Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Kevin R. Flaherty is active.

Publication


Featured researches published by Kevin R. Flaherty.


The New England Journal of Medicine | 2014

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

Luca Richeldi; Roland M. du Bois; Ganesh Raghu; Arata Azuma; Kevin K. Brown; Ulrich Costabel; Vincent Cottin; Kevin R. Flaherty; David M. Hansell; Yoshikazu Inoue; Dong Soon Kim; Martin Kolb; Andrew G. Nicholson; Paul W. Noble; Moisés Selman; Hiroyuki Taniguchi; Michèle Brun; Florence Le Maulf; Mannaïg Girard; Susanne Stowasser; Rozsa Schlenker-Herceg; Bernd Disse; Harold R. Collard

BACKGROUND Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. Georges Respiratory Questionnaire, both assessed over a 52-week period. RESULTS A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).


The New England Journal of Medicine | 2011

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

Luca Richeldi; Ulrich Costabel; Moisés Selman; Dong Soon Kim; David M. Hansell; Andrew G. Nicholson; Kevin K. Brown; Kevin R. Flaherty; Paul W. Noble; Ganesh Raghu; Michèle Brun; Abhya Gupta; Nolwenn Juhel; Matthias Klüglich; Roland M. du Bois

BACKGROUND Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. METHODS In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. Georges Respiratory Questionnaire [SGRQ]), and total lung capacity. RESULTS A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).


Annals of Internal Medicine | 2005

The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis

Fernando J. Martinez; Sharon Safrin; Derek Weycker; Karen M. Starko; Williamson Ziegler Bradford; Talmadge E. King; Kevin R. Flaherty; David A. Schwartz; Paul W. Noble; Ganesh Raghu; Kevin K. Brown

Context The natural history of idiopathic pulmonary fibrosis (IPF) is unclear. Contribution A total of 168 participants with mild to moderate IPF assigned to placebo in a randomized trial were followed at 12-week intervals for about 76 weeks. For 32 of 36 patients who died, IPF was a related or main cause of death. Although physiologic variables such as FVC changed little, acute clinical deterioration preceded death in half of the patients who died of IPF. Implications Clinicians may need to rethink referral timing for lung transplantation because many patients with IPF may experience precipitous clinical declines rather than gradual progression of disease. The Editors Idiopathic pulmonary fibrosis (IPF), the most frequent of the idiopathic interstitial pneumonias, is associated with the worst prognosis (1, 2). However, data on the natural history of IPF are sparse. To clearly describe the pace of progression and the cause of death in a well-characterized cohort with mild to moderate IPF, we analyzed data from the placebo group of a randomized, double-blind, controlled clinical trial evaluating therapy with interferon-1b in patients with IPF (3). These data provide important insight into the natural history of IPF and events preceding death in patients with IPF. The data suggest that a gradual, progressive decline does not occur in many patients, thereby supporting the need for early referral for lung transplantation. Methods Overview Using data from a recently completed clinical trial (3), we performed a series of exploratory analyses of physiologic variables, dyspnea measures, hospitalizations, and characteristics of mortality in patients randomly assigned to receive placebo. The prespecified primary end point analysis for the phase III study was to occur after the 306th randomly assigned patient was scheduled to complete 48 weeks of therapy. Patients were enrolled over an approximately 1-year period. Thus, follow-up times for the patients varied, and the numbers of patients available for visits beyond 48 weeks diminished over time. In the published report of the primary analysis of the trial, the median length of observation was 58 weeks (3). In the current report, we summarize data from randomization through the completion of blinded study therapy (the observation period); the median for this period was 76 weeks. Study Participants Study participants were all patients randomly assigned to the placebo group (n= 168) in the trial (3). Criteria for enrollment included a diagnosis of IPF according to American Thoracic Society criteria (4), an FVC of 50% to 90%, diffusing capacity of carbon monoxide (DLco) of 25% or greater, definite or probable IPF on high-resolution computed tomography according to prespecified criteria, and worsening of disease during the preceding year despite a total corticosteroid dose of 1800 mg or greater within the preceding 2 years (3). Patients were permitted to continue taking prednisone (15 mg/d) if the dosage remained stable. Data Collection Data were collected at 12-week intervals and recorded on standardized case report forms by trained research associates at each institution. Information derived from interview and examination of the patient included demographic and clinical data, physiologic assessments, measures of dyspnea, vital status, number of all-cause hospitalizations, and number of hospitalizations for which the primary reason was specified as respiratory. Physiologic measures included FVC, plethysmography, Dlco, and arterial blood gas at room-air ambient temperatures. The transition dyspnea score is derived from an instrument in which the patient assesses the extent of dyspnea in reference to his or her baseline at study entry (5). The transitions or changes in the patients dyspnea in 3 categories (function impairment, magnitude of task needed to evoke dyspnea, and magnitude of effort needed to evoke dyspnea) are rated in 7 grades from 3 (major deterioration) to 0 (unchanged) to 3 (major improvement); the final score ranged from 9 to 9. The lower the total score, the more severe the dyspnea. The validated University of California, San Diego, Shortness of Breath Questionnaire (6) has 24 items: Patients are asked to rate severity of shortness of breath using a 6-point scale (0 = not at all; 5 = maximal severity) during 21 different activities of daily living associated with varying levels of exertion; they are also asked to rate how their daily lives are limited by shortness of breath, fear of harm from overexertion, and fear of shortness of breath. Scores range from 0 to 120, with increasing score indicating worsening quality of life. The physician responsible for any patient who died during the study period completed a retrospective supplemental questionnaire. The investigator-physician, who had full access to all measurements obtained as a part of the study, specified the primary cause of death, whether the cause was respiratory, and whether death was related to IPF. Investigator-physicians were to cite IPF as the primary cause of death only in the absence of a known alternative cause and only if the event was witnessed. For deaths considered to be IPF-related, 1 of 4 categories was assigned on the basis of the interval from the onset of new or worsening symptoms or signs until death: abrupt (occurring within minutes to hours), acute (4 weeks), subacute (progressing over weeks or months), or unknown. In the current report, we combine the abrupt- and acute-onset events within a single category. Statistical Analysis Physiologic variables and measures of dyspnea were compared between baseline and week 72. The frequency of hospitalizations (all-cause and respiratory-related), number of hospital days in patients hospitalized, and mortality were assessed over the entire observation period. Mean values are followed by SDs. The relationships between baseline percentage predicted FVC and the incidence and length of hospitalization were examined by using the Fisher exact test or independent-sample t-test, as appropriate. Missing values were not imputed. The reasons for missing values are as follows: 1) To optimize data integrity, data obtained at visits outside a window of 7 days were not included in the analysis, 2) because trial enrollment was staggered, fewer patients were available for analysis at the latter time points, and 3) the value for a particular variable for a particular patient may be missing, even though all other values for that time point and patient are available. On the basis of the nature of the variations leading to the differences in available data over time, no apparent evidence indicated that the variations are not random. Data analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source InterMune, Inc., funded this study. Authors from InterMune (Drs. Safrin, Starko, and Bradford) participated in the design and analysis of the study, as did the other authors. All authors had full access to the data. The funding source had no role in the decision to publish the results. Results Patients We analyzed 168 patients (mean age, 64 years, SD 9). Most patients were male (66%), white (86%), and nonsmokers (that is, never-smokers or ex-smokers) (91%). Mean time since the diagnosis of IPF was 378 days, SD, 295. The diagnosis of IPF was confirmed by surgical lung biopsy in 58% of patients; in 83%, findings on high-resolution computed tomography met prespecified criteria for definite IPF. At study entry, 31% of patients used supplemental oxygen and 82% were receiving systemic corticosteroids. During the observation period, 2 patients (1.2%) used azathioprine and 1 patient (0.6%) used cyclophosphamide. Physiologic Variables and Measures of Dyspnea For patients who survived to week 72, the mean percentage predicted FVC decreased from 64.5%, SD 11.1%, to 61.0%, SD 14.1%; the mean percentage predicted DLco decreased from 37.8%, SD 11.1%, to 37.0%, SD 19.9%; and the mean alveolararterial gradient increased from 23.2 mm Hg, SD 10.9, to 26.9 mm Hg, SD 13.0. The mean transition dyspnea index score was 1.29, SD 3.6, at week 72, indicating worsening dyspnea, whereas the mean University of California, San Diego, Shortness of Breath Questionnaire score changed minimally (from 45.1, SD 23.4, to 46.8, SD 25.1) (Figure 1). For patients who died during the trial, we observed a general trend toward increases in alveolararterial gradient and dyspnea and toward decreases in FVC and DLco (Figure 2). The spaghetti plots (Figure 2) highlight the finding that although dyspnea or alveolararterial gradient often increased sharply before a patients death, significant intrapatient variability occurs over time. Figure 1. Measures of physiology and dyspnea from study entry through week 72 for patients who survived throughout trial. Figure 2. Measures of physiology and dyspnea for each of the 36 patients who died during the trial; each line represents a single patient. Hospitalizations Fifty-seven (34%) patients had a total of 95 all-cause hospitalizations during the observation period. Among those hospitalized, the mean total number of hospital days was 14.3, SD 13.5. Thirty-eight (23%) patients had 57 hospitalizations for a respiratory disorder, with a mean total number of hospital days of 15.0, SD 14.6. The most commonly reported reason for respiratory hospitalization (33%) was presumed infection. When stratified by the baseline median percentage predicted FVC, patients with more severely impaired lung function (62%) were more likely to be hospitalized for any reason than patients with baseline percentage predicted FVC greater than 62%35 (42%) versus 22 (26%) patients (P= 0.05) and 58 versus 37 hospitalizations overall. Respiratory hospitalizations were similarly more frequent in the subset of patients with baseline FVC of 62% or less: 25 (30%) versus 13 (15%) patients (P= 0.04). In hospitalized patients, the total number


