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In this randomized, controlled trial, the use of pirfenidone in patients with idiopathic pulmonary fibrosis led to a slower rate of loss in forced vital capacity than the use of placebo. Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal lung disease that is characterized by irreversible loss of lung function. 1 Although periods of transient clinical stability may be observed, continued progression of the disease is inevitable. 2 The prognosis is poor, with a 5-year survival rate that is similar to the rates for several cancers. 3 – 6 Pirfenidone is an oral antifibrotic therapy that has been evaluated for the treatment of idiopathic pulmonary fibrosis in three phase 3, randomized, controlled trials. One of these trials was conducted in Japan and involved 275 patients. It was followed by two multinational studies, Clinical Studies . . .

In a trial, patients with moderate to severely advanced idiopathic pulmonary fibrosis were treated with nintedanib plus sildenafil or nintedanib alone, with the goal of decreasing IPF symptoms. There were no between-group differences in any of three symptom measures.

Abstract Rationale Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. Objectives To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Methods Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. Measurements and Main Results On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were −13.3 (17.4) ml and −40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. Conclusions Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603).

Abstract Rationale Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and N-Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown. Objectives To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF. Methods LTL was measured from available DNA samples from PANTHER-IPF (interim analysis, n = 79; final analysis, n = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) (n = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF, n = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. Measurements and Main Results Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/N-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02–7.87; P = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52–33.84; P = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73–8.30; P = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials (P  interaction = 0.048), and the University of Texas Southwestern Medical Center IPF cohort (P  interaction = 0.00049). Conclusions LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.

Acetylcysteine, which has been advocated as a treatment for patients with idiopathic pulmonary fibrosis, showed no benefit over placebo with respect to loss of lung function in such patients at 60 weeks. Idiopathic pulmonary fibrosis is a chronic, progressive lung disease of unknown cause that is characterized by the histopathological or radiologic patterns of usual interstitial pneumonia in a typical clinical setting. 1 , 2 To date, no pharmacologic therapies have been shown to improve survival. 1 In the IFIGENIA study (Idiopathic Pulmonary Fibrosis International Group Exploring N -Acetylcysteine I Annual), investigators found that a three-drug regimen (prednisone, azathioprine, and acetylcysteine) preserved pulmonary function better than a two-drug regimen consisting of azathioprine plus prednisone. 3 In PANTHER-IPF (Prednisone, Azathioprine, and N -Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis), patients with mild-to-moderate impairment in . . .

Many treatments used for idiopathic pulmonary fibrosis (IPF) have not been rigorously tested. This article reports discontinuation of treatment with prednisone, azathioprine, and N -acetylcysteine (NAC) because of increased mortality, as compared with N -acetylcysteine alone or placebo. Idiopathic pulmonary fibrosis is a chronic, progressive lung disease of unknown cause characterized by the histopathological pattern of usual interstitial pneumonia. 1 The median survival of patients with idiopathic pulmonary fibrosis after diagnosis is 2 to 5 years. 1 The use of glucocorticoids or immunosuppressive agents has been the conventional approach to the treatment of patients with this disease. A consensus-based guideline suggested that a two-drug regimen (a combination of prednisone and either azathioprine or cyclophosphamide) be used in a subgroup of patients with idiopathic pulmonary fibrosis. 2 A survey of pulmonologists showed that almost 50% used a regimen of either two drugs . . .

Abstract Rationale Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis. Objectives In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC. Methods This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy. Measurements and Main Results The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks. Conclusions This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation. Clinical trial registered with www.clinicaltrials.gov (NCT00957242).

Abstract Rationale A previous trial of bosentan in idiopathic pulmonary fibrosis (IPF) showed a trend to delayed IPF worsening or death. Also, improvements in some measures of dyspnea and health-related quality of life were observed. Objectives To demonstrate that bosentan delays IPF worsening or death. Methods Prospective, randomized (2:1), double-blind, placebo-controlled, event-driven, parallel-group, morbidity–mortality trial of bosentan in adults with IPF of less than 3 years’ duration, confirmed by surgical lung biopsy, and without extensive honeycombing on high-resolution computed tomography. The primary endpoint was time to IPF worsening (a confirmed decrease from baseline in FVC ≥ 10% and diffusing capacity of the lung for carbon monoxide ≥ 15%, or acute exacerbation of IPF) or death up to End of Study. Effects of bosentan on health-related quality of life, dyspnea, and the safety and tolerability of bosentan were investigated. Measurements and Main Results Six hundred sixteen patients were randomized to bosentan (n = 407) or placebo (n = 209). No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% confidence interval, 0.66–1.10; P = 0.2110). No treatment effects were observed on health-related quality of life or dyspnea. Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide. The safety profile for bosentan was similar to that observed in other trials. Conclusions The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met. Bosentan was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00391443).

IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF. Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively. Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).

Abstract Rationale Respiratory-related hospitalizations of patients with idiopathic pulmonary fibrosis (IPF) are more frequent than those for acute IPF exacerbations and are associated with poor outcomes. Objectives To compare the risk of nonelective hospitalization by type (all-cause, respiratory related, and non–respiratory related) and death after hospitalization with use of pirfenidone versus placebo over 52 weeks using data derived from three phase III IPF clinical trials. Methods Individual patient data was pooled from three phase III randomized, placebo-controlled studies of pirfenidone for IPF (the two CAPACITY [Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes] trials and the ASCEND [Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis] trial), including all patients randomized to pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624). The risk of hospitalization over 52 weeks was compared using standard time-to-event methods. Among those hospitalized, the risk of death after hospitalization was compared with adjustment for treatment group propensity. Measurements and Main Results A total of 1,247 patients (692 from the CAPACITY trials and 555 from the ASCEND trial) were included in the pooled analysis. Pirfenidone was associated with lower risk of respiratory-related hospitalization than placebo (7% vs. 12%; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.36–0.77; P = 0.001), but all-cause (HR, 0.91; 95% CI, 0.70–1.19; P = 0.528) or non–respiratory-related hospitalization (HR, 1.32; 95% CI, 0.92–1.88; P = 0.145) was not. Among those hospitalized for any reason, treatment with pirfenidone was associated with lower risk of death after hospitalization up to 52 weeks after randomization, but this association was no longer significant with longer follow-up. Conclusions In a pooled analysis of three phase III IPF clinical trials, patients receiving pirfenidone had a lower risk of nonelective respiratory-related hospitalization over the course of 1 year. The effect of pirfenidone on death after hospitalization is uncertain.