Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial
Open accessAbstract
Background Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. Methods This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV 1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV 1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Findings Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV 1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Interpretation Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Funding Vertex Pharmaceuticals.
AI snapshot
Written from the paper’s full text.
TL;DR
In people with cystic fibrosis homozygous for F508del, elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) produced rapid, clinically robust improvements over TEZ/IVA alone after a 4-week TEZ/IVA run-in. The triple combination was well tolerated over 4 weeks, with no discontinuations and mostly mild or moderate adverse events.
Key findings
- ELX/TEZ/IVA improved ppFEV1 versus TEZ/IVA by a least squares mean difference of 10·0 percentage points (95% CI 7·4 to 12·6, p<0·0001) at week 4.
- Sweat chloride concentration improved by −45·1 mmol/L (95% CI −50·1 to −40·1, p<0·0001), and CFQ-R respiratory domain score improved by 17·4 points (95% CI 11·8 to 23·0, p<0·0001) versus TEZ/IVA.
- In the ELX/TEZ/IVA group, the least squares mean increase in CFQ-R RD score was 16·0 points (95% CI 12·1 to 19·9), exceeding the 4-point minimal clinically important difference.
- Adverse events occurred in 32 (58%) ELX/TEZ/IVA participants and 33 (63%) TEZ/IVA participants; serious adverse events occurred in 2 (4%) versus 1 (2%), with no discontinuations in either group.
Methods
- Phase 3, multicentre, randomised, double-blind, active-controlled trial at 44 sites in Belgium, the Netherlands, the UK, and the USA from 03 August to 28 December 2018; participants were aged ≥12 years, homozygous for F508del, with stable disease and ppFEV1 40–90 inclusive.
- After a 4-week TEZ/IVA run-in, 107 participants were randomised 1:1 to 4 weeks of ELX/TEZ/IVA (n=55) or TEZ/IVA (n=52); the primary endpoint was absolute change from baseline in ppFEV1 at week 4, with key secondary endpoints of sweat chloride and CFQ-R RD score.
- Efficacy was analysed in all randomised participants who received at least one dose, using mixed-effects models for repeated measures with treatment group, visit, treatment-by-visit interaction, baseline ppFEV1, and age as covariates; safety was summarised descriptively.
Limitations
- The paper states that a potential limitation is the 4-week treatment duration, although it was selected because short-term lung function changes with CFTR modulators have been demonstrated within 4 weeks and sustained through 24 weeks, and because safety from the concurrent 24-week heterozygous F508del trial was assumed applicable.
- The paper notes that BMI and weight analyses were not pre-defined, so their p values are nominal and not corrected for multiplicity.
- Evident from the text: the trial used an active control rather than placebo, so comparisons against placebo are inferred from prior TEZ/IVA trials; the sample was small (107 randomised) and long-term safety and durability were not assessed in this 4-week study.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
23 of 55 cited sources checked · 15 supported · 1 flagged · accuracy not yet measured
- Study design and conductcitation
A potential limitation of this trial is the 4-week duration.
“a potential limitation of this trial is the 4-week duration.7,11,12”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
The Methods (Study Subjects; page not provided) describe a 48-week trial, and the Discussion reports outcomes through 48 weeks. Our copy does not assess whether the citing authors’ 4-week trial duration is a limitation (searched: “4-week duration,” “short-term trial,” and “study duration”). (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [11] Wainwright, 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N Engl J Med source
The Methods (Study Design and Oversight) state that the cited TRAFFIC and TRANSPORT trials administered treatment for 24 weeks, not 4 weeks. The ≤4-week interval in Methods (Study Participants) was between screening and baseline, not the trial duration. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Premisecitation
Studies of lumacaftor/IVA and TEZ/IVA showed decreases in the rate of pulmonary exacerbations (a 35%-39% reduction) in people with cystic fibrosis homozygous for F508del.
“Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2·6–4·0 percentage points of the percentage of predicted forced expiratory volume in 1 second [ppFEV1]) and decreases in the rate of pulmonary exacerbations (a 35%–39% reduction) in pwCF homozygous for F508del.11,12”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2.6-4.0 percentage points of ppFEV1) in people with cystic fibrosis homozygous for F508del.
“Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2·6–4·0 percentage points of the percentage of predicted forced expiratory volume in 1 second [ppFEV1]) and decreases in the rate of pulmonary exacerbations (a 35%–39% reduction) in pwCF homozygous for F508del.11,12”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
Elexacaftor (ELX; VX-445) is a next-generation CFTR corrector that, in vitro, significantly increases the amount of mature CFTR protein and CFTR activity when added to TEZ/IVA.
“Elexacaftor (ELX; VX-445) is a next-generation CFTR corrector that was shown, in vitro, to significantly increase the amount of mature CFTR protein and CFTR activity when added to the combination of TEZ/IVA.15”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Keating, 2018, VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles, N Engl J Med source
- Interpretationown data
The resulting mean sweat chloride value in the ELX/TEZ/IVA group is below the diagnostic threshold for CF.
“the resulting mean value is below the diagnostic threshold for CF (figure 3B).18,19”
Quote in the paperSubstantial claim1 of 2 sources checked
- Findingown data
The mean sweat chloride concentration of 48.0 mmol/L at week 4 is below the diagnostic threshold for CF (60 mmol/L).
“which is below the diagnostic threshold for CF (60 mmol/L).18”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Farrell, 2017, Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation, J Pediatr source
- Interpretationcitation
The magnitude of clinical improvements with single corrector combinations was consistent with the degree of correction of F508del-CFTR by a single CFTR corrector.
“Given the multiple defects in F508del-CFTR affecting processing and trafficking, the magnitude of clinical improvements was consistent with the degree of correction of F508del-CFTR by a single CFTR corrector.13,14”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [13] Rabeh, 2012, Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function, Cell source
The Introduction and Discussion describe modest correction of ΔF508-CFTR by individual corrector molecules and link that limitation to multiple folding defects. They do not compare the degree of molecular correction with the magnitude of clinical improvements, so the clinical-consistency part of the claim is unsupported by this paper. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [14] Mendoza, 2012, Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences, Cell source
The Introduction (page unavailable) reports that single ΔF508 correctors reached only about 15% of wild-type efficacy, and the Discussion (page unavailable) links limited correction of individual folding defects to limited CFTR maturation and function. The paper does not report the magnitude of clinical improvements with a single corrector or compare clinical outcomes with its degree of correction; it expresses concern about whether that degree of correction would provide therapeutic benefit. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Interpretationcitation
The 10·0-percentage point improvement in lung function with ELX/TEZ/IVA compared with TEZ/IVA in pwCF homozygous for F508del observed in the current trial is similar to that seen with IVA in pwCF and the G551D mutation.
“The 10·0-percentage point improvement in lung function with ELX/TEZ/IVA compared with TEZ/IVA in pwCF homozygous for F508del observed in the current trial is similar to that seen with IVA in pwCF and the G551D mutation.7”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
- Interpretationcitation
Based on the known impact of IVA in a small subset of pwCF, the introduction of ELX/TEZ/IVA is likely to lead to meaningful improvements in the lives of pwCF homozygous for F508del.
“Based on the known impact of the benchmark therapy IVA in a small subset of pwCF, the introduction of ELX/TEZ/IVA is likely to lead to meaningful improvements in the lives of pwCF homozygous for F508del.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
- Premisecitation
Short-term improvements in lung function have been sustained through 24 weeks of treatment.
“these short-term improvements in lung function have been sustained through 24 weeks of treatment, 7,11,12”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
- cites [11] Wainwright, 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N Engl J Med source
- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Premisecitation
The majority of phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer.
“The majority of phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
The Methods (Study Oversight and Study Subjects; page unavailable) describe a phase 3 trial of the CFTR potentiator ivacaftor with a 48-week treatment period. This supports one example of a trial lasting at least 24 weeks, but the paper does not establish that a majority of phase 3 CFTR-modulator trials did so. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [11] Wainwright, 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N Engl J Med source
The Methods (Study Design and Oversight; page unavailable) describe two phase 3 CFTR-modulator efficacy trials with 24-week treatment periods. The paper does not establish that a majority of phase 3 CFTR-modulator trials used treatment periods of 24 weeks or longer. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Premisecitation
In the concurrent phase 3 trial in pwCF in whom a single F508del was responsible for the treatment response, marked improvements in clinical outcomes substantiate the ability of ELX/TEZ/IVA to restore F508del-CFTR function.
“In the concurrent phase 3 trial in pwCF in whom a single F508del was responsible for the treatment response, marked improvements in clinical outcomes substantiate the ability of ELX/TEZ/IVA to restore F508del-CFTR function.27”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [27] Middleton, 2019, Elexacaftor-tezacaftor-ivacaftor for CF with a single Phe508del allele, N Engl J Med source
- Premisecitation
In the longer companion trial in pwCF heterozygous for F508del, treatment with ELX/TEZ/IVA resulted in a 63% reduction in pulmonary exacerbations compared with placebo.
