***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: BACKGROUND Oral acetylcysteine ( also known as N-acetylcysteine ) is used with pirfenidone to treat idiopathic pulmonary fibrosis ( IPF ) in Europe . However , no r and omised studies have investigated the safety and tolerability of this combination . The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF . Exploratory efficacy endpoints were also assessed . METHODS We did a double-blind r and omised trial at 48 sites in eight countries . Patients with IPF aged 40 - 80 years and established on pirfenidone ( at least 1602 mg/day for 8 weeks or longer ) were r and omly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine ( 600 mg , three times daily ) or placebo for 24 weeks . A stratified blocked r and omisation scheme was used with a block size of 4 . R and omisation was stratified by dose of pirfenidone ( 2403 mg/day [ the maximum dose ] or < 2403 mg/day ) . Patients , physicians , study staff and the sponsor were masked to treatment group allocation . The primary endpoint was assessment of adverse events , which were collected at each visit and for 28 days after the last dose of study drug . Exploratory efficacy measurements included forced vital capacity ( FVC ) , carbon monoxide diffusing capacity , and 6 min walk distance . Analyses were done in the modified intention-to-treat population , which included all patients who were r and omised and received at least one dose of study medication . This study is registered with the European Clinical Trials Data base ( EudraCT number 2012 - 000564 - 14 ) and has been completed . FINDINGS 123 patients participated in the study between June 28 , 2013 , and Feb 24 , 2015 . 61 were assigned to the acetylcysteine group ( 60 received study medication and included in analysis ) and 62 were assigned to the placebo group ( all included in analysis ) . The occurrence of at least one adverse event ( 46 [ 77 % ] patients receiving acetylcysteine vs 50 [ 81 % ] receiving placebo ) , adverse events related to study treatment ( 17 [ 28 % ] vs 16 [ 26 % ] ) , and the number of patients experiencing severe adverse events ( three [ 5 % ] vs two [ 3 % ] ) , life-threatening adverse events ( one [ 2 % ] vs one [ 2 % ] ) , or death ( one [ 2 % ] vs three [ 5 % ] ) was similar between treatment groups . One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment . Nine serious adverse events were reported by seven patients  : dyspnoea , headache , hypertension , intervertebral disc protrusion , and malignant lung neoplasm in the acetylcysteine group , and aortic aneurysm , contusion , forearm fracture , and worsening IPF in the placebo group . The most common adverse events were cough , nasopharyngitis , and diarrhoea . Photosensitivity occurred more frequently with acetylcysteine ( eight [ 13 % ] patients ) than placebo ( one [ 2 % ] patient ; difference 11·7 % ; 95 % CI 2·6 - 20·9 ; p=0·016 ] ) , and was not attributable to differences in location , season , or concomitant medication . Four ( 7 % ) patients receiving acetylcysteine and three ( 5 % ) receiving placebo discontinued study treatment due to adverse events . In the exploratory analysis , change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely , with the possibility of a harmful effect in patients with IPF ( adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo ; difference -91·3 mL ; 95 % CI -174·4 to -8·3 ; p=0·031 ) . INTERPRETATION Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile  of pirfenidone , and is unlikely to be beneficial in IPF . FUNDING InterMune International AG ( Roche ) BACKGROUND A combination of prednisone , azathioprine , and N-acetylcysteine ( NAC ) has been widely used as a treatment for idiopathic pulmonary fibrosis . The safety and efficacy of this three-drug regimen is unknown . METHODS In this r and omized , double-blind , placebo-controlled trial , we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone , azathioprine , and NAC ( combination therapy ) , NAC alone , or placebo -- in a 1:1:1 ratio . The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period . RESULTS When approximately 50 % of data had been collected ( with 77 patients in the combination-therapy group and 78 in the placebo group ) , a planned interim analysis revealed that patients in the combination-therapy group , as compared with the placebo group , had an increased rate of death ( 8 vs. 1 , P=0.01 ) and hospitalization ( 23 vs. 7 , P<0.001 ) . These observations , coupled with no evidence of physiological or clinical benefit for combination therapy , prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks . Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here . CONCLUSIONS Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone , azathioprine , and NAC , as compared with placebo . These findings provide evidence against the use of this combination in such patients . ( Funded by the National Heart , Lung , and Blood Institute and the Cowlin Family Fund ; Clinical Trials.gov number , NCT00650091 . ) BACKGROUND Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function . The CAPACITY programme ( studies 004 and 006 ) was design ed to confirm the results of a phase 2 study that suggested that pirfenidone , a novel antifibrotic and anti-inflammatory drug , reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis . METHODS In two concurrent trials ( 004 and 006 ) , patients ( aged 40 - 80 years ) with idiopathic pulmonary fibrosis were r and omly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia , Europe , and North America . In study 004 , patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day , pirfenidone 1197 mg/day , or placebo ; in study 006 , patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo . The r and omisation code ( permuted block design ) was computer generated and stratified by region . All study personnel were masked to treatment group assignment until after final data base lock . Treatments were administered orally , 801 mg or 399 mg three times a day . The primary endpoint was change in percentage predicted forced vital capacity ( FVC ) at week 72 . Analysis was by intention to treat . The studies are registered with Clinical Trials.gov , numbers NCT00287729 and NCT00287716 . FINDINGS In study 004 , 174 of 435 patients were assigned to pirfenidone 2403 mg/day , 87 to pirfenidone 1197 mg/day , and 174 to placebo . In study 006 , 171 of 344 patients were assigned to pirfenidone 2403 mg/day , and 173 to placebo . All patients in both studies were analysed . In study 004 , pirfenidone reduced decline in FVC ( p=0·001 ) . Mean FVC change at week 72 was -8·0 % ( SD 16·5 ) in the pirfenidone 2403 mg/day group and -12·4 % ( 18·5 ) in the placebo group ( difference 4·4 % , 95 % CI 0·7 to 9·1 ) ; 35 ( 20 % ) of 174 versus 60 ( 35 % ) of 174 patients , respectively , had a decline of at least 10 % . A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints ( p=0·0007 ) . Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups . In study 006 , the difference between groups in FVC change at week 72 was not significant ( p=0·501 ) . Mean change in FVC at week 72 was -9·0 % ( SD 19·6 ) in the pirfenidone group and -9·6 % ( 19·1 ) in the placebo group , and the difference between groups in predicted FVC change at week 72 was not significant ( 0·6 % , -3·5 to 4·7 ) ; however , a consistent pirfenidone effect was apparent until week 48 ( p=0·005 ) and in an analysis of all study timepoints ( p=0·007 ) . Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea ( 125 [ 36 % ] of 345 vs 60 [ 17 % ] of 347 ) , dyspepsia ( 66 [ 19 % ] vs 26 [ 7 % ] ) , vomiting ( 47 [ 14 % ] vs 15 [ 4 % ] ) , anorexia ( 37 [ 11 % ] vs 13 [ 4 % ] ) , photosensitivity ( 42 [ 12 % ] vs 6 [ 2 % ] ) , rash ( 111 [ 32 % ] vs 40 [ 12 % ] ) , and dizziness ( 63 [ 18 % ] vs 35 [ 10 % ] ) than did those in the placebo group . Fewer overall deaths ( 19 [ 6 % ] vs 29 [ 8 % ] ) and fewer deaths related to idiopathic pulmonary fibrosis ( 12 [ 3 % ] vs 25 [ 7 % ] ) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups . INTERPRETATION The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis . FUNDING InterMune Idiopathic pulmonary fibrosis ( IPF ) is a progressive lung disease without proven effective therapy . A multicentre , double-blind , placebo-controlled , r and omised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone , a novel antifibrotic oral agent , over 52 weeks . Of 275 patients r and omised ( high-dose , 1,800 mg·day−1 ; low-dose , 1,200 mg·day−1 ; or placebo groups in the ratio 2:1:2 ) , 267 patients were evaluated for the efficacy of pirfenidone .  Prior to unblinding , the primary end-point was revised ; the change in vital capacity ( VC ) was assessed at week 52 . Secondary end-points included the progression-free survival ( PFS ) time . Significant differences were observed in VC decline ( primary end-point ) between the placebo group ( -0.16 L ) and the high-dose group ( -0.09 L ) ( p = 0.0416 ) ; differences between the two groups ( p = 0.0280 ) were also observed in the PFS ( the secondary end-point ) . Although photosensitivity , a well-established side-effect of pirfenidone , was the major adverse event in this study , it was mild in severity in most of the patients . Pirfenidone was relatively well tolerated in patients with IPF . Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks . Additional studies are needed to confirm these findings A r and omised , double-blind , phase II , dose escalation trial was conducted to assess the safety , tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib , alone and when added to ongoing pirfenidone therapy , in Japanese patients with idiopathic pulmonary fibrosis . 50 Japanese patients were r and omised to receive nintedanib or placebo in one of three cohorts ( nintedanib 50 mg twice daily or 100 mg twice daily for 14 days , or 150 mg twice daily for 28 days ) . Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo .  
    Output:
    
Our results showed that both pirfenidone and nintedanib , but not NAC , were significantly effective in reducing FVC decline and the risk of FVC ≥10 % decline in percent predicted over 12 months  .
Nintenadib significantly protected against the risk of acute exacerbation and mortality .
Pirfenidone and nintedanib showed a similar and good safety profile , whereas NAC provided a signal for increased adverse events .
CONCLUSIONS The rank of effectiveness emerging from this meta- analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib .