. 2023 Nov 20;2023(11):CD010966. doi: 10.1002/14651858.CD010966.pub4

Keating 2018.

*Study characteristics*
Methods	Phase 2, double‐blind RCT Parallel design Multicentre: 38 sites in the USA, the Netherlands, Belgium and Australia Duration: 4 weeks intervention period (12 weeks for those arms with a 4‐week run‐in and 4‐week washout) Randomisation of participants was stratified by FEV₁ % predicted being less than or equal to 70% versus greater than 70%, except for the first 10 F508del/MF participants who were not stratified.
Participants	All participants were aged 18 years or older, with CFTR genotype of either F508del/MF or F508del/F508del. They must have had FEV₁ % predicted between 40% and 90% at screening, as well as stable disease. 123 participants underwent randomisation and received at least 1 dose of the intervention. Participants with F508del/MF (n = 65) Elexacaftor 50 mg 1x daily plus tezacaftor 100 mg 1x daily plus ivacaftor 150 mg every 12 hours (n = 10) Age, mean (SD): 27.1 (7.4) years Sex: 4 males, 6 females FEV₁ % predicted, mean (SD): 56.4 (14.6)% Sweat chloride, mean (SD): 103.1 (7.8) mmol/L CFQ‐R score (respiratory domain), mean (SD): 62.8 (21.9) Elexacaftor 100 mg 1x daily plus tezacaftor 100 mg 1x daily plus ivacaftor 150 mg every 12 hours (n = 22) Age, mean (SD): 31.8 (8.3) years Sex: 15 males, 7 females FEV₁ % predicted, mean (SD): 60.0 (15.5)% Sweat chloride, mean (SD): 103.6 (12.2) mmol/L CFQ‐R score (respiratory domain), mean (SD): 65.9 (13.4) Elexacaftor 200 mg 1x daily plus tezacaftor 100 mg 1x daily plus ivacaftor 150 mg every 12 hours (n = 21) Age, mean (SD): 33.3 (10.3) years Sex: 10 males, 11 females FEV₁ % predicted, mean (SD): 59.4 (18.0)% Sweat chloride, mean (SD): 103.9 (9.7) mmol/L CFQ‐R score (respiratory domain), mean (SD): 61.1 (17.5) Triple placebo (n = 12) Age, mean (SD): 29.7 (7.5) years Sex: 10 males, 2 females FEV₁ % predicted, mean (SD): 59.0 (14.9)% Sweat chloride, mean (SD): 103.1 (8.2) mmol/L CFQ‐R score (respiratory domain), mean (SD): 57.4 (14.1) Participants with F508del/F508del (n = 28)* Elexacaftor 200 mg plus tezacaftor plus ivacaftor (n = 21) Age, mean (SD): 29.9 (7.6) years Sex: 12 males, 9 females FEV₁ % predicted, mean (SD): 60.0 (15.1)% Sweat chloride, mean (SD): 92.7 (11.1) mmol/L CFQ‐R score (respiratory domain), mean (SD): 71.2 (17.3) Placebo plus tezacaftor plus ivacaftor (n = 8) Age, mean (SD): 27.9 (8.0) years Sex: 6 males, 2 females FEV₁ % predicted, mean (SD): 62.8 (13.2)% Sweat chloride, mean (SD): 99.5 (9.0) mmol/L CFQ‐R score (respiratory domain), mean (SD): 73.0 (22.3) Had a 4‐week run‐in of tezacaftor‐ivacaftor and a further 4‐week post‐invention washout period of tezacaftor‐ivacaftor Participants with F508del/MF (n = 29)* Elexacaftor 200 mg plus tezacaftor plus VX‐561 (n = 21) Age, mean (SD): 30.6 (9.5) years Sex: 11 males, 10 females FEV₁ % predicted, mean (SD): 60.6 (17.5)% Sweat chloride, mean (SD): 100.8 (15.4) mmol/L CFQ‐R score (respiratory domain), mean (SD): 63.8 (18.2) Triple placebo (n = 8) Age, mean (SD): 27.8 (5.2) years Sex: 3 males, 5 females FEV₁ % predicted, mean (SD): 60.7 (14.0)% Sweat chloride, mean (SD): 96.4 (1.5) mmol/L CFQ‐R score (respiratory domain), mean (SD): 43.8 (21.9)
Interventions	Arm 1: 1x daily elexacaftor 50 mg or elexacaftor 100 mg or elexacaftor 200 mg plus tezacaftor 100 mg plus 2x daily (every 12 hours) ivacaftor 150 mg versus triple placebo Arm 2: 4‐week run in period of 1x daily tezacaftor 100 mg plus ivacaftor 150 mg for all participants; then 4‐week intervention period of 1x daily elexacaftor 200 mg and tezacaftor 100 mg plus 2x daily (every 12 hours) ivacaftor 150 mg versus matched placebo; then a 4‐week washout period of 1x daily tezacaftor 100 mg plus ivacaftor 150 mg for all participants Arm 3: 1x daily elexacaftor 200 mg and tezacaftor 100 mg and VX‐561 150 mg once daily versus triple placebo
Outcomes	Primary outcomes Safety (AEs, clinical laboratory values, ECGs, vital signs, pulse oximetry) Tolerability Absolute change in FEV₁ % predicted from baseline to day 29 Secondary outcomes Absolute change in sweat chloride concentrations from baseline to day 29 QoL ‐ absolute change in CFQ‐R respiratory domain from baseline to day 29
Funding source	Vertex Pharmaceuticals, who received funding from the CF Foundation to develop elexacaftor. The NIH gave a grant to the University of Alabama at Birmingham.
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation code made by Vertex Biostatistics or a "qualified randomisation vendor". Randomisation stratified by FEV₁ % predicted (less than or equal to 70% versus greater than 70%).
Allocation concealment (selection bias)	Low risk	Use of interactive web response system for allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All participants, site personnel and Vertex study team related to the study were blinded. A clear statement on when unblinding is necessary or permitted is provided in the protocol.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	All authors were only allowed access to study data after they were unblinded. No mention is made of other outcome assessors (e.g. clinicians who were not authors, but were involved in seeing participants and measuring outcomes of interest) and whether there was a possibility of them knowing the allocated intervention.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants who were randomised are accounted for.
Selective reporting (reporting bias)	Unclear risk	States in methods that 12‐lead ECG and vital signs would be measured; although these may have been measured, they are not stated in the results or supplement regardless of whether they were unremarkable or not.
Other bias	Low risk	Different groups of participants are balanced in baseline characteristics; no significant difference between them. Detail in paper and its supplement does not cause any concern about other sources of bias not previously mentioned.