“in which treatment with ELX/TEZ/IVA resulted in a 63% reduction in pulmonary exacerbations compared with placebo27”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [27] Middleton, 2019, Elexacaftor-tezacaftor-ivacaftor for CF with a single Phe508del allele, N Engl J Med source
- Premisecitation
Short-term changes in lung function have consistently been demonstrated within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials.
“observations that short-term changes in lung function have consistently been demonstrated within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
The Results > Clinical Efficacy section reports a significant improvement in FEV1 by day 15 in a randomized, placebo-controlled trial of ivacaftor, supporting a lung-function change within four weeks. This paper reports one CFTR potentiator trial; it does not establish that such early changes were consistently demonstrated across previous trials of CFTR modulators. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [11] Wainwright, 2015, Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR, N Engl J Med source
- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Premisecitation
Prior data with CFTR modulators show comparable safety data across numerous CF genotypes.
“prior data with CFTR modulators showing comparable safety data across numerous CF genotypes.7,8,28”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
The Results (Safety and Adverse-Event Profile; page not provided) report similar adverse-event incidence with ivacaftor and placebo, supporting comparable safety in this trial. But the Results (Subjects; page not provided) identify a study population selected for the G551D mutation; the paper does not establish comparable safety across numerous CF genotypes. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [8] Flume, 2012, Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation, Chest source
- cites [28] Rowe, 2017, Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR, Ann Am Thorac Soc source
- Findingown data
No participants had elevations of ALT/AST >3× upper limit of normal concurrent with an elevation in total bilirubin >2× upper limit of normal.
“No participants had elevations of ALT/AST >3× upper limit of normal concurrent with an elevation in total bilirubin >2× upper limit of normal.”
Quote in the paperNot a substantial claim - Findingown data
In the ELX/TEZ/IVA group, there was a least squares mean increase in the CFQ-R RD score of 16.0 points (95% CI 12·1 to 19·9).
“In the ELX/TEZ/IVA group, there was a least squares mean increase in the CFQ-R RD score of 16.0 points (95% CI 12·1 to 19·9) (figure 4; table 2)”
Quote in the paperSubstantial claim - Findingown data
Review of laboratory results showed an incidence of alanine transaminase or aspartate transaminase >3×, >5×, and >8× the upper limit of normal in four (7%), two (4%), and zero participants in the ELX/TEZ/IVA group, respectively, compared with zero participants at any of these thresholds in the TEZ/IVA group.
“Review of laboratory results showed an incidence of alanine transaminase or aspartate transaminase >3×, >5×, and >8× the upper limit of normal in four (7%), two (4%), and zero participants in the ELX/TEZ/IVA group, respectively, compared with zero participants at any of these thresholds in the TEZ/IVA group.”
Quote in the paperNot a substantial claim - Findingown data
At week 4, treatment with ELX/TEZ/IVA resulted in a least squares mean body weight increase of 1·6 kg (95% CI 1·0 to 2·1, nominal p<0·0001) compared with TEZ/IVA.
“and a least squares mean body weight increase of 1·6 kg (95% CI 1·0 to 2·1, nominal p<0·0001) compared with TEZ/IVA.”
Quote in the paperNot a substantial claim - Findingown data
In the current trial, baseline sweat chloride concentration was 90 mmol/L.
“The treatment effect of TEZ/IVA is reflected in the baseline sweat chloride concentration of 90 mmol/L”
Quote in the paperSubstantial claim - Findingown data
There was an increase in BMI in the ELX/TEZ/IVA group compared with TEZ/IVA alone over 4 weeks.
“there was an increase in BMI and weight in the ELX/TEZ/IVA group compared with those who received TEZ/IVA alone.”
Quote in the paperSubstantial claim - Findingown data
ELX/TEZ/IVA was well tolerated in people with cystic fibrosis homozygous for F508del.
“ELX/TEZ/IVA was well tolerated, with no discontinuations.”
Quote in the paperSubstantial claim - Findingown data
The least squares mean difference between ELX/TEZ/IVA and TEZ/IVA in absolute ppFEV1 was 10·0 percentage points (95% CI 7·4 to 12·6, p<0·0001) at week 4.
“The least squares mean difference between ELX/TEZ/IVA and TEZ/IVA in absolute ppFEV1 was 10·0 percentage points (95% CI 7·4 to 12·6, p<0·0001) at week 4.”
Quote in the paperSubstantial claim - Findingown data
In people with cystic fibrosis homozygous for F508del, treatment with ELX/TEZ/IVA for 4 weeks improved ppFEV1 compared with TEZ/IVA alone, with an absolute change from baseline of 10.0 percentage points (95% CI 7.4 to 12.6, p<0.0001).
“The ELX/TEZ/IVA group had improvements in ppFEV1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group.”
Quote in the paperSubstantial claim - Findingown data
There was an increase in weight in the ELX/TEZ/IVA group compared with TEZ/IVA alone over 4 weeks.
“there was an increase in BMI and weight in the ELX/TEZ/IVA group compared with those who received TEZ/IVA alone.”
Quote in the paperSubstantial claim - Findingown data
There were no adverse events that led to discontinuation of trial regimen in either treatment group.
“There were no adverse events that led to discontinuation of trial regimen in either treatment group.”
Quote in the paperNot a substantial claim - Findingown data
The treatment difference in the change in CFQ-R RD score compared with TEZ/IVA was 17·4 points (95% CI 11·8 to 23·0, p<0·0001).
“The treatment difference in the change in CFQ-R RD score compared with TEZ/IVA was 17·4 points (95% CI 11·8 to 23·0, p<0·0001).”
Quote in the paperSubstantial claim - Findingown data
Investigators reported elevated transaminase levels as adverse events in two (4%) participants in the ELX/TEZ/IVA group and in one (2%) participant in the TEZ/IVA group.
“Investigators reported elevated transaminase levels as adverse events in two (4%) participants in the ELX/TEZ/IVA group and in one (2%) participant in the TEZ/IVA group”
Quote in the paperNot a substantial claim - Findingown data
All other adverse events were mild or moderate.
“All other adverse events were mild or moderate.”
Quote in the paperNot a substantial claim - Findingown data
There were no clinically relevant differences between the two treatment groups in vital signs, oximetry, physical examinations, laboratory abnormalities, or electrocardiogram findings.
“There were no clinically relevant differences between the two treatment groups in vital signs, oximetry, physical examinations, laboratory abnormalities, or electrocardiogram findings.”
Quote in the paperSubstantial claim - Findingown data
No discontinuations occurred in the ELX/TEZ/IVA treatment group.
“ELX/TEZ/IVA was well tolerated, with no discontinuations.”
Quote in the paperNot a substantial claim - Findingown data
Cough occurred more frequently in the ELX/TEZ/IVA group (15% vs 8%).
“Cough occurred more frequently in the ELX/TEZ/IVA group (15% vs 8%)”
Quote in the paperNot a substantial claim - Findingown data
Most adverse events in the trial were mild or moderate.
“Most adverse events were mild or moderate; serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA.”
Quote in the paperSubstantial claim - Findingown data
In people with cystic fibrosis homozygous for F508del, treatment with ELX/TEZ/IVA for 4 weeks improved CFQ-R RD score compared with TEZ/IVA alone, with an absolute change from baseline of 17.4 points (95% CI 11.8 to 23.0, p<0.0001).
“The ELX/TEZ/IVA group had improvements in ppFEV1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group.”
Quote in the paperSubstantial claim - Findingown data
The most common adverse events, those that occurred in >10% of participants in either treatment group, were cough and pulmonary exacerbation.
“The most common adverse events, those that occurred in >10% of participants in either treatment group, were cough and pulmonary exacerbation.”
Quote in the paperNot a substantial claim - Findingown data
The improvements in ppFEV1 and sweat chloride concentration were consistent across all subgroups evaluated.
“The improvements in ppFEV1 and sweat chloride concentration were consistent across all subgroups evaluated (figures S2 and S3).”
Quote in the paperNot a substantial claim - Findingown data
The vast majority of adverse events resolved during the study.
“The vast majority of AEs resolved during the study.”
Quote in the paperNot a substantial claim - Findingown data
Pulmonary exacerbation occurred more often in the TEZ/IVA group (2% vs 12%).
“whereas pulmonary exacerbation occurred more often in the TEZ/IVA group (2% vs 12%).”
Quote in the paperNot a substantial claim - Findingown data
ELX/TEZ/IVA resulted in a least squares mean treatment difference in sweat chloride concentration of −45·1 mmol/L at week 4 (95% CI −50·1 to −40·1, p<0·0001) compared with TEZ/IVA.
“ELX/TEZ/IVA resulted in an improvement in sweat chloride concentration, with a least squares mean treatment difference of −45·1 mmol/L at week 4 (95% CI −50·1 to −40·1, p<0·0001) compared with the TEZ/IVA group”
Quote in the paperSubstantial claim - Findingown data
ELX/TEZ/IVA improved ppFEV1 by 10 percentage points compared with TEZ/IVA in the present trial.
“the improvements in lung function (10 percentage points in ppFEV1) observed with ELX/TEZ/IVA compared with TEZ/IVA in the present trial”
Quote in the paperSubstantial claim - Findingown data
No transaminase elevations required study drug interruption or discontinuation in this study.
“No transaminase elevations required study drug interruption or discontinuation in this study.”
Quote in the paperNot a substantial claim - Findingown data
In people with cystic fibrosis homozygous for F508del, treatment with ELX/TEZ/IVA for 4 weeks reduced sweat chloride concentration compared with TEZ/IVA alone, with an absolute change from baseline of −45.1 mmol/L (95% CI −50.1 to −40.1, p<0.0001).
“The ELX/TEZ/IVA group had improvements in ppFEV1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group.”
Quote in the paperSubstantial claim - Findingown data
At week 4, treatment with ELX/TEZ/IVA resulted in a least squares mean increase in BMI of 0·60 kg/m2 (95% CI 0·41 to 0·79, nominal p<0·0001) compared with TEZ/IVA.
“At Week 4, treatment with ELX/TEZ/IVA resulted in a least squares mean increase in BMI of 0·60 kg/m2 (95% CI 0·41 to 0·79, nominal p<0·0001)”
Quote in the paperNot a substantial claim - Findingown data
The addition of ELX to TEZ/IVA in this trial resulted in a mean sweat chloride concentration of 48.0 mmol/L at week 4.
“The addition of ELX to TEZ/IVA in this trial resulted in a mean sweat chloride concentration of 48·0 mmol/L at week 4”
Quote in the paperSubstantial claim - Findingown data
The safety profile was consistent among subgroups (age, baseline ppFEV1, gender and geographic region).
“The safety profile was consistent among subgroups (age, baseline ppFEV1, gender and geographic region).”
Quote in the paperNot a substantial claim - Findingown data
There was a reduction in reported adverse events of infective pulmonary exacerbation of CF in the ELX/TEZ/IVA group relative to the TEZ/IVA group in this 4-week trial.
“Although not defined as an efficacy outcome in this 4-week trial, there was a reduction in reported adverse events of infective pulmonary exacerbation of CF in the ELX/TEZ/IVA group relative to the TEZ/IVA group.”
Quote in the paperNot a substantial claim - Premisecitation
Improvements in weight and BMI were not observed in a 24-week study of TEZ/IVA in the same population.
“Improvements in weight and BMI were not observed in a 24-week study of TEZ/IVA in the same population.12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Study design and conductown data
Demographics and baseline characteristics were similar between intervention groups.
“Demographics and baseline characteristics were similar between intervention groups (table 1).”
Quote in the paperSubstantial claim - Interpretationown data
ELX/TEZ/IVA provides clinically robust benefit compared with TEZ/IVA alone in people with cystic fibrosis homozygous for F508del.
“ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del.”
Quote in the paperSubstantial claim- Rests on an assumption: The trial participants are representative of the broader population of people with cystic fibrosis homozygous for F508del.
- Premisecitation
Ivacaftor (IVA) alone does not restore F508del-CFTR function.
“IVA alone does not restore F508del-CFTR function8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Flume, 2012, Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation, Chest source
- Premisecitation
TEZ/IVA improved ppFEV1 by 4 percentage points compared with placebo in this population.
“the demonstrated impact of TEZ/IVA in this population (a 4-percentage point improvement in ppFEV1 compared with placebo).12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Interpretationown data
ELX/TEZ/IVA has a favourable safety profile in people with cystic fibrosis homozygous for F508del.
“ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del.”
Quote in the paperSubstantial claim- Rests on an assumption: The trial participants are representative of the broader population of people with cystic fibrosis homozygous for F508del.
- Premisecitation
pwCF homozygous for F508del treated with TEZ/IVA experienced a 4-percentage point increase in ppFEV1 compared with placebo.
“Comparatively, pwCF homozygous for F508del treated with TEZ/IVA experienced a 4-percentage point increase in ppFEV1 compared with placebo.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Interpretationown data
The increase in CFQ-R RD score in the ELX/TEZ/IVA group exceeds the known 4-point minimal clinically important difference in pwCF with stable disease.
“which exceeds the known 4-point improvement corresponding to the minimal clinically important difference in pwCF with stable disease.20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Quittner, 2009, Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection, Chest source
- Interpretationown data
The most commonly reported adverse events were consistent with typical manifestations of CF.
“The most commonly reported adverse events were consistent with typical manifestations of CF.”
Quote in the paperNot a substantial claim - Interpretationcitation
The baseline sweat chloride concentration in the current trial is comparable to that observed at the end of the TEZ/IVA versus placebo trial.
“which is comparable to that observed at the end of the TEZ/IVA versus placebo trial,12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Taylor-Cousar, 2017, Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del, N Engl J Med source
- Interpretationreasoning
ELX/TEZ/IVA demonstrates the potential to lead to transformative improvements in the lives of people with cystic fibrosis homozygous for F508del.
“demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del.”
Quote in the paperNot a substantial claim- Rests on an assumption: The trial participants are representative of the broader population of people with cystic fibrosis homozygous for F508del.
- Rests on an assumption: Short-term improvements in ppFEV1, sweat chloride, and CFQ-R RD are likely to translate into transformative improvements in the lives of people with cystic fibrosis homozygous for F508del.
- Premisecitation
Weight in pwCF is closely correlated with improvements in lung function.
“Weight and BMI in pwCF are closely correlated with improvements in lung function and are independent predictors of survival.24,25”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
This phase 3 trial demonstrated the efficacy and safety of ELX/TEZ/IVA in participants homozygous for F508del over the 4-week study period.
“this phase 3 trial demonstrated the efficacy and safety of ELX/TEZ/IVA in participants homozygous for F508del over the 4-week study period.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The safety profile observed in the concurrent 24-week trial of ELX/TEZ/IVA in pwCF heterozygous for F508del is applicable to pwCF homozygous for F508del.
- Classified as probably not a substantial claim. 18
- May combine two claims. 16
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIVA therapy has been shown to be associated with a decreased need for lung transplant and improved survival with long-term use.
“IVA therapy has also been shown to be associated with a decreased need for lung transplant and improved survival with long-term use.22,23”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [22] Bessonova, 2018, Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor, Thorax source
- cites [23] Volkova, 2019, Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries, J Cyst Fibros source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFollowing 24 weeks of IVA therapy, the 10.6 percentage point increase in ppFEV1 and a substantial reduction in pulmonary exacerbations compared with placebo were sustained in a 96-week trial.
“Following 24 weeks of IVA therapy, the 10.6 percentage point increase in ppFEV1 and a substantial reduction in pulmonary exacerbations compared with placebo7 were sustained in a 96-week trial.21”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [7] Ramsey, 2011, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation, N Engl J Med source
- cites [21] McKone, 2014, Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST), Lancet Respir Med source
May combine two claims.
PremisecitationELX/TEZ/IVA improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for F508del.
“The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del.”
- Also stated in: § Introduction · hedged
“ELX/TEZ/IVA showed encouraging results in a phase 2 study of this triple combination in a small sample of pwCF homozygous for F508del.15”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Keating, 2018, VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles, N Engl J Med source
- Also stated in: § Introduction · hedged
May combine two claims.
Findingown dataSerious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA.
“serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataBoth rash events in participants receiving ELX/TEZ/IVA resolved during the trial.
“Both rash events in participants receiving ELX/TEZ/IVA resolved during the trial.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRash was seen in two (4%) participants in the ELX/TEZ/IVA group and two (4%) participants in the TEZ/IVA group.
“Rash was seen in two (4%) participants in the ELX/TEZ/IVA group and two (4%) participants in the TEZ/IVA group.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAdverse events occurred in 32 (58%) participants in the ELX/TEZ/IVA group and in 33 (63%) participants in the TEZ/IVA group.
“Adverse events occurred in 32 (58%) participants in the ELX/TEZ/IVA group and in 33 (63%) participants in the TEZ/IVA group (table 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNo participants in the ELX/TEZ/IVA group and one (2%) in the TEZ/IVA group had an adverse event reported as severe.
“No participants in the ELX/TEZ/IVA group and one (2%) in the TEZ/IVA group had an adverse event reported as severe.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll four participants with rash were female, and all events were mild in severity; none required interruption or discontinuation of trial drugs.
“All four participants with rash were female, and all events were mild in severity; none required interruption or discontinuation of trial drugs.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSerious adverse events occurred in two (4%) participants in the ELX/TEZ/IVA group and one (2%) participant in the TEZ/IVA group.
“Serious adverse events occurred in two (4%) participants in the ELX/TEZ/IVA group (rash in one participant and pulmonary exacerbation in another) and one (2%) participant in the TEZ/IVA group (pulmonary exacerbation).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCFTR dysfunction caused by F508del is multifactorial, involving defective protein processing and trafficking to the cell surface, reduced channel gating, and high turnover once at the cell surface.
“CFTR dysfunction caused by F508del is multifactorial, with defective protein processing and trafficking to the cell surface, reduced channel gating, and high turnover once at the cell surface.2,9,10”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Dalemans, 1991, Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation, Nature source
- cites [9] Welsh, 1993, Dysfunction of CFTR bearing the delta F508 mutation, J Cell Sci Suppl source
- cites [10] Lukacs, 1993, 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 source
May combine two claims.
Interpretationown dataELX/TEZ/IVA was generally safe and well tolerated in this 4-week trial.
“ELX/TEZ/IVA was generally safe and well tolerated in this 4-week trial.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataRandomisation was stratified by ppFEV1 (<70 vs ≥70) and age (<18 vs ≥18 years).
“Randomisation was stratified by ppFEV1 (<70 vs ≥70, as determined during the run-in period) and age (<18 vs ≥18 years at the screening visit).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIn this phase 3 trial in pwCF homozygous for F508del, treatment with ELX/TEZ/IVA resulted in substantial improvements in lung function, sweat chloride concentration, respiratory-related quality of life, and nutritional parameters compared with TEZ/IVA alone.
“In this phase 3 trial in pwCF homozygous for F508del, in which all participants had a 4 week pre-treatment period with TEZ/IVA, treatment with ELX/TEZ/IVA resulted in substantial improvements in lung function, sweat chloride concentration, respiratory-related quality of life, and nutritional parameters compared with TEZ/IVA alone.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSafety was monitored by an independent data monitoring committee.
“Safety was monitored by an independent data monitoring committee.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenA hierarchical testing procedure was used to control the overall type I error at an alpha of 0·05 for the primary endpoint and the key secondary endpoints tested.
“A hierarchical testing procedure was used to control the overall type I error at an alpha of 0·05 for the primary endpoint and the key secondary endpoints tested.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataFollowing the run-in, 107 participants were randomised and completed the 4-week treatment period.
“Following the run-in, 107 participants were randomised and completed the 4-week treatment period.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningThe trial was designed to have >90% power to detect a 5 percentage point difference in mean absolute change in ppFEV1 from baseline at week 4 between treatment groups, assuming a within-group standard deviation of 7 percentage points and a 5% dropout rate.
“a sample size of 50 participants per treatment group was expected to achieve >90% power to detect a difference of 5 percentage points for the mean absolute change in the ppFEV1 from baseline at week 4 between the two treatment groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataParticipants were randomised in a 1:1 ratio by an interactive web response system.
“Participants were randomised in a 1:1 ratio by an interactive web response system to either ELX/TEZ/IVA or TEZ/IVA”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenPlacebo tablets were used to maintain the blind.
“Placebo tablets were used to maintain the blind.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe trial was a phase 3, multi-centre, randomised, double-blind, active-controlled trial.
“A phase 3, multi-centre, randomised, double-blind, active-controlled trial of ELX in triple combination with TEZ/IVA (ELX/TEZ/IVA) in pwCF homozygous for F508del was conducted.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataELX/TEZ/IVA was well tolerated, with a safety profile comparable to that in the control group using TEZ/IVA alone.
“ELX/TEZ/IVA was well tolerated, with a safety profile comparable to that in the control group using TEZ/IVA alone.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenClinical results following treatment with IVA in pwCF with the G551D mutation are considered to be the benchmark for treatment with CFTR modulators.
“To date, clinical results following treatment with IVA in pwCF with the G551D mutation are considered to be the benchmark for treatment with CFTR modulators.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe BMI and body weight analyses were not pre-defined, so they were not corrected for multiplicity and their p values are considered nominal.
“Because these analyses were not pre-defined, they were not corrected for multiplicity and p values are considered nominal.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPulmonary exacerbations in pwCF are associated with decreased survival.
“Pulmonary exacerbations are important life events for pwCF and are associated with a greater rate of lung function decline and decreased survival.24,26”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBMI in pwCF is closely correlated with improvements in lung function.
“Weight and BMI in pwCF are closely correlated with improvements in lung function and are independent predictors of survival.24,25”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBMI in pwCF is an independent predictor of survival.
“Weight and BMI in pwCF are closely correlated with improvements in lung function and are independent predictors of survival.24,25”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationWeight in pwCF is an independent predictor of survival.
“Weight and BMI in pwCF are closely correlated with improvements in lung function and are independent predictors of survival.24,25”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPulmonary exacerbations in pwCF are associated with a greater rate of lung function decline.
“Pulmonary exacerbations are important life events for pwCF and are associated with a greater rate of lung function decline and decreased survival.24,26”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
Treatment with lumacaftor/IVA or TEZ/IVA is standard of care for people with cystic fibrosis homozygous for F508del.
“Because treatment with lumacaftor/IVA or TEZ/IVA is standard of care for pwCF homozygous for F508del, and to ensure a reliable on-treatment baseline before the triple combination treatment period, participants completed a 4-week TEZ/IVA run-in period following a 4-week screening period as described in Taylor-Cousar et al.16”
The paper relies on this without support.
The trial participants are representative of the broader population of people with cystic fibrosis homozygous for F508del.
“ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del.”
The paper relies on this without support.
Short-term improvements in ppFEV1, sweat chloride, and CFQ-R RD are likely to translate into transformative improvements in the lives of people with cystic fibrosis homozygous for F508del.
“demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del.”
The authors state this as an assumption.
The safety profile observed in the concurrent 24-week trial of ELX/TEZ/IVA in pwCF heterozygous for F508del is applicable to pwCF homozygous for F508del.
“the premise that the safety profile observed in the concurrent 24-week trial of ELX/TEZ/IVA in pwCF heterozygous for F508del27 would be applicable to pwCF homozygous for F508del.”
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 [15]
For the homozygous F508del patients to whom this citation is attached, Results > Efficacy reports a 10.0-percentage-point ppFEV1 improvement versus tezacaftor/ivacaftor at week 4. The retrieved passages do not give the claimed 60%–65% mean baseline ppFEV1 or establish the resulting degree of ‘partial normalization.’ The sentence cites a different study for the heterozygous patients’ 24-week result. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn 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 [17]
The Results > Efficacy section reports statistically significant improvements in ppFEV1, CFQ-R respiratory-domain score, and sweat chloride concentration in this trial of people homozygous for F508del. The paper describes a companion trial in the Discussion but does not report all three outcomes for that trial, so this source alone does not support the claim about both trials. (LLM, conf=0.87)
Experimental — accuracy not yet measuredParticipants 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 [17]
Results > Efficacy reports a BMI increase of 0.60 kg/m² at week 4 with ELX/TEZ/IVA compared with TEZ/IVA. The Discussion emphasizes that treatment lasted only four weeks and says longer-term outcomes remained to be evaluated. This supports an increase in BMI, but not the claim that increases were steady and sustained. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA concurrent phase 3 trial involving patients with two Phe508del alleles showed substantially improved outcomes, including increased lung function and decreased patient-reported respiratory symptoms, as compared with the dual combination of tezacaftor-ivacaftor.
“The restoration of Phe508del CFTR by elexacaftor–tezacaftor–ivacaftor was further confirmed by a concurrent phase 3 trial involving patients with two Phe508del alleles, which showed substantially improved outcomes, including increased lung function and decreased patient-reported respiratory symptoms, as compared with the dual combination of tezacaftor–ivacaftor.32”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [32]
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].”
In patients with the F/F genotype, ELX/TEZ/IVA improvements were superior to those seen with TEZ/IVA.
“In patients with the F/F genotype, these improvements were superior to those seen with TEZ/IVA.”
In the pivotal Studies 445-102 and 445-103, participants who received ELX/TEZ/IVA had rapid and statistically significant increases in FEV1 % pred and CFQ-R respiratory domain score along with significant decreases in sweat chloride concentration.
“In the pivotal Studies 445-102 and 445-103, participants who received ELX/TEZ/IVA had rapid and statistically significant increases in FEV1 % pred and CFQ-R respiratory domain score along with significant decreases in sweat chloride concentration [17, 18].”
