Ganesh Raghu

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

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.).

Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis

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 randomized, 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; ClinicalTrials.gov number, NCT00650091.).

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

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 .).

Adult-onset pulmonary fibrosis caused by mutations in telomerase

Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology. Some individuals with IPF have a familial disorder that segregates as a dominant trait with incomplete penetrance. Here we used linkage to map the disease gene in two families to chromosome 5. Sequencing a candidate gene within the interval, TERT, revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families. TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase (TERC), is required to maintain telomere integrity. Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT. A heterozygous mutation in TERC also was found in one family. Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations. Thus, mutations in TERT or TERC that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset IPF.

The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis

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

High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis

The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF). Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons. The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity. In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline

BACKGROUND This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. METHODS Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. RESULTS After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions. CONCLUSIONS The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.

Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

RATIONALE Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. OBJECTIVES To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. METHODS Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. CONCLUSIONS A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.

An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease

BACKGROUND The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. PURPOSE To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. METHODS A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committees conclusions and recommendations are based. RESULTS Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. CONCLUSIONS When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.

Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.

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 randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically 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 clinically 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.clinicaltrials.gov (NCT 00063869).