KONDUCT 2015.

Methods	Phase 3, double‐blind, RCT of parallel design. Multicentre: 31 centres reported. Duration: 24 weeks with an open‐label extension phase for up to 104 weeks. Participants were not re‐randomised for the extension phase.
Participants	69 participants aged 6 years or older with CF with at least 1 allele of the R117H‐CFTR mutation were enrolled. Total: control n = 35, intervention n = 34; 6 ‐ 11 years control n = 8, intervention n = 9; ≥ 18 years control n = 26, intervention n = 24. Age years, mean (SD) Overall: treatment group: 29.2 (16.6); placebo group: 32.7 (17.4). 6 ‐ 11 years: treatment group 8.8 (1.9); placebo group 9 (1.6). ≥ 18 years: treatment group 37.5 (12.1); placebo group 40.6 (12.6). Gender n (%) Overall: treatment group 19 (56%) females; placebo group 20 (57%) females. 6 ‐ 11 years: treatment group 5 (56%) females; placebo group 3 (38%) females. ≥ 18 years: treatment group 13 (54%); placebo group 16 (62%). Weight kg, mean (SD) Overall: treatment group: 66.1 (25.5); placebo group: 62.8 (25.4). 6 ‐ 11 years: treatment group 32.9 (13.3); placebo group 34.0 (9.1). ≥ 18 years: treatment group 77.9 (16.7); placebo group 71.7 (22.5). BMI kg/m2, mean (SD) Overall: treatment group: 24.5 (6.3); placebo group: 23.1 (6). 6 ‐ 11 years: treatment group 17.6 (3.3); placebo group 17.1 (2.4). ≥ 18 years: treatment group 26.9 (5.2); placebo group 24.9 (5.7). FEV1 % predicted, mean (SD) Participants with baseline FEV1 40% to 90% (for participants aged 12 years or older) or 40% to 105% (for participants aged 6 to 11 years) of the predicted value for age, sex, and height were eligible. Overall: treatment group: 75.7 (19.3); placebo group: 70.2 (18.9). 6 ‐ 11 years: treatment group 97.5 (8.6); placebo group 94.0 (8.4). ≥ 18 years: treatment group 67.0 (15.4); placebo group 62.3 (14.4). FEV1 % predicted, n (%) <70% Overall: treatment group: 13 (38%); placebo group: 15 (43%). 6 ‐ 11 years: treatment group 0; placebo group 0. ≥ 18 years: treatment group 13 (54%); placebo group 15 (58%). ≥ 70 to ≤ 90% Overall: treatment group: 14 (41%); placebo group: 14 (40%). 6 ‐ 11 years: treatment group 3 (33%); placebo group 2 (25%). ≥ 18 years: treatment group 10 (42%); placebo group 11 (42%). > 90% Overall: treatment group: 7 (21%); placebo group: 6 (17%). 6 ‐ 11 years: treatment group 6 (67%); placebo group 6 (75%). ≥ 18 years: treatment group 1 (4%); placebo group 0. Sweat chloride n/mmol/l, mean (SD) Overall: treatment group: 32/67.3 (23.5); placebo group: 35/73.4 (19.7). 6 ‐ 11 years: treatment group 8/64.2 (22.6); placebo group 8/74.7 (28.6). ≥ 18 years: treatment group 23/69.3 (24.1); placebo group 26/73.0 (17.3). CFQ‐R score for respiratory domain, n/score, mean (SD) Overall: treatment group: 33/75.3 (20.1); placebo group: 34/66.4 (24.4). 6 ‐ 11 years: treatment group 8/92.7 (7.0); placebo group 7/91.7 (6.8). ≥ 18 years: treatment group 24/68.4 (19.1); placebo group 26/59.2 (23.2). CFTR genotype (Arg117His/Phe508del), mean (SD) Overall: treatment group: 28 (82%); placebo group: 25 (71%). 6 ‐ 11 years: treatment group 8 (89%); placebo group 6 (75%). ≥ 18 years: treatment group 19 (79%); placebo group 19 (73%).
Interventions	Ivacaftor 150 mg orally 2x daily for 24 weeks.
Outcomes	Primary outcome: 1. absolute change from baseline in % predicted FEV1 (through 24 weeks). Secondary outcomes: 1. change from baseline in BMI (through 24 weeks); 2. change from baseline in sweat chloride (through 24 weeks); 3. change from baseline in the respiratory domain of the CFQ‐R (through 24 weeks); 4. time to first pulmonary exacerbation (through 24 weeks); 5. number of participants with adverse events and serious adverse events (through 24 weeks).
Notes	The responsible funding body was Vertex Pharmaceuticals Incorporated. * These outcomes are presented in the review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were assigned to receive placebo or ivacaftor (1:1) via a randomisation specification and randomisation code. The code list was sent to the IVRS.
Allocation concealment (selection bias)	Low risk	A masked biostatistician created the randomisation specification and dummy randomisation code, this was then approved by an unmasked biostatistician not associated with the trial, prior to generating the final randomisation list. An unblinded quality check biostatistician reviewed and approved final randomisation list. The biostatistician not associated with the trial provided the final list to IVRS.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Described as double blinded. Other than the biostatisticians, it is not stated which trial personnel were blinded or how they were blinded.
Blinding of participants	Unclear risk	Described as double blinded. There is no report on details of the tablets (e.g. colour, size, taste).
Incomplete outcome data (attrition bias) All outcomes	Low risk	In total, 69 participants were randomised. 2 withdrew from the intervention group with reasons given. A full analysis set included all randomised participants who received at least 1 dose of trial drug.
Selective reporting (reporting bias)	High risk	No protocol was available online to compare outcomes in the protocol with those published. The author was approached for further information and a protocol synopsis provided. This showed the following tertiary outcomes which were reported in the protocol but no with no published results. 1. PK parameter estimates of ivacaftor and metabolites, M1 and M6, derived from plasma concentration‐time data 2. Change from baseline in nonrespiratory domains of the CFQ‐R 3. Change from baseline in weight 4. Change from baseline in height 5. CF‐related complications (pancreatitis or distal ileal obstruction syndrome 6. Change from baseline in inflammatory mediators 7. Change from baseline in qualitative microbiological cultures 8. Change from baseline in IRT 9. Change from baseline in fecal elastase‐1
Other bias	Low risk	Similar baseline characteristics. There were only 2 participants between 12 ‐ 17 years of age so no age subgroup statistical analysis were performed for this group. They were included in overall analysis. No comment was made regarding the reason for low enrolment in this age group.