Cites
Quanjer, P. H., Stanojevic, S., Cole, T. J., Baur, X., Hall, G. L., Culver, B. H., Enright, P., Hankinson, J., Ip, M., Zheng, J., et al. (2012) · European Respiratory Journal · doi:10.1183/09031936.00080312 · Cited by 5,944 · see citing works
Webb, A. K. (2006) · Cited by 4,369 · see citing works
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
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., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Self-citationA CFTR Potentiator in Patients with Cystic Fibrosis and the <i>G551D</i> Mutation
Ramsey, B. W., Davies, J., McElvaney, N. G., Tullis, E., Bell, S. C., Dřevínek, P., Griese, M., McKone, E. F., Wainwright, C. E., Konstan, M. W., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1105185 · Cited by 2,195 · see citing works
Self-citationElborn, J. S. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00576-6 · Cited by 1,710 · see citing works
Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del <i>CFTR</i>
Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J. C., De Boeck, K., Flume, P. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1409547 · Cited by 1,622 · see citing works
Self-citationDiagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation
Farrell, P. M., White, T. B., Ren, C. L., Hempstead, S. E., Accurso, F., Derichs, N., Howenstine, M., McColley, S. A., Rock, M., Rosenfeld, M., et al. (2017) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2016.09.064 · Cited by 953 · see citing works
Self-citationTezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del
Taylor-Cousar, J. L., Munck, A., McKone, E. F., van der Ent, C. K., Moeller, A., Simard, C., Wang, L. T., Ingenito, E. P., McKee, C., Lu, Y., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709846 · Cited by 794 · see citing works
Self-citationECFS best practice guidelines: the 2018 revision
Castellani, C., Duff, A. J. A., Bell, S. C., Heijerman, H. G. M., Munck, A., Ratjen, F., Sermet-Gaudelus, I., Southern, K. W., Barben, J., Flume, P. A., et al. (2018) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2018.02.006 · Cited by 765 · see citing works
Self-citationPredictive 5-year survivorship model of cystic fibrosis
Liou, T. G., Adler, F. R., FitzSimmons, S. C., Cahill, B. C., Hibbs, J. R., & Marshall, B. C. (2001) · American Journal of Epidemiology · doi:10.1093/aje/153.4.345 · Cited by 749 · see citing works
VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
Keating, D., Marigowda, G., Burr, L., Daines, C., Mall, M. A., McKone, E. F., Ramsey, B. W., Rowe, S. M., Sass, L. A., Tullis, E., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1807120 · Cited by 726 · see citing works
Self-citationAltered chloride ion channel kinetics associated with the ΔF508 cystic fibrosis mutation
Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Jallat, S., Dott, K., Dreyer, D., Crystal, R. G., Pavirani, A., Lecocq, J.-P., et al. (1991) · Nature · doi:10.1038/354526a0 · Cited by 707 · see citing works
Quittner, A. L., Modi, A. C., Wainwright, C., Otto, K., Kirihara, J., & Montgomery, A. B. (2009) · Chest · doi:10.1378/chest.08-1190 · Cited by 400 · see citing works
Lukacs, G. L., Chang, X. B., Bear, C., Kartner, N., Mohamed, A., Riordan, J. R., & Grinstein, S. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80582-1 · Cited by 387 · see citing works
Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation
Flume, P. A., Liou, T. G., Borowitz, D. S., Li, H., Yen, K., Ordoñez, C. L., & Geller, D. E. (2012) · Chest · doi:10.1378/chest.11-2672 · Cited by 338 · see citing works
Self-citationYen, E. H., Quinton, H., & Borowitz, D. (2013) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2012.08.040 · Cited by 306 · see citing works
Rabeh, W. M., Bossard, F., Xu, H., Okiyoneda, T., Bagdany, M., Mulvihill, C. M., Du, K., di Bernardo, S., Liu, Y., Konermann, L., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.024 · Cited by 280 · see citing works
Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences
Mendoza, J. L., Schmidt, A., Li, Q., Nuvaga, E., Barrett, T., Bridges, R. J., Feranchak, A. P., Brautigam, C. A., & Thomas, P. J. (2012) · Cell · doi:10.1016/j.cell.2011.11.023 · Cited by 261 · see citing works
Volkova, N., Moy, K., Evans, J., Campbell, D., Tian, S., Simard, C., Higgins, M., Konstan, M. W., Sawicki, G. S., Elbert, A., et al. (2020) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2019.05.015 · Cited by 258 · see citing works
Self-citationEffect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis
Waters, V., Stanojevic, S., Atenafu, E. G., Lu, A., Yau, Y., Tullis, E., & Ratjen, F. (2012) · European Respiratory Journal · doi:10.1183/09031936.00159111 · Cited by 256 · see citing works
Self-citationBessonova, L., Volkova, N., Higgins, M., Bengtsson, L., Tian, S., Simard, C., Konstan, M. W., Sawicki, G. S., Sewall, A., Nyangoma, S., et al. (2018) · Thorax · doi:10.1136/thoraxjnl-2017-210394 · Cited by 214 · see citing works
Self-citationMcKone, E. F., Borowitz, D., Drevinek, P., Griese, M., Konstan, M. W., Wainwright, C., Ratjen, F., Sermet-Gaudelus, I., Plant, B., Munck, A., et al. (2014) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(14)70218-8 · Cited by 211 · see citing works
Self-citationTaylor-Cousar, J. L., Mall, M. A., Ramsey, B. W., McKone, E. F., Tullis, E., Marigowda, G., McKee, C. M., Waltz, D., Moskowitz, S. M., Savage, J., et al. (2019) · ERJ Open Research · doi:10.1183/23120541.00082-2019 · Cited by 105 · see citing works
Self-citationLumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for <i>F508del-CFTR</i>
Rowe, S. M., McColley, S. A., Rietschel, E., Li, X., Bell, S. C., Konstan, M. W., Marigowda, G., Waltz, D., & Boyle, M. P. (2017) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201609-689oc · Cited by 92 · see citing works
Self-citationGoor, F. V., Yu, H. D., Burton, B., Huang, C.-J., Hoffman, B. J., Cao, H., Machuca, T., Yeung, J. C., Bonato, R., Duan, C., et al. (2012) · Cited by 76 · see citing works
Dysfunction of CFTR bearing the AF508 mutation
Welsh, M. J., Denning, G. M., Ostedgaard, L. S., & Anderson, M. P. (1993) · Journal of Cell Science · doi:10.1242/jcs.1993.supplement_17.33 · Cited by 47 · see citing works
Introduction to “Cystic Fibrosis Foundation Consensus Guidelines for Diagnosis of Cystic Fibrosis”
Farrell, P. M., & White, T. B. (2017) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2016.09.062
Flagged first, then by citations
Cited by
Sorted by citations
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
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., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Self-citationShteinberg, M., Haq, I. J., Polineni, D., & Davies, J. C. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32542-3 · Cited by 682 · see citing works
CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine
Lopes‐Pacheco, M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01662 · Cited by 571 · see citing works
Pharmacological targeting of endoplasmic reticulum stress in disease
Marciniak, S., Chambers, J. E., & Ron, D. (2021) · Nature reviews. Drug discovery · doi:10.1038/s41573-021-00320-3 · Cited by 1 · see citing works
Nichols, D. P., Paynter, A., Heltshe, S. L., Donaldson, S. H., Frederick, C. A., Freedman, S. D., Gelfond, D., Hoffman, L. R., Kelly, A., Narkewicz, M. R., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202108-1986oc · Cited by 410 · see citing works
Self-citationPhysiology and pathophysiology of human airway mucus
Hill, D. B., Button, B. M., Rubinstein, M., & Boucher, R. C. (2022) · Physiological Reviews · doi:10.1152/physrev.00004.2021 · Cited by 373 · see citing works
Cystic fibrosis in the year 2020: A disease with a new face
Boeck, K. D. (2020) · Acta Paediatrica · doi:10.1111/apa.15155 · Cited by 339 · see citing works
Ong, T., & Ramsey, B. W. (2023) · JAMA · doi:10.1001/jama.2023.8120 · Cited by 327 · see citing works
Self-citationZemanick, E. T., Taylor‐Cousar, J. L., Davies, J. C., Gibson, R. L., Mall, M. A., McKone, E. F., McNally, P., Ramsey, B. W., Rayment, J. H., Rowe, S. M., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202102-0509oc · Cited by 315 · see citing works
Self-citationTriple Therapy for Cystic Fibrosis Phe508del –Gating and –Residual Function Genotypes
Barry, P. J., Mall, M. A., Fernández, A. Á., Colombo, C., Groot, K. M. D. W., Fajac, I., McBennett, K., McKone, E. F., Ramsey, B. W., Sutharsan, S., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2100665 · Cited by 284 · see citing works
Self-citationBurgel, P., Durieu, I., Chiron, R., Ramel, S., Danner‐Boucher, I., Prévötat, A., Grenet, D., Marguet, C., Reynaud‐Gaubert, M., Macey, J., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202011-4153oc · Cited by 276 · see citing works