Thorax | 2003

Radiological versus histological diagnosis in UIP and NSIP: survival implications

Kevin R. Flaherty; E. L. Thwaite; Ella A. Kazerooni; Barry H. Gross; Galen B. Toews; Thomas V. Colby; William D. Travis; Jeanette A. Mumford; Susan Murray; Andrew Flint; Joseph P. Lynch; Fernando J. Martinez

Background: High resolution computed tomography (HRCT) has an important diagnostic role in idiopathic interstitial pneumonia (IIP). We hypothesised that the HRCT appearance would have an impact on survival in patients with IIP. Methods: HRCT scans from patients with histological usual interstitial pneumonia (UIP; n=73) or histological non-specific interstitial pneumonia (NSIP; n=23) were characterised as definite UIP, probable UIP, indeterminate, probable NSIP, or definite NSIP. Cox regression analysis examined the relationships between histopathological and radiological diagnoses and mortality, controlling for patient age, sex, and smoking status. Results: All 27 patients with definite or probable UIP on HRCT had histological UIP; 18 of 44 patients with probable or definite NSIP on HRCT had histological NSIP. Patients with HRCT diagnosed definite or probable UIP had a shorter survival than those with indeterminate CT (hazards ratio (HR) 2.43, 95% CI 1.06 to 5.58; median survival 2.08 v 5.76 years) or HRCT diagnosed definite or probable NSIP (HR 3.47, 95% CI 1.58 to 7.63; median survival 2.08 v 5.81 years). Patients with histological UIP with no HRCT diagnosis of probable or definite UIP fared better than patients with histological UIP and an HRCT diagnosis of definite or probable UIP (HR 0.49, 95% CI 0.25 to 0.98; median survival 5.76 v 2.08 years) and worse than those with a histological diagnosis of NSIP (HR 5.42, 95% CI 1.25 to 23.5; median survival 5.76 v >9 years). Conclusions: Patients with a typical HRCT appearance of UIP experience the highest mortality. A surgical lung biopsy is indicated for patients without an HRCT appearance of UIP to differentiate between histological UIP and NSIP.


The New England Journal of Medicine | 2010

A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.

David A. Zisman; Marvin I. Schwarz; Kevin J. Anstrom; Harold R. Collard; Kevin R. Flaherty; Gary W. Hunninghake

BACKGROUND Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value. METHODS We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil. RESULTS A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P=0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups. CONCLUSIONS This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00517933.)


European Respiratory Journal | 2002

Clinical significance of histological classification of idiopathic interstitial pneumonia

Kevin R. Flaherty; Galen B. Toews; W. D. Travis; T. V. Colby; Ella A. Kazerooni; Barry H. Gross; A. Jain; Iii L. Strawderman; R. Paine; A. Flint; Iii P. Lynch; Fernando J. Martinez

Patients with idiopathic interstitial pneumonias (IIPs) can be subdivided into groups based on the histological appearance of lung tissue obtained by surgical biopsy. The quantitative impact of histological diagnosis, baseline factors and response to therapy on survival has not been evaluated. Surgical lung biopsy specimens from 168 patients with suspected IIP were reviewed according to the latest diagnostic criteria. The impact of baseline clinical, physiological, radiographic and histological features on survival was evaluated using Cox regression analysis. The predictive value of honeycombing on high-resolution computed tomography (HRCT) as a surrogate marker for usual interstitial pneumonia (UIP) was examined. The response to therapy and survival of 39 patients treated prospectively with high-dose prednisone was evaluated. The presence of UIP was the most important factor influencing mortality. The risk ratio of mortality when UIP was present was 28.46 (95% confidence interval (CI) 5.5–148.0; p=0.0001) after controlling for patient age, duration of symptoms, radiographic appearance, pulmonary physiology, smoking history and sex. Honeycombing on HRCT indicated the presence of UIP with a sensitivity of 90% and specificity of 86%. Patients with nonspecific interstitial pneumonia were more likely to respond or remain stable (9 of 10) compared to patients with UIP (14 of 29) after treatment with prednisone. Patients remaining stable had the best prognosis. The risk ratio of mortality for stable patients compared to nonresponders was 0.32 (95% CI 0.11–0.93; p=0.04) in all patients and 0.33 (95% CI 0.12–0.96; p=0.04) in patients with UIP. The histological diagnosis of usual interstitial pneumonia is the most important factor determining survival in patients with suspected idiopathic interstitial pneumonia. The presence of honeycombing on high-resolution computed tomography is a good surrogate for usual interstitial pneumonia and could be utilized in patients unable to undergo surgical lung biopsy. Patients with nonspecific interstitial pneumonia are more likely to respond or remain stable following a course of prednisone. Patients remaining stable following prednisone therapy have the best prognosis.


