor-Cousar JL, Munck A, McKone EF, Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 2017; 377: 2013– 23. 29099344 source
  • Premisecitation

    The triple-combination regimen includes the next-generation corrector elexacaftor plus the corrector tezacaftor and the potentiator ivacaftor to more fully restore the function of Phe508del CFTR.

    “The combination includes the next-generation corrector elexacaftor plus the corrector tezacaftor and the potentiator ivacaftor to more fully restore the function of Phe508del CFTR.18”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Keating D, Marigowda G, Burr L, VX-445-tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1612– 20. 30334692 PMC6289290 source

      The Background identifies VX-445 as a next-generation corrector used with tezacaftor and ivacaftor to restore Phe508del CFTR function. The in vitro Results report greater chloride transport with the triple combination than with one- or two-drug treatments. Our copy does not identify VX-445 by the name elexacaftor, so that specific identification cannot be verified from this source alone. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The efficacy and safety findings of this trial are consistent with those of the phase 2 trial of elexacaftor-tezacaftor-ivacaftor.

    “In this 24-week trial of triple-combination CFTR modulator therapy in patients with cystic fibrosis who have a single Phe508del allele, elexacaftor–tezacaftor–ivacaftor treatment resulted in improvements in lung function, the rate of pulmonary exacerbations, sweat chloride concentration, CFQ-R respiratory domain scores, and BMI and was generally safe with an acceptable side-effect profile,”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Keating D, Marigowda G, Burr L, VX-445-tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1612– 20. 30334692 PMC6289290 source
  • Premisecitation

    The improvement in the primary end point of absolute change in percentage of predicted FEV1 was 10.6 points in patients with the Gly551Asp allele.

    “The improvement in the primary end point of absolute change in percentage of predicted FEV1 was 10.6 points in patients with the Gly551Asp allele.10”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Ramsey BW, Davies J, McElvaney NG, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663– 72. 22047557 PMC3230303 source
  • Premisecitation

    In proof-of-concept trials, elexacaftor-tezacaftor-ivacaftor led to improvements in spirometry, patient-reported respiratory symptoms, and sweat chloride concentration in patients with cystic fibrosis with a single Phe508del allele.

    “In proof-of-concept trials that evaluated this therapeutic approach,16,18 elexacaftor–tezacaftor–ivacaftor led to improvements in spirometry, patient-reported respiratory symptoms, and sweat chloride concentration, a marker of CFTR activity, in patients with cystic fibrosis with a single Phe508del allele.18”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Davies JC, Moskowitz SM, Brown C, VX-659-tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1599– 611. 30334693 PMC6277022 source

      The Results (Phase 2 Efficacy; page not provided) report improved FEV1, sweat chloride concentration, and CFQ-R respiratory scores in patients with a single Phe508del allele. But the Methods (Clinical Development; page not provided) identify the treatment as VX-659–tezacaftor–ivacaftor, not elexacaftor–tezacaftor–ivacaftor. This source therefore supports the outcomes and patient group, but not the named regimen. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [18] Keating D, Marigowda G, Burr L, VX-445-tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379: 1612– 20. 30334692 PMC6289290 source
    • Rests on an assumption: Sweat chloride concentration is a marker of CFTR activity.
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 22

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pulmonary exacerbations are important clinical events associated with disease progression.

    “Pulmonary exacerbations are important clinical events associated with disease progression21-24; elexacaftor–tezacaftor–ivacaftor resulted in a lower rate of pulmonary exacerbations, including severe events leading to hospitalization or treatment with intravenous antibiotics, than placebo.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [21] Amadori A, Antonelli A, Balteri I, Schreiber A, Bugiani M, De Rose V. Recurrent exacerbations affect FEV(1) decline in adult patients with cystic fibrosis. Respir Med 2009; 103: 407– 13. 19027279 source
    • cites [22] De Boer K, Vandemheen KL, Tullis E, Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax 2011; 66: 680– 5. 21680566 source
    • cites [23] Konstan MW, Wagener JS, Vandevanter DR, Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. J Cyst Fibros 2012; 11: 405– 11. 22561369 PMC4086189 source
    • cites [24] Sanders DB, Zhao Q, Li Z, Farrell PM. Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes. Pediatr Pulmonol 2017; 52: 1268– 75. 28881091 PMC5639928 source

  • May combine two claims.

    Premisecitation

    CFTR modulators treat the underlying cause of disease and improve clinical outcomes in persons with specific CFTR mutations.

    “CFTR modulators treat the underlying cause of disease and have improved clinical outcomes in persons with specific CFTR mutations.9-12”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [9] Wainwright CE, Elborn JS, Ramsey BW, Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; 373: 220– 31. 25981758 PMC4764353 source
    • cites [10] Ramsey BW, Davies J, McElvaney NG, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663– 72. 22047557 PMC3230303 source
    • cites [11] Taylor-Cousar JL, Munck A, McKone EF, Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 2017; 377: 2013– 23. 29099344 source
    • cites [12] Rowe SM, Daines C, Ringshausen FC, Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377: 2024– 35. 29099333 PMC6472479 source

  • May combine two claims.

    Interpretationcitation

    The efficacy outcomes confirm the hypothesis that elexacaftor-tezacaftor-ivacaftor effectively modulates the function of Phe508del CFTR from a single allele, providing pronounced benefits in a population of patients in whom previous CFTR modulator therapies were not effective.

    “The efficacy outcomes confirm the hypothesis that elexacaftor–tezacaftor–ivacaftor effectively modulates the function of Phe508del CFTR from a single allele, providing pronounced benefits in a population of patients in whom previous CFTR modulator therapies were not effective.15,19”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [15] Rowe SM, McColley SA, Rietschel E, Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc 2017; 14: 213– 9. 27898234 PMC5461999 source
    • cites [19] Clancy JP. Rapid therapeutic advances in CFTR modulator science. Pediatr Pulmonol 2018; 53: Suppl 3: S4– S11. PMC6585954 30289627 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The current benchmark for highly effective CFTR modulator therapy is ivacaftor for patients with the Gly551Asp CFTR mutation, in whom disease modification has been shown with long-term use, including decreased lung-function decline and decreased mortality.

    “The current benchmark for highly effective CFTR modulator therapy is ivacaftor for patients with the Gly551Asp CFTR mutation,10 in whom disease modification has been shown with long-term use, including decreased lung-function decline and decreased mortality.25-28”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [10] Ramsey BW, Davies J, McElvaney NG, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663– 72. 22047557 PMC3230303 source
    • cites [25] Sawicki GS, McKone EF, Pasta DJ, Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 2015; 192: 836– 42. 26132840 source
    • cites [26] Volkova N, Moy K, Evans J, Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries. J Cyst Fibros 2019 6 10 (Epub ahead of print). 31196670 source
    • cites [27] Rowe SM, Heltshe SL, Gonska T, Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175– 84. 24927234 PMC4226057 source
    • cites [28] Bessonova L, Volkova N, Higgins M, Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73: 731– 40. 29748252 PMC6204955 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

    “Cystic fibrosis is a lethal, inherited, autosomal recessive disorder that affects approximately 80,000 people worldwide and is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein that lead to reduced CFTR function.1-3”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891– 904. 19403164 source
    • cites [2] Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519– 31. 27140670

      Not checked in the free run.

    • cites [3] Sanders DB, Fink AK. Background and epidemiology. Pediatr Clin North Am 2016; 63: 567– 84. 27469176 PMC4967225 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ivacaftor and tezacaftor-ivacaftor are approved therapies with well-characterized safety profiles.

    “Ivacaftor and tezacaftor–ivacaftor, two components of this triple combination, are approved therapies, with well-characterized safety profiles.10-12,30”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [10] Ramsey BW, Davies J, McElvaney NG, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663– 72. 22047557 PMC3230303 source

      The Discussion reports that 48 weeks of ivacaftor was not associated with greater safety risk than placebo, supporting the ivacaftor safety portion. This paper does not establish approval status or address the safety of tezacaftor–ivacaftor; it describes ivacaftor as investigational at the time of the study. Page numbers were not supplied for these passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [11] Taylor-Cousar JL, Munck A, McKone EF, Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 2017; 377: 2013– 23. 29099344 source
    • cites [12] Rowe SM, Daines C, Ringshausen FC, Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377: 2024– 35. 29099333 PMC6472479 source

      The Discussion reports that tezacaftor–ivacaftor was safe and well tolerated in this trial and that ivacaftor recapitulated its well-established safety profile; the Results > Safety section provides supporting adverse-event data. Our copy does not state that both treatments were approved therapies, so it does not support that part of the claim. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [30] Habib AR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A systematic review of the clinical efficacy and safety of CFTR modulators in cystic fibrosis. Sci Rep 2019; 9: 7234. 31076617 PMC6510767 source

      The Discussion (page not provided) concludes that ivacaftor is safe for people with a G551D mutation and that tezacaftor–ivacaftor is safer than lumacaftor–ivacaftor in F508del-homozygous individuals. It also says long-term placebo-controlled effects remain unclear. Our copy supports safety findings in those studied groups, but does not establish that both therapies are approved or that their safety profiles are well characterized without those limits. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In the elexacaftor-tezacaftor-ivacaftor group, elevated levels of alanine aminotransferase or aspartate aminotransferase greater than three times, greater than five times, and greater than eight times the upper limit of the normal range occurred in 16 patients (7.9%), 5 patients (2.5%), and 3 patients (1.5%), respectively, as compared with 11 patients (5.5%), 3 patients (1.5%), and 2 patients (1.0

    “In the elexacaftor–tezacaftor–ivacaftor group, elevated levels of alanine aminotransferase or aspartate aminotransferase that were greater than three times, greater than five times, and greater than eight times the upper limit of the normal range occurred in 16 patients (7.9%), 5 patients (2.5%), and 3 patients (1.5%), respectively, as compared with 11 patients (5.5%), 3 patients (1.5%), and 2”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sustained improvement in percentage of predicted FEV1 was seen through week 24, with a mean treatment difference of 14.3 points relative to placebo (P<0.001).

    “Sustained improvement in percentage of predicted FEV1 was seen through week 24 (final analysis), with a mean treatment difference of 14.3 points relative to placebo (P<0.001) (Table 2 and Fig. 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serious adverse events occurred in 28 patients (13.9%) in the elexacaftor-tezacaftor-ivacaftor group and 42 patients (20.9%) in the placebo group; excluding serious adverse events of pulmonary exacerbation, serious adverse events occurred in 20 patients (9.9%) in the elexacaftor-tezacaftor-ivacaftor group and 16 patients (8.0%) in the placebo group.

    “Serious adverse events occurred in 28 patients (13.9%) in the elexacaftor–tezacaftor–ivacaftor group and 42 patients (20.9%) in the placebo group (Table 3 and Table S6); excluding serious adverse events of pulmonary exacerbation, serious adverse events occurred in 20 patients (9.9%) in the elexacaftor–tezacaftor–ivacaftor group and 16 patients (8.0%) in the placebo group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two patients (1.0%) in the elexacaftor-tezacaftor-ivacaftor group discontinued the trial regimen because of adverse events: rash in 1 patient and portal hypertension in a patient with preexisting cirrhosis.

    “Two patients (1.0%) in the elexacaftor–tezacaftor–ivacaftor group discontinued the trial regimen because of adverse events: rash in 1 patient and portal hypertension in a patient with preexisting cirrhosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The baseline mean systolic and diastolic blood pressures in the elexacaftor-tezacaftor-ivacaftor group were 113.4 mm Hg and 69.4 mm Hg, and they increased by 3.1 mm Hg and 1.9 mm Hg, respectively, at week 24.

    “The baseline mean systolic and diastolic blood pressures in the elexacaftor–tezacaftor–ivacaftor group were 113.4 mm Hg and 69.4 mm Hg, and they increased by 3.1 mm Hg and 1.9 mm Hg, respectively, at week 24 (Table S9).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In both trial groups, rash was more common in female patients than in male patients and more common in female patients who used hormonal contraceptives than in those who did not.

    “In both trial groups, rash was more common in female patients than in male patients and more common in female patients who used hormonal contraceptives than in those who did not (Table S7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The percentage of patients with at least one adverse event was 93.1% in the elexacaftor-tezacaftor-ivacaftor group and 96.0% in the placebo group; excluding adverse events of pulmonary exacerbation, the percentage was 92.6% in the elexacaftor-tezacaftor-ivacaftor group and 93.0% in the placebo group.

    “The percentage of patients with at least one adverse event was 93.1% in the elexacaftor–tezacaftor–ivacaftor group and 96.0% in the placebo group; excluding adverse events of pulmonary exacerbation, the percentage was 92.6% in the elexacaftor–tezacaftor–ivacaftor group and 93.0% in the placebo group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Elevated levels of creatine kinase were often associated with exercise, and no elevations of creatine kinase led to discontinuation of the trial regimen.

    “Elevated levels of creatine kinase were often associated with exercise, and no elevations of creatine kinase led to discontinuation of the trial regimen (Table S8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Additional observations included elevated levels of creatine kinase and blood-pressure changes in the elexacaftor-tezacaftor-ivacaftor group.

    “Additional observations included elevated levels of creatine kinase and blood-pressure changes in the elexacaftor–tezacaftor–ivacaftor group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    The elevated serum levels of creatine kinase that were observed were generally asymptomatic and often associated with exercise.

    “The elevated serum levels of creatine kinase that were observed were generally asymptomatic and often associated with exercise.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An increase in the incidence of elevated aminotransferase levels was observed with elexacaftor-tezacaftor-ivacaftor treatment; these adverse events were low grade in 20 of 22 patients (91%) and were not treatment-limiting.

    “An increase in the incidence of elevated aminotransferase levels, which occur sporadically in many persons with cystic fibrosis, was observed with elexacaftor–tezacaftor–ivacaftor treatment; these adverse events were low grade (i.e., mild or moderate) in 20 of 22 patients (91%) and were not treatment-limiting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    In general, cases of rash were mild to moderate and did not lead to alteration of treatment administration.

    “In general, cases of rash were mild to moderate and did not lead to alteration of treatment administration.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A Lan-DeMets alpha-spending function was applied to control the overall type I error rate of 0.05 for the primary end point.

    “A Lan–DeMets alpha-spending function was applied to control the overall type I error rate of 0.05 for the primary end point.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    FEV1 is a strong predictor of clinical status in cystic fibrosis.

    “FEV1 is a strong predictor of clinical status in cystic fibrosis,20 and elexacaftor–tezacaftor–ivacaftor resulted in sustained improvements in this end point.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326: 1187– 91. 1285737 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Patients were randomly assigned in a 1:1 ratio to receive elexacaftor-tezacaftor-ivacaftor or matched placebo.

    “Patients were randomly assigned in a 1:1 ratio to receive elexacaftor (200 mg once daily) in triple combination with tezacaftor (100 mg once daily) and ivacaftor (150 mg every 12 hours) or matched placebos.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A prespecified interim analysis was conducted for the primary end point when at least 140 patients had completed the week 4 visit and at least 100 patients had completed the week 12 visit.

    “A prespecified interim analysis was conducted for the primary end point when at least 140 patients had completed the week 4 visit and at least 100 patients had completed the week 12 visit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Overall, 405 patients underwent randomization, and 403 received at least one dose of the trial regimen (200 in the elexacaftor-tezacaftor-ivacaftor group and 203 in the placebo group).

    “Overall, 405 patients underwent randomization, and 403 received at least one dose of the trial regimen (200 in the elexacaftor–tezacaftor–ivacaftor group and 203 in the placebo group) (Fig. S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.

    “This phase 3, multicenter, randomized, double-blind, placebo-controlled trial of elexacaftor–tezacaftor–ivacaftor involved patients 12 years of age or older with cystic fibrosis and Phe508del-minimal function genotypes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Assuming a 5% dropout rate at week 4 and a within-group standard deviation of 7 percentage points, an interim-analysis sample size of 70 patients per trial group would provide approximately 98% power to detect a between-group difference of 5.0 points for the mean absolute change from baseline in percentage of predicted FEV1 at week 4, using a two-sided, two-sample t-test at a significance level of

    “Assuming a 5% dropout rate at week 4 and a within-group standard deviation of 7 percentage points, we estimated that an interim-analysis sample size of 70 patients per trial group would provide approximately 98% power to detect a between-group difference of 5.0 points for the mean absolute change from baseline in percentage of predicted FEV1 at week 4, using a two-sided, two-sample t-test at a”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The Phe508del CFTR mutation causes defective intracellular processing and trafficking and decreased stability, drastically reducing the quantity of CFTR protein at the apical surface of epithelial cells.

