Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. Pirfenidone in idiopathic pulmonary fibrosis Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Anticoagulant therapy for idiopathic pulmonary fibrosis. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. High-dose acetylcysteine in idiopathic pulmonary fibrosis. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
BACKGROUND Several studies have shown the efficacy , tolerability , and ease of administration of pemetrexed-an antifolate antineoplastic agent-in  patients with advanced non-small-cell lung cancer . We assessed pemetrexed as maintenance therapy in patients with this disease . METHODS This r and omised double-blind study was undertaken in 83 centres in 20 countries . 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy  were r and omly assigned ( 2:1 ratio ) to receive pemetrexed ( 500 mg/m(2 ) , day 1 ) plus best supportive care ( n=441 ) or placebo plus best supportive care ( n=222 ) in 21-day cycles until disease progression . Treatment was r and omised with the Simon and Pocock minimisation method . Patients and investigators were masked to treatment . All patients received vitamin B(12 ) , folic acid , and dexamethasone . The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT00102804 . FINDINGS All r and omly assigned participants were analysed . Pemetrexed significantly improved progression-free survival ( 4.3 months [ 95 % CI 4.1 - 4.7 ] vs 2.6 months [ 1.7 - 2.8 ] ; hazard ratio [ HR ] 0.50 , 95 % CI 0.42 - 0.61 , p<0.0001 ) and overall survival ( 13.4 months [ 11.9 - 15.9 ] vs 10.6 months [ 8.7 - 12.0 ] ; HR 0.79 , 0.65 - 0.95 , p=0.012 ) compared with placebo . Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group ( 21 [ 5 % ] vs three [ 1 % ] ) . Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo ( 70 [ 16 % ] vs nine [ 4 % ] ; p<0.0001 ) , specifically fatigue ( 22 [ 5 % ] vs one [ 1 % ] , p=0.001 ) and neutropenia ( 13 [ 3 % ] vs 0 , p=0.006 ) . No  pemetrexed-related deaths occurred . Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy ( 227 [ 51 % ] vs 149 [ 67 % ] ; p=0.0001 ) . INTERPRETATION Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer . FUNDING Eli Lilly BACKGROUND Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists . We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function . METHODS 826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries , the USA , and Canada . Patients were r and omly assigned ( double-blind ) in a 2:1 ratio to receive 200 microg interferon gamma-1b ( n=551 ) or equivalent placebo ( n=275 ) subcutaneously , three times per week . Eligible patients were aged 40 - 79 years , had been diagnosed in the past 48 months , had a forced vital capacity of 55 - 90 % of the predicted value , and a haemoglobin-corrected carbon monoxide diffusing capacity of 35 - 90 % of the predicted value . The primary endpoint was overall survival time from r and omisation measured at the second interim analysis , when the proportion of deaths had reached 75 % of those expected by the study conclusion . This study is registered with Clinical Trials.gov , number NCT00075998 . FINDINGS At the second interim analysis , the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo ( 1.15 , 95 % CI 0.77 - 1.71 , p=0.497 ) , and indicated that the study should be stopped . After a median duration of 64 weeks ( IQR 41 - 84 ) on treatment , 80 ( 15 % ) patients on interferon gamma-1b and 35 ( 13 % ) on placebo had died . Almost all patients reported at least one adverse event , and more patients on interferon gamma-1b group had constitutional signs and symptoms ( influenza-like illness , fatigue , fever , and chills ) than did those on placebo . Occurrence of serious adverse events ( eg , pneumonia , respiratory failure ) was similar for both treatment groups . Treatment adherence was good and few patients discontinued treatment prematurely in either group . INTERPRETATION We can not recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis , which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function . FUNDING InterMune In a r and omised , controlled study alternate day prednisolone with an initial high dose phase ( " prednisolone only series " ) has been compared with cyclophosphamide plus alternate day low dose prednisolone ( " cyclophosphamide-prednisolone series " ) in 43 patients with previously untreated fibrosing alveolitis ( five patients had received prednisolone in minimal dosage ) . In the prednisolone only series prednisolone 60 mg daily was given for one month and then reduced by 5 mg a week to 20 mg on alternate days or the minimum dose to maintain early improvement . Patients in the cyclophosphamide-prednisolone series received 100 , 110 , or 120 mg cyclophosphamide daily ( depending on body weight ) plus 20 mg prednisolone on alternate days . Treatment was continued indefinitely , or changed to the alternative regimen if the patient deteriorated , failed to improve , or developed drug toxicity . For response to treatment ( as judged by change in breathlessness score , radiographic appearance , and lung function ) patients were classified as improved , stable , or deteriorating . Deaths from cryptogenic fibrosing alveolitis were also analysed . Improvement had occurred at one or more assessment s in seven of the 22 patients in the prednisolone only series and in five of the 21 patients in the cyclophosphamide-prednisolone series . At three years , however , only two of the 22 patients in the prednisolone only series were still improved and three stable , compared with one and seven of the 21 patients in the cyclophosphamide-prednisolone series ( three of the seven had stopped treatment because of toxicity ) . Life table analysis suggested better survival in patients in the cyclophosphamide-prednisolone series but this was not significant . At three years 10 of 22 patients in the prednisolone only series had died compared with three of 21 patients in the cyclophosphamide-prednisolone series . With death or failure of first treatment regimen as outcome there was a significant advantage to the patients having cyclophosphamide-prednisolone . This advantage was explained in part by the better lung volumes in this group on admission . After allowance had been made for total lung capacity ( TLC ) , no other factor was predictive of outcome . Analyses of subgroups according to TLC on admission showed that patients with a TLC below 60 % predicted did badly and those with a TLC of 80 % or more predicted did well with both regimens . Patients with an initial TLC of 60 - 79 % predicted did better with the cyclophosphamide-prednisolone regimen . Side effects were uncommon in both series and those due to cyclophosphamide resolved when treatment was stopped . The combination of cyclophosphamide with prednisolone may be an alternative to prednisolone alone with an initial high dose phase . Many patients , however , failed to respond to either treatment 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 BACKGROUND Idiopathic pulmonary fibrosis is a progressive , fatal disease with no known efficacious therapy . METHODS In a double-blind , multinational trial , we r and omly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo . RESULTS Over a median of 58 weeks , interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival , defined as the time to disease progression or death , and no significant treatment effect was observed on measures of lung function , gas exchange , or the quality of life . Ten percent of patients in the interferon gamma-1b group died , as compared with 17 percent of patients in the placebo group ( P=0.08 ) . Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms . However , the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups . More pneumonias were reported among patients in the interferon gamma-1b group , but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups . CONCLUSIONS In a well-defined population of patients with idiopathic pulmonary fibrosis , interferon gamma-1b did not affect progression-free survival , pulmonary function , or the quality of life . Owing to the size and duration of the trial , a clinical ly significant survival benefit could not be ruled out 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 Twenty-six symptomatic subjects with clinical evidence plus either high-resolution computed tomography ( H RCT , n = 25 ) or open-lung biopsy ( OLB , n = 1 ) patterns typical for idiopathic usual interstitial pneumonia ( idiopathic UIP ) were entered into a r and omized prospect i ve treatment trial using high-dose prednisone ( n = 12 ) versus colchicine ( n = 14 ) . The minimum dose of prednisone used was 60 mg/d for 1 mo , tapered to 40 mg/d over the second month , tapered to 40 mg every other day during the third month , with subsequent doses adjusted as clinical ly indicated . The dose of colchicine was 0.6 - 1.2 mg/d , as tolerated . The presence of a rim of subpleural honeycomb change was present in all of the 25 subjects who had H RCT . Subjects treated with high-dose prednisone alone experienced a higher incidence of serious side effects and also exhibited a trend ( not statistically significant , p = 0.391 ) to more rapid decline of pulmonary function and shortened survival than did those treated with colchicine alone . In most subjects with typical clinical and H RCT features of idiopathic UIP , neither prednisone nor colchicine result ed in objective improvement , and the disease continued to progress in the majority . Colchicine appears to be a safer alternative to a trial of high-dose prednisone but may be no different than no therapy RATIONALE An efficacious medical therapy for idiopathic pulmonary fibrosis ( IPF ) remains elusive . OBJECTIVES To explore the efficacy and safety of etanercept in the treatment of IPF . METHODS This was a r and omized , prospect i ve , double-blind , placebo-controlled , multicenter exploratory trial in subjects with clinical ly progressive IPF . Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin ( Dl(CO(Hb ) ) ) and change in the alveolar to arterial oxygen pressure difference P(a-a)(O(2 ) ) at rest from baseline over 48 weeks . MEASUREMENTS AND MAIN RESULTS Eighty-eight subjects received subcutaneous etanercept ( 25 mg ) or placebo twice weekly as their sole treatment for IPF . No differences in baseline demographics and disease status were detected between treatment groups ; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9 % of predicted . At 48 weeks , no significant differences in efficacy endpoints were observed between the groups . A nonsignificant reduction in disease progression was seen in several physiologic , functional , and quality -of-life endpoints among subjects receiving etanercept . There was no difference in adverse events between treatment groups . CONCLUSIONS In this exploratory study in patients with clinical ly progressive IPF , etanercept was well tolerated . Although there were no differences in the predefined endpoints , a decreased rate of disease progression was observed on several measures . Further evaluation of TNF antagonists in the treatment of IPF may be warranted . Clinical trial registered with www . clinical trials.gov ( NCT 00063869 ) STUDY OBJECTIVE To evaluate the effect of anticoagulant therapy on the survival of patients with idiopathic pulmonary fibrosis ( IPF ) . DESIGN Prospect i ve study . SETTING Five hospitals located in the Miyagi prefecture in Japan , including a university hospital , a Red Cross hospital , two public general hospitals , and a municipal hospital . PATIENTS Fifty-six patients with IPF ( mean age , 69.4 years ; range , 47 to 89 ) admitted to the hospitals from April 2001 to April 2004 . INTERVENTIONS Patients were assigned to receive prednisolone alone or prednisolone plus anticoagulant therapy . The anticoagulants included oral warfarin in an outpatient setting and low-molecular-weight heparin for rehospitalized patients with severely progressive respiratory failure . MEASUREMENTS AND RESULTS There was no difference in baseline characteristics , including age , gender , clinical condition , pulmonary function , and plasma d-dimer level between the non-anticoagulant group and the anticoagulant group . The overall survival and hospitalization-free periods were assessed . There was a significant difference between survival curves of the non-anticoagulant group and the anticoagulant group , with a 2.9 hazard ratio ( p = 0.04 , Cox regression model ) . There was no significant difference in the probability of a hospitalization-free period between groups . The major cause of clinical deterioration was acute exacerbation during follow-up in the present study . Therefore , the mortality and plasma d-dimer levels in patients with an acute exacerbation were also assessed . The mortality associated with acute exacerbations of IPF in the anticoagulant group was significantly reduced compared to that in the non-anticoagulant group ( 18 % vs 71 % , respectively ; p = 0.008 , Fisher Exact Test ) . Furthermore , the plasma d-dimer levels in patients who died were significantly higher than those in survivors during acute exacerbation of IPF ( 3.3 + /- 2.3 microg/mL vs 0.9 + /- 0.7 microg/mL , p < 0.0001 ) . Histologic analysis performed in three patients who died due to an exacerbation of IPF in the non-anticoagulant group demonstrated the features of usual interstitial pneumonia and acute lung injury . CONCLUSIONS Our data suggested that plasma d-dimer levels are associated with mortality in patients with an acute exacerbation of IPF , and that anticoagulant therapy has a beneficial effect on survival in patients with IPF Twenty-seven newly diagnosed patients with idiopathic pulmonary fibrosis ( IPF ) who were previously untreated for IPF were enrolled in a prospect i ve , double-blind , r and omized , placebo-controlled study to compare the therapeutic effect of combined prednisone/azathioprine  ( n = 14 ) with prednisone plus placebo  ( n = 13 ) . Prednisone was started at 1.5 mg/kg/day ( not to exceed 100 mg/day ) for the first 2 wk followed by a biweekly taper to a maintenance dose of 20 mg/day . Azathioprine was administered at a daily dose of 3 mg/kg ( not to exceed 200 mg/day ) . The patients tolerated the use of azathioprine well with few associated side effects . Changes in lung function at 1 yr , as measured by resting alveolar-arterial oxygen difference P[A-a]O2 , FVC , and single breath diffusing capacity for carbon monoxide ( DLCOSB ) , were all somewhat better in the azathioprine/prednisone group compared with the prednisone alone group , although none of these comparisons were statistically significant . Six of 14 ( 43 % ) patients r and omized to prednisone plus azathioprine  died during the 9-yr follow-up period , compared with 10 of 13 ( 77 % ) patients r and omized to prednisone plus placebo . A Cox model survival analysis shows a nonsignificant but potentially large survival advantage for azathioprine/prednisone ( hazard ratio 0.48 , with 95 % confidence interval increasing from 0.17 to 1.38 ) . When adjusted for age , the survival advantage of azathioprine/prednisone becomes marginally significant ( hazard ratio 0.26 , with 95 % confidence interval increasing from 0.08 to 0.88 ; p = 0.02 by large sample approximation , p = 0.05 by r and omization test ) . We conclude that combined prednisone and azathioprine is a safe and possibly effective regimen for the treatment of IPF . ( ABSTRACT TRUNCATED AT 250 WORDS RATIONALE Idiopathic pulmonary fibrosis ( IPF ) is a progressive , fatal lung disease lacking effective treatment . OBJECTIVES To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF . METHODS In a double-blind , multicenter trial , patients with IPF were r and omized to receive oral bosentan 62.5 mg twice daily for 4 weeks , increased to 125 mg twice daily thereafter , or placebo , for 12 months or longer . The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity , as measured by a modified six-minute-walk test . Secondary endpoints were time to death or disease progression ( worsening pulmonary function tests [ PFTs ] or acute decompensation ) , change in PFT scores , and quality of life ( QOL ) assessed using Short-Form 36 and St. George 's Respiratory Question naire . MEASUREMENTS AND MAIN RESULTS A total of 158 patients r and omly received  bosentan ( n = 74 ) or placebo ( n = 84 ) . Bosentan showed no superiority over placebo in six-minute-walk distance ( 6MWD ) up to Month 12 , the primary efficacy endpoint . A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression ( hazard ratio [ HR ] , 0.613 ; 95 % confidence interval [ CI ] , 0.328 - 1.144 ; P = 0.119 ) , which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy ( post hoc analysis ; HR , 0.315 ; 95 % CI , 0.126 - 0.789 ; P = 0.009 ) . Changes from baseline up to Month 12 in assessment s of dyspnea and QOL favored treatment with bosentan . No unexpected adverse events were reported . CONCLUSIONS Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD . A trend in delayed time to death or disease progression , and improvement in QOL , was observed with bosentan . The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation . Clinical trial registered with www . clinical trials.gov ( NCT 00071461 ) BACKGROUND Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis . METHODS We conducted a double-blind , r and omized , placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine ( 600 mg three times daily ) added to st and ard therapy with prednisone plus azathioprine . The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity ( DL(CO ) ) . RESULTS A total of 182 patients were r and omly assigned to treatment ( 92 to acetylcysteine and 90 to placebo ) . Of these patients , 155 ( 80 assigned to acetylcysteine and 75 to placebo ) had usual interstitial pneumonia , as confirmed by high-resolution computed tomography and histologic findings review ed by expert committees , and did not withdraw consent before the start of treatment . Fifty-seven of the 80 patients taking acetylcysteine ( 71 percent ) and 51 of the 75 patients taking placebo ( 68 percent ) completed one year of treatment . Acetylcysteine slowed the deterioration of vital capacity and DL(CO ) : at 12 months , the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter ( 95 percent confidence interval , 0.03 to 0.32 ) , or a relative difference of 9 percent , for vital capacity ( P=0.02 ) , and 0.75 mmol per minute per kilopascal ( 95 percent confidence interval , 0.27 to 1.23 ) , or 24 percent , for DL(CO ) ( P=0.003 ) . Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo ( P=0.69 ) . There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo , except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine ( P=0.03 ) . CONCLUSIONS Therapy with acetylcysteine at a dose of 600 mg three times daily , added to prednisone and azathioprine , preserves vital capacity and DL(CO ) in patients with idiopathic pulmonary fibrosis better than does st and ard therapy alone RATIONALE Idiopathic pulmonary fibrosis ( IPF ) is a progressive lung disease with no known efficacious therapy . Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease . OBJECTIVES To investigate the safety and clinical effects of imatinib in patients with IPF . METHODS We studied 119 patients in an investigator-initiated , multicenter , multinational , double-blind clinical trial to receive imatinib or placebo for 96 weeks . MEASUREMENTS AND MAIN RESULTS Over 96 weeks of follow-up , imatinib did not differ significantly from placebo ( log rank P = 0.89 ) for the primary endpoint defined as time to disease progression ( 10 % decline in percent predicted FVC from baseline ) or time to death . There was no effect of imatinib therapy on change in FVC at 48 , 72 , or 96 weeks ( P > or = 0.39 at all time points ) or change in diffusing capacity of carbon monoxide at 48 , 72 , or 96 weeks ( P > or = 0.26 at all time points ) . Change in resting Pa(O(2 ) ) favored imatinib therapy at 48 weeks ( P = 0.005 ) but not at 96 weeks ( P = 0.074 ) . During the 96-week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group ( log rank test P = 0.64 ) . Thirty-five ( 29 % ) patients discontinued the study without reaching the primary endpoint ( imatinib , 32 % ; placebo , 27 % ; P = 0.51 ) . Serious adverse events ( SAEs ) were not more common in the imatinib group ( imatinib , 18 SAEs in 17 patients ; placebo , 19 SAEs in 18 patients ) . CONCLUSIONS In a r and omized , placebo-controlled trial of patients with mild to moderate IPF followed for 96 weeks , imatinib did not affect survival or lung function . Clinical trial registered with www . clinical trials.gov ( NCT00131274 ) BACKGROUND AND METHODS Patients with idiopathic pulmonary fibrosis have progressive scarring of the lung and usually die within four to five years after symptoms develop . Treatment with oral glucocorticoids is often ineffective . We conducted an open , r and omized trial of treatment with a combination of interferon gamma-1b , which has antifibrotic properties , and an oral glucocorticoid . We studied 18 patients with idiopathic pulmonary fibrosis who had not had responses to glucocorticoids or other immunosuppressive agents . Nine patients were treated for 12 months with oral prednisolone alone ( 7.5 mg daily , which could be increased to 25 to 50 mg daily ) , and nine with a combination of 200 microg of interferon gamma-1b ( given three times per week subcutaneously ) and 7.5 mg of prednisolone ( given once a day ) . RESULTS All the patients completed the study . Lung function deteriorated in all nine patients in the group given prednisolone alone : total lung capacity decreased from a mean ( + /-SD ) of 66+/-8 percent of the predicted value at base line to 62+/-6 percent at 12 months . In contrast , in the group receiving interferon gamma-1b plus prednisolone , total lung capacity increased ( from 70+/-6 percent of the predicted value at base line to 79+/-12 percent at 12 months , P<0.001 for the difference between the groups ) . In the group that received interferon gamma-1b plus prednisolone , the partial pressure of arterial oxygen at rest increased from 65+/-9 mm Hg at base line to 76+/-8 mm Hg at 12 months , whereas in the group that received prednisolone alone it decreased from 65+/-6 to 62+/-4 mm Hg ( P<0.001 for the difference in the change from baseline values between the two groups ) ; on maximal exertion , the value increased from 55+/-6 to 65+/-8 mm Hg in the group that received combined treatment and decreased from 55+/-6 mm Hg to 52+/-5 mm Hg in the group given prednisolone alone ( P<0.001 ) . The side effects of interferon gamma-1b , such as fever , chills , and muscle pain , subsided within the first 9 to 12 weeks . CONCLUSIONS In a preliminary study , 12 months of treatment with interferon gamma-1b plus prednisolone was associated with substantial improvements in the condition of patients with idiopathic pulmonary fibrosis who had had no response to glucocorticoids PURPOSE Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer ( NSCLC ) . This r and omized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine ( CG ) plus bevacizumab in this setting . PATIENTS AND METHODS Patients were r and omly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2 ) for up to six cycles plus low-dose bevacizumab ( 7.5 mg/kg ) , high-dose bevacizumab ( 15 mg/kg ) , or placebo every 3 weeks until disease progression . The trial was not powered to compare the two doses directly . The primary end point was amended from overall survival ( OS ) to progression-free survival ( PFS ) .  Between February 2005 and August 2006 , 1,043 patients were r and omly assigned ( placebo , n = 347 ; low dose , n = 345 ; high dose , n = 351 ) . RESULTS PFS was significantly prolonged ; the hazard ratios for PFS were 0.75 ( median PFS , 6.7 v 6.1 months for placebo ; P = .003 ) in the low-dose group and 0.82 ( median PFS , 6.5 v 6.1 months for placebo ; P = .03 ) in the high-dose group compared with placebo . Objective response rates were 20.1 % , 34.1 % , and 30.4 % for placebo , low-dose bevacizumab , and high-dose bevacizumab plus CG , respectively . Duration of follow-up was not sufficient for OS analysis . Incidence of grade 3 or greater adverse events was similar across arms . Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5 % for all arms despite 9 % of patients receiving therapeutic anticoagulation . CONCLUSION Combining bevacizumab ( 7.5 or 15 mg/kg ) with CG significantly improved PFS and objective response rate .  Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC
The magnitude of treatment effect can be assessed by a number of methods .
One method of collectively analysing data is that used by the Cochrane Collaboration .
Their systematic review s identify , analyse and present research -based evidence in an accessible format .
These review s may contain meta-analyses combining data from multiple studies to provide robust evaluations of overall treatment effects .