American Journal of Respiratory and Critical Care Medicine | 2012

A Placebo-Controlled Randomized Trial of Warfarin in Idiopathic Pulmonary Fibrosis

Imre Noth; Kevin J. Anstrom; Sara Bristol Calvert; Joao A. de Andrade; Kevin R. Flaherty; Craig S. Glazer; Robert J. Kaner; Mitchell A. Olman

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.


Annals of Internal Medicine | 2013

Treatment of idiopathic pulmonary fibrosis with Ambrisentan: A parallel, randomized trial

Ganesh Raghu; Juergen Behr; Kevin K. Brown; Jim J. Egan; Steven M. Kawut; Kevin R. Flaherty; Fernando J. Martinez; Steven D. Nathan; Athol U. Wells; Harold R. Collard; Ulrich Costabel; Luca Richeldi; Joao A. de Andrade; Nasreen Khalil; Lake Morrison; David J. Lederer; Lixin Shao; Xiaoming Li; Patty S. Pedersen; A. Bruce Montgomery; Jason W. Chien; Thomas G. O'Riordan

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.


American Journal of Respiratory and Critical Care Medicine | 2009

Serum CC-Chemokine Ligand 18 Concentration Predicts Outcome in Idiopathic Pulmonary Fibrosis

Antje Prasse; Corinna Probst; Elena Bargagli; Gernot Zissel; Galen B. Toews; Kevin R. Flaherty; Manfred Olschewski; Paola Rottoli; Joachim Müller-Quernheim

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. There is great effort to find predictors of outcome. Conclusive data for any serum biomarker are lacking. We have recently documented that serum CCL18 concentrations correlate with the course of pulmonary function data in patients with pulmonary fibrosis of various causes. OBJECTIVES To test the value of serum CCL18 concentrations in IPF, we included 72 patients in a prospective study. METHODS IPF was defined according to the ATS/ERS criteria. Serum CCL18 concentrations were measured by a commercially available ELISA. Patients were followed for 24 months. Pulmonary function tests were performed at least every 6 months. MEASUREMENTS AND MAIN RESULTS Baseline serum CCL18 concentrations predicted the change in TLC and FVC at the 6-month follow-up. Receiver operating characteristics (ROC) revealed a significant relation between survival and baseline CCL18 concentrations. By ROC analysis, the cutoff value with the highest diagnostic accuracy was defined as 150 ng/ml (sensitivity, 0.83; specificity, 0.77). There was a significantly higher mortality in patients with serum CCL18 concentrations above 150 ng/ml (P < 0.0001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0. There was a higher incidence of disease progression in the group with high serum CCL18 concentrations. CONCLUSIONS Our data demonstrate that serum CCL18 concentrations have a predictive value in IPF and may be a useful tool in the clinical management of patients with IPF and in clinical trials.


Archive | 2013

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a randomized trial

Ganesh Raghu; Juergen Behr; Kevin K. Brown; Jim J. Egan; Steven M. Kawut; Kevin R. Flaherty; Fernando J. Martinez; Steven D. Nathan; Athol U. Wells; Harold R. Collard; Ulrich Costabel; Luca Richeldi; Joao A. de Andrade; Nasreen Khalil; Lake Morrison; David J. Lederer; Lixin Shao; Xiaoming Li; Patty S. Pedersen; A. Bruce Montgomery; Jason W. Chien; Thomas O’Riordan

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Collaboration


Dive into the Kevin R. Flaherty's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Kevin K. Brown

University of Colorado Denver

View shared research outputs
Top Co-Authors

Avatar

Ganesh Raghu

University of Washington

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Ella A. Kazerooni

University of Wisconsin-Madison

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Luca Richeldi

Catholic University of the Sacred Heart

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Athol U. Wells

National Institutes of Health

View shared research outputs
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge