***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Rationale : Tezacaftor ( formerly VX‐661 ) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator ( CFTR ) in vitro , and improves CFTR function alone and in combination with ivacaftor . Objectives : To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D . Methods : This was a r and omized , placebo‐controlled , double‐blind , multicenter , phase 2 study ( NCT01531673 ) . Subjects homozygous for F508del received tezacaftor ( 10 to 150 mg ) every day alone or in combination with ivacaftor ( 150 mg every 12 h ) in a dose escalation phase , as well as in a dosage regimen testing phase . Subjects compound heterozygous for F508del and G551D , taking physician‐prescribed ivacaftor  , received tezacaftor ( 100 mg every day ) . Measurements and Main Results : Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28 . Secondary endpoints included change in percent predicted FEV1 ( ppFEV1 ) from baseline through Day 28 and pharmacokinetics . The incidence of adverse events was similar across treatment arms . Tezacaftor ( 100 mg every day)/ivacaftor ( 150 mg every 12 h ) result ed in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV1 in subjects homozygous for F508del , and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 ( P < 0.05 for all ) . Conclusions : These results support continued clinical development of tezacaftor ( 100 mg every day ) in combination with ivacaftor ( 150 mg every 12 h ) in subjects with cystic fibrosis . Clinical trial registered with www . clinical trials.gov ( NCT01531673 ) BACKGROUND Ivacaftor has been shown to be a safe , effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation . We aim ed to assess the safety , pharmacokinetics , and pharmacodynamics of ivacaftor in children aged 2 - 5 years . METHODS In the two-part KIWI study , we enrolled children aged 2 - 5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA , UK , and Canada . Participants received oral ivacaftor 50 mg ( if bodyweight < 14 kg ) or 75 mg ( if bodyweight ≥14 kg ) every 12 h for 4 days in part A ( to establish the short-term safety of doses for subsequent assessment in part B ) , and then for 24 weeks in part B ( to assess safety and longer-term pharmacodynamics ) . Children could participate in both or just one part of the study . Primary outcomes were pharmacokinetics and safety , analysed in all patients who received at least one dose of ivacaftor . Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight , body-mass index ( BMI ) , and height Z scores , and pharmacokinetic parameter estimation of ivacaftor  . This study is registered with Clinical Trials.gov , number NCT01705145 . FINDINGS Between Jan 8 , 2013 , and March 1 , 2013 , nine patients were enrolled onto part A of the study , all of whom completed the 4 day treatment period , and eight of whom took part in part B. Between June 28 , 2013 , and Sept 26 , 2013 , 34 patients were enrolled in part B , 33 of whom completed the 24 week treatment period . All patients received at least one dose of ivacaftor . Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults ( median Cmin were 536 ng/mL for the 50 mg dose ; 580 ng/mL for the 75 mg dose ; median ivacaftor  AUC values were 9840 ng × h/mL and 10 200 ng × h/mL , respectively ) . Common adverse events in part B included cough ( in 19 [ 56 % ] of 34 patients ) and vomiting ( in ten [ 29 % ] ) . Five ( 15 % ) patients had liver function test ( LFT ) results that were more than eight times higher than the upper limit of normal , four of whom had study drug interrupted , and one of whom had study drug discontinued . Six ( 18 % ) of 34 patients had seven serious adverse events ; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that result ed in study treatment discontinuation . At week 24 , in patients for whom we had data , sweat chloride had changed from baseline by a mean of -46·9 mmol/L ( SD 26·2 , p<0·0001 ) , weight Z score by 0·2 ( 0·3 ; p<0·0001 ) , BMI Z score by 0·4 ( 0·4 , p<0·0001 ) , and height Z score by -0·01 ( 0·3 ; p=0·84 ) . INTERPRETATION Ivacaftor at doses of 50 mg and 75 mg seems to be safe  in children aged 2 - 5 years with cystic fibrosis with a gating mutation followed up for 24 weeks , although the frequency of elevated LFTs suggests that monitoring should be frequent in young children , particularly those with a history of elevated LFTs . Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted . FUNDING Vertex Pharmaceuticals Incorporated BACKGROUND Increasing the activity of defective cystic fibrosis transmembrane conductance regulator ( CFTR ) protein is a potential treatment for cystic fibrosis . METHODS We conducted a r and omized , double-blind , placebo-controlled trial to evaluate ivacaftor ( VX-770 ) , a CFTR potentiator , in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation . Subjects were r and omly assigned to receive 150 mg of ivacaftor every 12 hours ( 84 subjects , of whom 83 received at least one dose ) or placebo ( 83 , of whom 78 received at least one dose ) for 48 weeks . The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second ( FEV(1 ) ) . RESULTS The change from baseline through week 24 in the percent of predicted FEV(1 ) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group ( P<0.001 ) . Effects on pulmonary function were noted by 2 weeks , and a significant treatment effect was maintained through week 48 . Subjects receiving ivacaftor were 55 % less likely to have a pulmonary exacerbation than were patients receiving placebo , through week 48 ( P<0.001 ) . In addition , through week 48 , subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Question naire-revised instrument ( a 100-point scale , with higher numbers indicating a lower effect of symptoms on the patient 's quality of life ) ( P<0.001 ) . By 48 weeks , patients treated with ivacaftor had gained , on average , 2.7 kg more weight than had patients receiving placebo ( P<0.001 ) . The change from baseline through week 48 in the concentration of sweat chloride , a measure of CFTR activity , with ivacaftor as compared with placebo was -48.1 mmol per liter ( P<0.001 ) . The incidence of adverse events was similar with ivacaftor and placebo , with a lower proportion of serious adverse events with ivacaftor than with placebo ( 24 % vs. 42 % ) . CONCLUSIONS Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks . Substantial improvements were also observed in the risk of pulmonary exacerbations , patient-reported respiratory symptoms , weight , and concentration of sweat chloride . ( Funded by Vertex Pharmaceuticals and others ; VX08 - 770 - 102 Clinical Trials.gov number , NCT00909532 . ) BACKGROUND The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two r and omised controlled trials ( RCTs ) -TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation . We aim ed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS , the long-term extension of TRAFFIC and TRANSPORT . METHODS PROGRESS was a phase 3 , parallel-group , multicentre , 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries . Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation . Exclusion criteria included any comorbidity or laboratory abnormality that , in the opinion of the investigator , might confound the results of the study or pose an additional risk in administering the study drug to the participant , history of drug intolerance , and history of poor compliance with the study drug . Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS . Patients who had received placebo in TRANSPORT or TRAFFIC were r and omly assigned ( 1:1 ) to receive lumacaftor ( 400 mg every 12 h)/ivacaftor ( 250 mg every 12 h ) or lumacaftor ( 600 mg once daily)/ivacaftor ( 250 mg every 12 h ) . The primary outcome was to assess the long-term safety of combined therapy . The estimated annual rate of decline in percent predicted FEV1 ( ppFEV1 ) in treated patients was compared with that of a matched registry cohort . Efficacy analyses were based on modified intention-to-treat , such that data were included for all patients who were r and omly assigned and received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01931839 . FINDINGS Between Oct 24 , 2013 , and April 7 , 2016 , 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS , and 1029 received at least one dose of study drug . 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h ; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h , the commercially available dose , for which data are presented . The most common adverse events were infective pulmonary exacerbations , cough , increased sputum , and haemoptysis . Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS . For patients continuing treatment , the mean change from baseline in ppFEV1 was 0·5 ( 95 % CI -0·4 to 1·5 ) at extension week 72 and 0·5 ( -0·7 to 1·6 ) at extension week 96 ; change in BMI was 0·69 ( 0·56 to 0·81 ) at extension week 72 and 0·96 ( 0·81 to 1·11 ) at extension week 96 . The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 ( 0·65 , 0·56 to 0·75 ) remained lower than the placebo rate in TRAFFIC and TRANSPORT . The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls ( -1·33 , -1·80 to -0·85 vs -2·29 , -2·56 to -2·03 ) . The efficacy and safety profile  of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups . INTERPRETATION The long-term safety 
    Output:
    
Both tezacaftor-ivacaftor ( TEZ-IVA ) and lumacaftor-ivacaftor ( LUM-IVA ) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo .
IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation .
Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals , TEV-IVA and LUM-IVA in F508del homozygous individuals , and IVA in adults with a R117H mutation