Nick, J. A., Dedrick, R. M., Gray, A. L., Vladar, E. K., Smith, B. E., Freeman, K. G., Malcolm, K. C., Epperson, L. E., Hasan, N. A., Hendrix, J., et al. (2022) · Cell · doi:10.1016/j.cell.2022.04.024 · Cited by 251 · see citing works
Veit, G., Roldan, A., Hancock, M. A., Da Fonte, D. F., Xu, H., Hussein, M., Frenkiel, S., Matouk, E., Velkov, T., & Lukacs, G. L. (2020) · JCI Insight · doi:10.1172/jci.insight.139983 · Cited by 250 · see citing works
Mall, M. A., Mayer-Hamblett, N., & Rowe, S. M. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201910-1943so · Cited by 229 · see citing works
Self-citationMall, M. A., Burgel, P., Castellani, C., Davies, J. C., Salathe, M. A., & Taylor‐Cousar, J. L. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00538-6 · Cited by 223 · see citing works
Self-citationNichols, D. P., Morgan, S. J., Skalland, M., Vo, A. T., Dalfsen, J. M. V., Singh, S. B., Ni, W., Hoffman, L. R., McGeer, K., Heltshe, S. L., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci167957 · Cited by 219 · see citing works
Self-citationCystic Fibrosis Lung Disease: An Overview
Turcios, N. L. (2020) · Respiratory Care · doi:10.4187/respcare.06697 · Cited by 217 · see citing works
Schaupp, L., Addante, A., Völler, M., Fentker, K., Kuppe, A., Bardua, M., Duerr, J., Piehler, L., Röhmel, J., Thee, S. A., et al. (2023) · European Respiratory Journal · doi:10.1183/13993003.02153-2022 · Cited by 193 · see citing works
Self-citationPetersen, M. C., Begnel, L., Wallendorf, M., & Litvin, M. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.11.012 · Cited by 180 · see citing works
Graeber, S. Y., Vitzthum, C., Pallenberg, S. T., Naehrlich, L., Stahl, M., Rohrbach, A., Drescher, M., Minso, R., Ringshausen, F. C., Rueckes-Nilges, C., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202110-2249oc · Cited by 175 · see citing works
Self-citationCFTR modulator therapy: Transforming the landscape of clinical care in cystic fibrosis
Taylor-Cousar, J. L., Robinson, P. D., Shteinberg, M., & Downey, D. G. (2023) · The Lancet · doi:10.1016/s0140-6736(23)01609-4 · Cited by 173 · see citing works
Self-citationMcGarry, M. E., & McColley, S. A. (2021) · Pediatric Pulmonology · doi:10.1002/ppul.25285 · Cited by 173 · see citing works
Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies
Li, G., Cheng, Y., Han, C., Song, C., Huang, N., & Du, Y. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00206j · Cited by 170 · see citing works
Griese, M., Costa, S., Linnemann, R. W., Mall, M. A., McKone, E. F., Polineni, D., Quon, B. S., Ringshausen, F. C., Taylor-Cousar, J. L., Withers, N. J., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202008-3176le · Cited by 163 · see citing works
Self-citationLopez, A., Daly, C., Vega-Hernandez, G., MacGregor, G., & Rubin, J. L. (2023) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2023.02.004 · Cited by 163 · see citing works
Laselva, O., Bartlett, C., Gunawardena, T. N. A., Ouyang, H., Eckford, P. D. W., Moraes, T. J., Bear, C. E., & Gonska, T. Y. (2020) · European Respiratory Journal · doi:10.1183/13993003.02774-2020 · Cited by 162 · see citing works
Mycobacterium abscessus, an Emerging and Worrisome Pathogen among Cystic Fibrosis Patients
Degiacomi, G., Sammartino, J. C., Chiarelli, L. R., Riabova, O., Makarov, V., & Pasca, M. R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20235868 · Cited by 157 · see citing works
Mall, M. A., Brugha, R. E., Gärtner, S., Legg, J. P., Mœller, A., Mondéjar-López, P., Prais, D., Pressler, T., Ratjen, F. A., Reix, P., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202202-0392oc · Cited by 152 · see citing works
Self-citationSutharsan, S., McKone, E. F., Downey, D. G., Duckers, J., MacGregor, G., Tullis, E., Braeckel, E. V., Wainwright, C. E., Watson, D., Ahluwalia, N., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00454-9 · Cited by 151 · see citing works
Self-citationGoralski, J. L., Hoppe, J. E., Mall, M. A., McColley, S. A., McKone, E. F., Ramsey, B. W., Rayment, J. H., Robinson, P. J., Stehling, F., Taylor‐Cousar, J. L., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202301-0084oc · Cited by 147 · see citing works
Self-citationThe future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches
Graeber, S. Y., & Mall, M. A. (2023) · The Lancet · doi:10.1016/s0140-6736(23)01608-2 · Cited by 147 · see citing works
Self-citationFuture therapies for cystic fibrosis
Allen, L., Allen, L. J., Carr, S. B., Davies, G., Downey, D. G., Egan, M. E., Forton, J. T., Gray, R. D., HAWORTH, C. S., Horsley, A. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36244-2 · Cited by 143 · see citing works
Self-citationBower, J. K., Volkova, N., Ahluwalia, N., Sahota, G., Xuan, F., Chin, A., Weinstock, T. G., Ostrenga, J., & Elbert, A. (2023) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2023.03.002 · Cited by 140 · see citing works
Self-citationMayer-Hamblett, N., Ratjen, F. A., Russell, R., Donaldson, S. H., Riekert, K. A., Sawicki, G. S., Odem‐Davis, K., Young, J., Rosenbluth, D., Taylor‐Cousar, J. L., et al. (2022) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(22)00434-9 · Cited by 140 · see citing works
Self-citationA multinational report to characterise SARS-CoV-2 infection in people with cystic fibrosis
Cosgriff, R., Ahern, S., Bell, S. C., Brownlee, K. G., Burgel, P., Byrnes, C., Corvol, H., Cheng, S. Y., Elbert, A., Faro, A., et al. (2020) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2020.04.012 · Cited by 138 · see citing works
Self-citationKeating, C. L., Yonker, L. M., Vermeulen, F. L., Prais, D., Linnemann, R. W., Trimble, A. T., Kotsimbos, T. C., Mermis, J. D., Braun, A. T., O’Carroll, M., et al. (2025) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(24)00411-9 · Cited by 132 · see citing works
Self-citationESPEN-ESPGHAN-ECFS guideline on nutrition care for cystic fibrosis
Wilschanski, M. A., Munck, À., Carrión‐Jaramillo, E., Cipolli, M., Collins, S., Colombo, C., Declercq, D., Hatziagorou, E., Hulst, J. M., Kalnins, D., et al. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.12.017 · Cited by 130 · see citing works
A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion
Sharma, J., Du, M., Wong, E., Mutyam, V., Li, Y., Chen, J., Wangen, J. R., Thrasher, K., Fu, L., Peng, N., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24575-x · Cited by 129 · see citing works
Self-citationEffect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis
Casey, M., Gabillard-Lefort, C., McElvaney, O. F., McElvaney, O. J., Carroll, T. P., Heeney, R. C., Gunaratnam, C., Reeves, E. P., Murphy, M. P., & McElvaney, N. G. (2023) · Thorax · doi:10.1136/thorax-2022-219943 · Cited by 127 · see citing works
Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review
Dagenais, R., Su, V., & Quon, B. S. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm10010023 · Cited by 126 · see citing works
A new era for people with cystic fibrosis
Bierlaagh, M. C., Muilwijk, D., Beekman, J. M., & van der Ent, C. K. (2021) · European Journal of Pediatrics · doi:10.1007/s00431-021-04168-y · Cited by 124 · see citing works
Taylor‐Cousar, J. L., & Jain, R. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.03.006 · Cited by 122 · see citing works
Self-citationCorrection of CFTR function in intestinal organoids to guide treatment of cystic fibrosis
Ramalho, A. S., Fürstová, E., Vonk, A. M., Ferrante, M., Verfaillie, C., Dupont, L., Boon, M., Proesmans, M., Beekman, J. M., Sarouk, I., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.02426-2019 · Cited by 121 · see citing works
Self-citationGraeber, S. Y., Renz, D. M., Stahl, M., Pallenberg, S. T., Sommerburg, O., Naehrlich, L., Berges, J., Dohna, M., Ringshausen, F. C., Doellinger, F., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202201-0219oc · Cited by 120 · see citing works
Self-citationRidley, K., & Condren, M. E. (2020) · The Journal of Pediatric Pharmacology and Therapeutics · doi:10.5863/1551-6776-25.3.192 · Cited by 117 · see citing works
Bacalhau, M., Camargo, M., Magalhães‐Ghiotto, G. A. V., Drumond, S., Castelletti, C. H. M., & Lopes‐Pacheco, M. (2023) · Pharmaceuticals · doi:10.3390/ph16030410 · Cited by 114 · see citing works
McDonald, C. M., Alvarez, J. A., Bailey, J., Bowser, E. K., Farnham, K., Mangus, M., Padula, L., Porco, K., & Rozga, M. (2020) · Journal of the Academy of Nutrition and Dietetics · doi:10.1016/j.jand.2020.03.015 · Cited by 112 · see citing works
Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease
Shteinberg, M., & Taylor‐Cousar, J. L. (2020) · European Respiratory Review · doi:10.1183/16000617.0112-2019 · Cited by 110 · see citing works
Self-citationDana, J., Debray, D., Bèaufrere, A., Hillaire, S., Fabrè, M., Reinhold, C., Baumert, T. F., Berteloot, L., & Vilgrain, V. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.09.042 · Cited by 109 · see citing works
Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR
Veit, G., Vaccarin, C., & Lukács, G. L. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.03.011 · Cited by 107 · see citing works
Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis
Jarosz-Griffiths, H., Scambler, T., Wong, C. H., Reyna, S. J. L., Holbrook, J. A., Martinon, F., Savic, S., Whitaker, P., Etherington, C., Spoletini, G., et al. (2020) · eLife · doi:10.7554/elife.54556 · Cited by 106 · see citing works
Bailey, J., Rozga, M., McDonald, C. M., Bowser, E. K., Farnham, K., Mangus, M., Padula, L., Porco, K., & Alvarez, J. A. (2020) · Journal of the Academy of Nutrition and Dietetics · doi:10.1016/j.jand.2020.03.014 · Cited by 106 · see citing works
Gramegna, A., Contarini, M., Aliberti, S., Casciaro, R., Blasi, F., & Castellani, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165882 · Cited by 102 · see citing works
Spoletini, G., Gillgrass, L., Pollard, K., Shaw, N., Williams, E., Etherington, C., Clifton, I., & Peckham, D. G. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.05.001 · Cited by 102 · see citing works
Daines, C. L., Tullis, E., Costa, S., Linnemann, R. W., Mall, M. A., McKone, E. F., Polineni, D., Quon, B. S., Ringshausen, F. C., Rowe, S. M., et al. (2023) · European Respiratory Journal · doi:10.1183/13993003.02029-2022 · Cited by 100 · see citing works
Self-citationJust breathe: a review of sex and gender in chronic lung disease
Somayaji, R., & Chalmers, J. D. (2022) · European Respiratory Review · doi:10.1183/16000617.0111-2021 · Cited by 100 · see citing works
Sellers, Z. M., Assis, D. N., Paranjape, S. M., Sathe, M., Bodewes, F. A. J. A., Bowen, M., Cipolli, M., Debray, D., Green, N., Hughan, K. S., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000646 · Cited by 100 · see citing works
Pregnancy in cystic fibrosis: Review of the literature and expert recommendations
Jain, R., Kazmerski, T. M., Zuckerwise, L. C., West, N. E., Montemayor, K., Aitken, M. L., Cheng, E., Roe, A. H., Wilson, A. W. M., Mann, C., et al. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.07.019 · Cited by 99 · see citing works
Self-citationCFTR Modulators: Impact on Fertility, Pregnancy, and Lactation in Women with Cystic Fibrosis
Taylor‐Cousar, J. L. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9092706 · Cited by 98 · see citing works
Self-citationCystic Fibrosis Modulator Therapies
Jia, S., & Taylor‐Cousar, J. L. (2022) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-021447 · Cited by 97 · see citing works
Self-citationElexacaftor/Ivacaftor/Tezacaftor: First Approval
Hoy, S. M. (2019) · Drugs · doi:10.1007/s40265-019-01233-7 · Cited by 96 · see citing works
Cystic Fibrosis, CFTR, and Colorectal Cancer
Scott, P. M., Anderson, K., Singhania, M., & Cormier, R. T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082891 · Cited by 96 · see citing works
McNally, P., Lester, K., Stone, G., Elnazir, B., Williamson, M. J., Cox, D., Linnane, B. M., Kirwan, L., Rea, D. J., O’Regan, P., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202308-1317oc · Cited by 92 · see citing works
Self-citationSheikh, S. I., Britt, R. D., Ryan‐Wenger, N. A., Khan, A. Q., Lewis, B. W., Gushue, C. A., Ozuna, H., Jaganathan, D., McCoy, K., & Kopp, B. T. (2022) · Pediatric Pulmonology · doi:10.1002/ppul.26261 · Cited by 91 · see citing works
Self-citationGoss, C. H., Heltshe, S. L., West, N. E., Skalland, M., Sanders, D. B., Jain, R., Barto, T. L., Fogarty, B., Marshall, B. C., VanDevanter, D. R., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202102-0461oc · Cited by 90 · see citing works
Self-citationDrug exposure to infants born to mothers taking Elexacaftor, Tezacaftor, and Ivacaftor
Collins, B., Fortner, C. N., Cotey, A., Esther, C. R., & Trimble, A. T. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.12.004 · Cited by 87 · see citing works
Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis
DiMango, E., Overdevest, J. B., Keating, C. L., Francis, S. F., Dansky, D., & Gudis, D. A. (2020) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2020.07.002 · Cited by 86 · see citing works
Graeber, S. Y., Boutin, S., Wielpütz, M. O., Joachim, C., Frey, D. L., Wege, S., Sommerburg, O., Kauczor, H., Stahl, M., Dalpke, A. H., et al. (2021) · Annals of the American Thoracic Society · doi:10.1513/annalsats.202008-1054oc · Cited by 86 · see citing works
Self-citationBeswick, D. M., Humphries, S. M., Balkissoon, C. D., Strand, M. J., Vladar, E. K., Lynch, D. A., & Taylor-Cousar, J. L. (2021) · Annals of the American Thoracic Society · doi:10.1513/annalsats.202101-057oc · Cited by 84 · see citing works
Self-citationJain, R., Wolf, A., Molad, M., Taylor‐Cousar, J. L., Esther, C. R., & Shteinberg, M. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.10.004 · Cited by 80 · see citing works
Self-citationJain, R., Magaret, A., Vu, P. T., VanDalfsen, J. M., Keller, A. E., Wilson, A. W. M., Putman, M. S., Mayer-Hamblett, N., Esther, C. R., & Taylor‐Cousar, J. L. (2022) · BMJ Open Respiratory Research · doi:10.1136/bmjresp-2022-001289 · Cited by 79 · see citing works
Self-citationMainz, J. G., Zagoya, C., Polte, L., Naehrlich, L., Sasse, L., Eickmeier, O., Smaczny, C., Barucha, A., Bechinger, L., Duckstein, F., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.877118 · Cited by 78 · see citing works
Uluer, A., MacGregor, G., Azevedo, P., Indihar, V., Keating, C. L., Mall, M. A., McKone, E. F., Ramsey, B. W., Rowe, S. M., Rubenstein, R. C., et al. (2023) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(22)00504-5 · Cited by 77 · see citing works
Self-citationThe Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status
Bass, R., Brownell, J. N., & Stallings, V. A. (2021) · Nutrients · doi:10.3390/nu13092907 · Cited by 75 · see citing works
Southern, K. W., Castellani, C., Lammertyn, E. J., Smyth, A. R., VanDevanter, D. R., Koningsbruggen-Rietschel, S. V., Barben, J., Bevan, A., Brokaar, E. J., Collins, S., et al. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.10.002 · Cited by 75 · see citing works
Self-citationSutharsan, S., Dillenhoefer, S., Welsner, M., Stehling, F., Brinkmann, F., Burkhart, M., Ellemunter, H., Dittrich, A., Smaczny, C., Eickmeier, O., et al. (2023) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2023.100690 · Cited by 75 · see citing works
ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies
Mall, M. A. (2020) · European Respiratory Journal · doi:10.1183/13993003.00946-2020 · Cited by 74 · see citing works
Self-citationStahl, M., Steinke, E., Graeber, S. Y., Joachim, C., Seitz, C., Kauczor, H., Eichinger, M., Hämmerling, S., Sommerburg, O., Wielpütz, M. O., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202102-0278oc · Cited by 74 · see citing works
Self-citationShaughnessy, C. A., Zeitlin, P. L., & Bratcher, P. E. (2021) · Scientific Reports · doi:10.1038/s41598-021-99184-1 · Cited by 74 · see citing works
Sosinski, L. M., Christian Martin, H., Neugebauer, K. A., Ghuneim, L.-A. J., Guzior, D. V., Castillo-Bahena, A., Mielke, J., Thomas, R. G., McClelland, M., Conrad, D., et al. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.11.003 · Cited by 74 · see citing works
Treating Cystic Fibrosis with mRNA and CRISPR
Sanchez, A. D. S., Paunovska, K., Cristian, A., & Dahlman, J. E. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.137 · Cited by 72 · see citing works
Nichols, D. P., Donaldson, S. H., Frederick, C. A., Freedman, S. D., Gelfond, D., Hoffman, L. R., Kelly, A. T., Narkewicz, M. R., Pittman, J. E., Ratjen, F. A., et al. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.02.003 · Cited by 72 · see citing works
Self-citationPartial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment
Capurro, V., Tomati, V., Sondo, E., Renda, M., Borrelli, A., Pastorino, C., Guidone, D., Venturini, A., Giraudo, A., Bertozzi, S. M., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105262 · Cited by 72 · see citing works
Wucherpfennig, L., Triphan, S. M. F., Wege, S., Kauczor, H., Heußel, C. P., Schmitt, N., Wuennemann, F., Mayer, V. L., Sommerburg, O., Mall, M. A., et al. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.03.011 · Cited by 72 · see citing works
Self-citationChmiel, J. F., Flume, P. A., Downey, D. G., Dozor, A. J., Colombo, C., Mazurek, H., Sapiejka, E., Rachel, M., Constantine, S., Conley, B., et al. (2020) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2020.09.008 · Cited by 71 · see citing works
Self-citationWainwright, C. E., McColley, S. A., McNally, P., Powers, M., Ratjen, F. A., Rayment, J. H., Retsch‐Bogart, G. Z., Roesch, E. A., Ahluwalia, N., Chin, A., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202301-0021oc · Cited by 71 · see citing works
Self-citationVaidyanathan, S., Baik, R., Chen, L., Bravo, D. T., Suarez, C. J., Abazari, S. M., Salahudeen, A. A., Dudek, A. M., Teran, C. A., Davis, T., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.03.023 · Cited by 70 · see citing works
Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!
Zampoli, M., Morrow, B. M., & Paul, G. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1163391 · Cited by 70 · see citing works
Davies, J. C., Sermet‐Gaudelus, I., Naehrlich, L., Harris, R. S., Campbell, D., Ahluwalia, N., Short, C., Haseltine, E. L., Panorchan, P., Saunders, C. J., et al. (2020) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2020.07.023 · Cited by 69 · see citing works
Self-citationO’Shea, K. M., O’Carroll, O., Carroll, C., Grogan, B., Connolly, A., O'Shaughnessy, L., Nicholson, T. T., Gallagher, C. G., & McKone, E. F. (2020) · European Respiratory Journal · doi:10.1183/13993003.03079-2020 · Cited by 69 · see citing works
Self-citationSouthern, K. W., Murphy, J. P., Sinha, I. P., & Nevitt, S. J. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010966.pub3 · Cited by 69 · see citing works
Modulators of CFTR. Updates on clinical development and future directions
Bardin, E., Pastor, A., Semeraro, M., Golec, A., Hayes, K., Chevalier, B., Berhal, F., Prestat, G., Hinzpeter, A., Gravier‐Pelletier, C., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113195 · Cited by 69 · see citing works
Hoppe, J. E., Kasi, A. S., Pittman, J. E., Jensen, R., Thia, L. P., Robinson, P. J., Tirakitsoontorn, P., Ramsey, B. W., Mall, M. A., Taylor‐Cousar, J. L., et al. (2025) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(24)00407-7 · Cited by 69 · see citing works
Self-citationGómez‐Montes, E., Lobato, E. S., Izquierdo, A. G., Alcázar, D. G., Villalaín, C., Moral‐Pumarega, M. T., Lozano, G. B., & Luna‐Paredes, C. (2023) · Fetal Diagnosis and Therapy · doi:10.1159/000530261 · Cited by 68 · see citing works
Filho, L. V. R. F. D. S., Zampoli, M., Cohen‐Cymberknoh, M., & Kabra, S. K. (2020) · Paediatric Respiratory Reviews · doi:10.1016/j.prrv.2020.07.004 · Cited by 67 · see citing works
Cardiovascular complications in cystic fibrosis: A review of the literature
Poore, T. S., Taylor‐Cousar, J. L., & Zemanick, E. T. (2021) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.04.016 · Cited by 67 · see citing works
Self-citationThe Changing Epidemiology of Cystic Fibrosis
Burgel, P., Burnet, E., Regard, L., & Martin, C. (2022) · CHEST Journal · doi:10.1016/j.chest.2022.07.004 · Cited by 67 · see citing works
Human Nasal Epithelial Organoids for Therapeutic Development in Cystic Fibrosis
Liu, Z., Anderson, J. D., Deng, L., Mackay, S., Bailey, J., Kersh, L., Rowe, S. M., & Guimbellot, J. S. (2020) · Genes · doi:10.3390/genes11060603 · Cited by 66 · see citing works
Self-citationMartin, C., Reynaud‐Gaubert, M., Hamidfar, R., Durieu, I., Murris‐Espin, M., Danner‐Boucher, I., Chiron, R., Leroy, S., Douvry, B., Grenet, D., et al. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.01.012 · Cited by 66 · see citing works
CFTR Modulators in People with Cystic Fibrosis: Real-World Evidence in France
Regard, L., Martin, C., Burnet, E., Silva, J. D., & Burgel, P. (2022) · Cells · doi:10.3390/cells11111769 · Cited by 65 · see citing works
- Authors
- Heijerman, H. G. M., McKone, E. F., Downey, D. G., Van Braeckel, E., Rowe, S. M., Tullis, E., Mall, M. A., Welter, J. J., Ramsey, B. W., McKee, C. M., Marigowda, G., Moskowitz, S. M., Waltz, D., Sosnay, P. R., Simard, C., Ahluwalia, N., Xuan, F., Zhang, Y., Taylor-Cousar, J. L., McCoy, K. S., McCoy, K., Donaldson, S., Walker, S., Chmiel, J., Rubenstein, R., Froh, D. K., Neuringer, I., Jain, M., Moffett, K., Taylor-Cousar, J. L., Barnett, B., Mueller, G., Flume, P., Livingston, F., Mehdi, N., Teneback, C., Welter, J., Jain, R., Kissner, D., Patel, K., Calimano, F. J., Johannes, J., Daines, C., Keens, T., Scher, H., Chittivelu, S., Reddivalam, S., Klingsberg, R. C., Johnson, L. G., Verhulst, S., Macedo, P., Downey, D., Connett, G., Nash, E., Withers, N., Lee, T., Bakker, M., Heijerman, H., Vermeulen, F., Van Braeckel, E., Knoop, C., De Wachter, E., van der Meer, R., Merkus, P., & Majoor, C.
- Affiliations
- University College Dublin (IE)
- University of Alabama at Birmingham (US)
- St. Michael's Hospital (CA)
- German Center for Lung Research (DE)
- Seattle Children's Hospital (US)
- Vertex Pharmaceuticals (United States) (US)
- ORCID
- McKone, Edward F
- Rowe, Steven M
- Tullis, Elizabeth
- Mall, Marcus A
- Ramsey, Bonnie W
- Moskowitz, Samuel M
- Waltz, David
- Sosnay, Patrick R
- Ahluwalia, Neil
- Xuan, Fengjuan
- Zhang, Yaohua
- Donaldson, Scott
- Chmiel, James
- Rubenstein, Ronald
- Froh, Deborah K.
- Jain, Manu
- Moffett, Kathryn
- Flume, Patrick
- Jain, Raksha
- Patel, Kapilkumar
- Daines, Cori
- Verhulst, Stijn
- Macedo, Patricia
- Connett, Gary
- Nash, Edward
- Withers, Nicholas
- Lee, Timothy
- Bakker, Marleen
- Knoop, Christiane
- Majoor, Christof
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 394
- Issue
- 10212
- Pages
- 1940-1948
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC7571408
- OpenAlex
- W2982296199
- Cited by
- 1,414
- References
- 27
- Citations by year
- 2026: 157 · 2025: 215 · 2024: 210 · 2023: 245 · 2022: 226 · 2021: 204 · 2020: 143 · 2019: 13
- FWCI
- 107.62
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-05-30)
- Open access
- bronze
- doi.org
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- PubMed Central (acceptedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Portal (Queen's University Belfast) (submittedVersion, cc-by-nc-nd)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institutes of Health (P30DK072482, R35HL135816, U54TR001368)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- cystic fibrosis, F508del mutation, elexacaftor, tezacaftor, ivacaftor, CFTR modulators, FEV1, sweat chloride, lung function, treatment safety, adverse events
- MeSH terms
- Adolescent, Aminophenols, Child, Cystic Fibrosis, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Indoles, Male, Pyrazoles, Pyridines, Pyrrolidines, Sweat, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, 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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