    “The Phe508del CFTR mutation causes defective intracellular processing and trafficking and decreased stability, which drastically reduces the quantity of CFTR protein at the apical surface of epithelial cells.4,7,8”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352: 1992– 2001. 15888700 source
    • cites [7] Dalemans W, Barbry P, Champigny G, Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 1991; 354: 526– 8. 1722027 source
    • cites [8] Lukacs GL, Chang XB, Bear C, The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane: determination of functional half-lives on transfected cells. J Biol Chem 1993; 268: 21592– 8. 7691813 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Randomization was performed in permuted blocks, with stratification according to percentage of predicted FEV1 at screening (<70% vs. ≥70%), age at screening (<18 years vs. ≥18 years), and sex.

    “Randomization was performed in permuted blocks, with stratification according to percentage of predicted FEV1 at screening (<70% vs. ≥70%), age at screening (<18 years vs. ≥18 years), and sex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The mean adherence to the trial regimen was more than 98% in both trial groups.

    “The mean adherence to the trial regimen was more than 98% in both trial groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Phe508del CFTR protein exhibits defective channel gating, which further limits anion transport.

    “Phe508del CFTR protein also exhibits defective channel gating, which further limits anion transport.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Dalemans W, Barbry P, Champigny G, Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 1991; 354: 526– 8. 1722027 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nearly 90% of persons with cystic fibrosis have at least one copy of the Phe508del CFTR mutation.

    “Although there are hundreds of different disease-causing mutations, nearly 90% of persons with cystic fibrosis have at least one copy of the most common mutation, the Phe508del CFTR mutation.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Marshall B, Faro A, Fink AK, Cystic fibrosis patient registry: 2017 annual data report. Bethesda, MD: Cystic Fibrosis Foundation, 2018.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Efficacy analyses included all patients who underwent randomization and received at least one dose of elexacaftor-tezacaftor-ivacaftor or placebo.

    “Efficacy analyses included all patients who underwent randomization and received at least one dose of elexacaftor–tezacaftor–ivacaftor or placebo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Similar to ivacaftor and tezacaftor-ivacaftor, elexacaftor-tezacaftor-ivacaftor therapy was associated with adverse events that were mostly mild to moderate, generally represented common manifestations of cystic fibrosis, and led to few treatment discontinuations.

    “Similar to these agents, elexacaftor–tezacaftor–ivacaftor therapy was associated with adverse events that were mostly mild to moderate, that generally represented common manifestations of cystic fibrosis, and that led to few treatment discontinuations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results provide evidence that elexacaftor-tezacaftor-ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients.

    “These results provide evidence that elexacaftor–tezacaftor–ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Sweat chloride concentration is a marker of CFTR activity.
33 of 33

  • The paper relies on this without support.

    Sweat chloride concentration is a marker of CFTR activity.

    “elexacaftor–tezacaftor–ivacaftor led to improvements in spirometry, patient-reported respiratory symptoms, and sweat chloride concentration, a marker of CFTR activity, in patients with cystic fibrosis with a single Phe508del allele.18”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Clinical trials with Trikafta showed only partial normalization of the 60%-65% mean baseline ppFEV1 after 24 weeks in compound heterozygous F508del or at 4 weeks in homozygous F508del patients.

    “The clinical trials with Trikafta showed only partial normalization of the 60%–65% mean baseline ppFEV1 after 24 weeks of treatment in compound heterozygous F508del (16) or at 4 weeks in homozygous F508del patients (15).”

    From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [16]

    The Results (Efficacy; page unavailable) report a sustained improvement in ppFEV1 through 24 weeks in patients with one Phe508del allele and a minimal-function mutation, consistent with improvement short of full normalization. The passages do not give the claimed 60%–65% mean baseline ppFEV1 or a week-24 value establishing the degree of normalization. The homozygous-patient result is attached to a different citation and is not assessed here. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In two pivotal phase 3 trials, up to 24 weeks of treatment with ELX/TEZ/IVA was efficacious and safe in patients with cystic fibrosis ≥12 years of age who have at least one F508del allele.

    “The efficacy and safety of the triple combination of ELX, TEZ and IVA (ELX/TEZ/IVA) were established in two phase 3 pivotal trials in people with CF ≥12 years of age who were heterozygous for F508del and a minimal function mutation (F/MF) or had the F/F genotype [17–19].”

