***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 Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator ( CFTR ) in placebo-controlled studies and patients aged 6 - 11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study . We report efficacy and safety  of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6 - 11 years homozygous for F508del-CFTR . METHODS In this phase 3 , r and omised , double-blind , placebo-controlled , multicentre study , patients were enrolled at 54 hospitals and medical centres in nine countries ( the USA , Australia , Belgium , Canada , Denmark , France , Germany , Sweden , and the UK ) . Eligible patients weighed at least 15 kg , with a confirmed diagnosis of cystic fibrosis , percent predicted forced expiratory volume in 1 s ( FEV1 ) of 70 or more , and lung clearance index2·5 ( LCI2·5 ) of 7·5 or more at screening ( values less than these thresholds were permitted at day 1 ) . All patients were tested for CFTR genotype at screening ; eligible patients had to have the F508del-CFTR mutation on both alleles . Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient . Patients were stratified by weight ( < 25 kg vs ≥25 kg ) and ppFEV1 severity ( < 90 vs ≥90 ) determined at the screening visit , and r and omly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks . Patients , all site personnel including the investigator and the site monitor , and the study team were blinded , with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements . The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24 . All r and omly assigned patients who were exposed to any amount of study drug , with treatment assignment as assigned were included in primary and other efficacy analyses . All patients who were exposed to any amount of study drug , with treatment assignment as treated , were included in the safety analysis . This study was registered with Clinical Trials.gov , number NCT02514473 . FINDINGS Between July 23 , 2015 , and Sept 20 , 2016 , a total of 206 patients were enrolled and r and omly assigned to receive lumacaftor and ivacaftor ( n=104 ) or placebo ( n=102 ) . Two r and omly assigned patients were never dosed with study drug ( one in the placebo arm due to in eligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests ) and were not included in the analyses . 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo . For the primary endpoint , the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit , least squares mean difference was -1·09 units ( 95 % CI -1·43 to -0·75 , p<0·0001 ) for lumacaftor and ivacaftor versus placebo . For the key secondary endpoint of sweat chloride concentration , the least squares mean difference versus placebo was -20·8 mmol/L ( 95 % CI -23·4 to -18·2 , average absolute change at day 15/week 4 ; p<0·0001 ) . The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 ( 95 % CI 0·4 - 4·4 , p=0·0182 ) . 196 ( 96 % ) of 204 patients reported adverse events , most of which were mild ( 87 [ 43 % ] ) or moderate ( 98 [ 48 % ] ) . Treatment was discontinued due to adverse events in three ( 3 % ) of 103 patients in the lumacaftor and ivacaftor group and two ( 2 % ) of 101 patients in the placebo group . Serious adverse events were reported in 13 ( 13 % ) of 103 patients in the lumacaftor and ivacaftor group and 11 ( 11 % ) of 101 patients in the placebo group . INTERPRETATION Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function , as measured by LCI2·5 and ppFEV1 , versus placebo in patients aged 6 - 11 years with cystic fibrosis homozygous for F508del-CFTR . The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor . FUNDING Vertex Pharmaceuticals Rationale : Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del‐CFTR , but it has not been assessed in younger patients . Objectives : In this open‐label phase III trial , we evaluated the safety , tolerability , pharmacodynamics , and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6‐11 years with cystic fibrosis who were homozygous for F508del‐CFTR . Methods : Patients ( N = 58 ) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications . Measurements and Main Results : Lumacaftor/ivacaftor was well tolerated ; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients . Four patients discontinued ( two because of drug‐related adverse events : elevated liver transaminases , n = 1 ; rash , n = 1 ) . No safety concerns were associated with spirometry . No significant changes in percent predicted FEV1 were observed ( change from baseline at Week 24 , + 2.5 percentage points ; 95 % confidence interval [ CI ] , −0.2 to 5.2 ; P = 0.0671 ) . At Week 24 , significant improvements from baseline were observed in sweat chloride ( −24.8 mmol/L ; 95 % CI , −29.1 to −20.5 ; P < 0.0001 ) , body mass index z score ( + 0.15 ; 95 % CI , 0.08 to 0.22 ; P < 0.0001 ) , Cystic Fibrosis Question naire‐Revised respiratory domain score ( + 5.4 ; 95 % CI , 1.4 to 9.4 ; P = 0.0085 ) , and lung clearance index based on lung volume turnover required to reach 2.5 % of starting N2 concentration ( −0.88 ; 95 % CI , −1.40 to −0.37 ; P = 0.0018 ) . Conclusions : Lumacaftor/ivacaftor was well tolerated in this young population ; no new safety concerns were identified . Improvements in lung clearance index , sweat chloride , nutritional status , and health‐related quality of life were observed after 24 weeks of treatment . Clinical trial registered with www . clinical trials.gov ( NCT01897233 ) 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· 
    Output:
    
Conclusions CFTR corrector and potentiator combination therapy effectively improves lung function , nutritional status and clinical score  in CF patients with the F508del-CFTR homozygous mutation , and has an acceptable safety profile