Boyle 2014.

Methods	Phase 2 placebo‐controlled RCT with 3 different cohorts. Only cohort 1 was included in this review (n = 62). (The following information will refer to cohort 1 only ‐ see 'Notes'.) Parallel design. Multicentre study conducted at 69 different sites in North America, Europe and Australia. Duration: Cohort 1 lasted 21 days.
Participants	Mutation: participants homozygous for F508del mutation. Age: participants in Cohort 1 have a mean age of 29.1 years. Gender split: 50% of participants are male Lung function: all participants in Cohort 1 have a FEV1 ≥ 40% of predicted normal for age, gender, and height and a mean (range) predicted FEV1 of 66.9% (32.8 ‐ 117.1). Sweat chloride levels: participants in Cohort 1 have a mean (range) level of 101.9 mmol/L (87.5 ‐ 121.0).
Interventions	Intervention 1: lumacaftor (also known as VX‐809, a CFTR corrector) alone. Intervention 2: lumacaftor in combination with ivacaftor (also known as VX‐770, a CFTR potentiator). Intervention 3: placebo. Cohort 1 (n = 62) Study drug participants: 200 mg lumacaftor once daily for 14 days; then from day 15, participants continue to take 200 mg of lumacaftor in addition to either 150 mg or 250 mg of ivacaftor twice daily until day 21. Placebo participants: placebo for 21 days.
Outcomes	Primary outcomes 1. Change in sweat chloride when ivacaftor is administered in combination with lumacaftor* 2. Safety and tolerability assessments based on adverse events, plasma samples (haematology, clinical chemistry, coagulation), urinalysis, ECGs, and vital signs* Secondary outcomes 1. Change in % predicted FEV1* 2. Change in sweat chloride of increasing doses of lumacaftor administered alone* 3. PK parameters (including exposure, concentration and half‐life) of lumacaftor and metabolite in plasma in the presence and absence of ivacaftor 4. PK parameters (including exposure, concentration and half‐life) of ivacaftor and metabolites in plasma in the presence of lumacaftor
Funding source	Vertex Pharmaceuticals, and the Cystic Fibrosis Foundation Therapeutics Development Network.
Notes	* denotes outcomes relevant to this review. Only data from Cohort 1 were included in this review. This was because data for placebo participants from Cohorts 2 and 3 were pooled, although randomisation in these cohorts occurred separately. This meant that the effects of randomisation in these cohorts were undone. Data for participants in Cohorts 2 and 3 were excluded.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A random sequence was generated by a computer by an independent party.
Allocation concealment (selection bias)	Low risk	"Site pharmacists dispensed drugs on the basis of an interactive voice response system".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Drug doses were prepared by an independent unmasked pharmacist and dispensed by site pharmacists who were masked to treatment assignment. Participant blinding was maintained by placebo which was matched to intervention by the quantity of tablets and by size, colour, coating and packaging.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Site investigators and the study sponsor were also masked to treatment assignment and to sweat chloride levels ‐ data that could have potentially disclosed treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Participant data were excluded from the analysis due to insufficient data, e.g. participants were excluded from the analysis of sweat chloride concentration if insufficient amount of sweat were provided. We judged this trial as having an unclear risk of attrition bias because it was unclear how these exclusions would have affected the balance between groups in baseline characteristics.
Selective reporting (reporting bias)	Low risk	We compared the outcomes reported on the US NIH trials registry (www.clinicaltrials.gov) to the outcomes reported in the results of the published paper as the protocol was not available. No selective outcome reporting was identified.
Other bias	Low risk	Similar baseline characteristics.