    From Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one <i>F508del</i> allele: 144-week interim results from a 192-week open-label extension study (2023) · cites this paper as [18]

    The Discussion reports that this 24-week phase 3 trial found ELX/TEZ/IVA efficacious and generally safe in patients aged 12 or older with a Phe508del–minimal-function genotype. This paper reports one trial, not two, and does not itself establish efficacy or safety in patients with the F/F genotype; its References list a separate F/F trial. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In both pivotal trials, ELX/TEZ/IVA treatment led to significant improvements in FEV1 % pred, CFQ-R respiratory domain score and sweat chloride concentration.

    “In both trials, ELX/TEZ/IVA treatment led to significant improvements in FEV1 % pred, CFQ-R respiratory domain score and sweat chloride concentration.”

    From Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one <i>F508del</i> allele: 144-week interim results from a 192-week open-label extension study (2023) · cites this paper as [18]

    The Results > Efficacy passages report significant improvements in percentage of predicted FEV1, CFQ-R respiratory domain score, and sweat chloride concentration. But Methods > Participants, Trial Design, and Oversight identifies this paper as reporting one phase 3 trial; it does not establish these outcomes in both pivotal trials. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Participants taking ELX/TEZ/IVA in the parent studies had steady and sustained increases in BMI.

    “Participants taking ELX/TEZ/IVA in the parent studies had steady and sustained increases in BMI [17, 18].”

    From Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one <i>F508del</i> allele: 144-week interim results from a 192-week open-label extension study (2023) · cites this paper as [18]

    The Results (Efficacy) report a significant BMI improvement at week 24 in participants taking ELX/TEZ/IVA compared with placebo. Our copy does not establish that BMI rose steadily throughout the study; its explicit statement about sustained improvement concerns lung function, not BMI. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • During the first 144 weeks of this extension study, the estimated pulmonary exacerbation rate for patients with F/MF genotypes (0.20) was lower than in the ELX/TEZ/IVA arm of the 24-week parent study (0.37).

    “During the first 144 weeks of this extension study, the estimated pulmonary exacerbation rate for patients with F/MF genotypes (0.20) was lower than in the ELX/TEZ/IVA arm of the 24-week parent study (0.37) [18] and the rate of pulmonary exacerbations for participants in both genotype groups was lower than in the previous 24-week interim analysis of this extension study (0.19 versus 0.30) [23].”

    From Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one <i>F508del</i> allele: 144-week interim results from a 192-week open-label extension study (2023) · cites this paper as [18]

    The parent study’s Methods describe a 24-week treatment period, and Results > Efficacy report fewer pulmonary exacerbations with ELX/TEZ/IVA. But the 0.37 reported there is the rate ratio versus placebo, not the treatment arm’s estimated exacerbation rate. This source also does not report the extension study’s first 144 weeks or its 0.20 rate (page not provided). (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., Marigowda, G., McKee, C. M., Moskowitz, S. M., Nair, N., Savage, J., Simard, C., Tian, S., Waltz, D., Xuan, F., Rowe, S. M., & Jain, R.
Affiliations
  • The University of Sydney (AU)
  • From the Department of Respiratory and Sleep Medicine, Westmead Hospital and CF Research Group, Ludwig Engel Centre for Respiratory Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia (P.G.M.); the Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité–Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.); the Department of Medical Microbiology, Department of...
  • University College Dublin (IE)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2019-11-07
Volume
381
Issue
19
Pages
1809-1819
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1908639
PMC
PMC7282384
OpenAlex
W2985405196
Cited by
2,198
References
38
Citations by year
2026: 273 · 2025: 357 · 2024: 336 · 2023: 349 · 2022: 350 · 2021: 294 · 2020: 222 · 2019: 13 · 2014: 1
FWCI
161.15
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lirias (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
Vertex Pharmaceuticals Incorporated
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
elexacaftor/tezacaftor/ivacaftor, CFTR correctors, F508del mutation, CFTR function, FEV1, pulmonary exacerbations, sweat chloride, Cystic Fibrosis Questionnaire-Revised, respiratory quality of life, CFTR modulator therapy, drug safety
MeSH terms
Adolescent, Adult, Aminophenols, Child, Chlorides, Cystic Fibrosis, Double-Blind Method, Drug Combinations, Female, Forced Expiratory Volume, Genotype, Humans, Indoles, Male, Mutation, Pyrazoles, Pyridines, Pyrrolidines, Sweat, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, Young Adult, Chloride Channel Agonists

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-04.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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