Steven D Nathan

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

All-Cause Mortality Rate in Patients with Idiopathic Pulmonary Fibrosis. Implications for the Design and Execution of Clinical Trials

RATIONALE FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials. OBJECTIVES To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. METHODS The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. MEASUREMENTS AND MAIN RESULTS A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. CONCLUSIONS The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.

P13 Safety of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF): Integrated analysis of cumulative data from 5 clinical trials

Introduction and objectives IPF is a chronic, progressive and irreversible disease that requires long-term clinical management. To further evaluate the clinical safety of pirfenidone in patients with IPF, we performed a comprehensive integrated analysis of safety data from 5 clinical trials. Methods All patients assigned to receive pirfenidone (2403 mg/d) in the Phase 3 ASCEND (016) and CAPACITY (004/006) studies and all patients receiving ≥1 dose of pirfenidone in either of two ongoing open-label studies (studies 002 and 012) comprised the integrated population. EAP (002) is a compassionate use study in the U.S.; RECAP (012) is evaluating pirfenidone in patients who completed one of the Phase 3 studies. Analyses were based on the January 15, 2014 interim data cut. Results 1299 patients were included in the integrated population. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range, 1 week–9.9 years); 545 (42%) patients received pirfenidone for ≥2 years and 325 (25%) patients received pirfenidone for ≥4 years. The majority of patients (75.8%) received a mean daily dose of ≥1800 mg. Consistent with prior observations, gastrointestinal and skin-related events were among the most common treatment emergent adverse events (Table 1); these were almost always mild to moderate in severity, reversible with dose modification and rarely led to treatment discontinuation. Cough, dyspnoea and IPF were the most common respiratory adverse events in the integrated population—a finding that is consistent with expectations in patients with a chronic progressive respiratory disease followed over a long period of observation. Aminotransferase (ALT or AST) elevations (>3 × ULN) occurred in 40/1299 (3.0%) patients in the integrated population.Abstract P13 Table 1 Treatment emergent adverse events in the integrated population compared with the pooled pirfenidone 2403 mg/d and placebo groups in the Phase 3 trials* Integrated population (N = 1299)† OE = treatment emergent adverse event ment emergent adverse events d sun exposure during treatment with pirfenidone. the skin du Median (range) duration of exposure, yr 1.7 (>0, 9.9) Treatment emergent adverse event,% Nausea 37.6 Cough 35.1 Dyspnea 30.9 Upper respiratory tract infection 30.6 Idiopathic pulmonary fibrosis 29.3 Fatigue 28.2 Diarrhoea 28.1 Rash 25.0 Bronchitis 23.8 Headache 21.6 Nasopharyngitis 21.3 Dizziness 21.2 Dyspepsia 18.4 Vomiting 15.9 Weight decreased 15.6 Back pain 15.4 Anorexia 15.2 *Occurring in ≥15% of patients in the cumulative clinical database. †Includes 2 patients in Study 002 with a diagnosis of “pulmonary fibrosis.” Conclusions A comprehensive integrated analysis of safety outcomes in a large, well–defined cohort of 1299 patients with IPF who were treated with pirfenidone for up to 9.9 years demonstrated that treatment with pirfenidone is safe and generally well tolerated. These observations provide further evidence to support the long-term clinical safety of pirfenidone in patients with IPF.

IPF clinical trial design and endpoints

Purpose of review There remains a dire need for therapies that impact the clinical course of patients with idiopathic pulmonary fibrosis (IPF). Indeed, there is a surge of interest in IPF therapeutics, with many candidate agents in various stages of development. Optimal design and implementation of the appropriate prospective clinical trials are essential to demonstrate clinical efficacy of promising drugs for the treatment of IPF. A key element in the success of such clinical trials is the choice of the best endpoint(s) to match the design of the study. Recent findings Although the results of many IPF clinical trials have been disappointing, these trials have provided valuable insights into the epidemiology and natural history of the disease and have sparked debate into the best clinical trial designs and endpoints. Summary This review will discuss the various clinical trial endpoints that have been used or proposed with a focus on their potential utility, as well as possible pitfalls that investigators should consider in the design of such studies. Video abstract http://links.lww.com/COPM/A13

Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis.

IPF patients have heightened propensity for pulmonary hypertension, which portends a worse outcome. Presence of pulmonary hypertension may be reflected in an enlarged pulmonary artery. We investigated pulmonary artery size measured on high-resolution computed tomography (HRCT) as an outcome predictor in IPF. We retrospectively reviewed all IPF patients evaluated at a tertiary-care centre between 2008 and 2013. Pulmonary artery and ascending aorta diameters were measured from chest HRCT with pulmonary artery:ascending aorta diameter (PA:A) ratio calculations. Outcome analysis defined by either death or lung transplant based on pulmonary artery size and PA:A ratio over 60 months was performed. Independent effects of different variables on overall outcomes were evaluated using the Cox proportional hazards model. 98 IPF patients with available HRCT scans had a mean pulmonary artery diameter and PA:A ratio of 32.8 mm and 0.94, respectively. Patients with a PA:A ratio >1 had higher risk of death or transplant compared with a PA:A ratio ≤1 (p<0.001). A PA:A ratio >1 was also an independent predictor of outcomes in unadjusted and adjusted outcomes analyses (hazard ratio 3.99, p<0.001 and hazard ratio 3.35, p=0.002, respectively). A PA:A ratio >1 is associated with worse outcomes in patients with IPF. HRCT PA:A ratio measurement may assist in risk stratification and prognostication of IPF patients. Pulmonary artery measurements on imaging can be utilised for risk stratification and prognostication in IPF http://ow.ly/WNO2h

M32 Effect of pirfenidone on all-cause mortality (acm) and forced vital capacity (fvc) in idiopathic pulmonary fibrosis (ipf) patients with low fvc and/or low dlco: analysis of pooled data from ascend and capacity

Introduction The pivotal trials of the two approved therapies in IPF, pirfenidone and nintedanib, assessed patients with protocol-defined mild to moderate disease. The effect of pirfenidone in patients with more severe lung function impairment warrants further investigation. Pooled Results from ASCEND and CAPACITY studies (NCT01366209, NCT00287729 and NCT00287716) showed a significant reduction at 12 months in the risk of ACM (hazard ratio [HR], 0.52; 95% CI, 0.31, 0.87)1 and in decline of percent predicted FVC (%FVC; 14.8% vs. 26.3% patients with ≥10% decline in%FVC or death, p<0.0001)2 for patients treated with pirfenidone vs. placebo. We present pooled subgroup analyses from ASCEND and CAPACITY for patients with low baseline%FVC (<50%) and/or low percent predicted diffusing capacity for carbon monoxide (%DLCO <35%) to further inform on treatment effect of pirfenidone in patients with more severe lung function impairment. Methods ACM was compared using the log-rank test, and HR was estimated using Cox regression. The categorical change in%FVC was summarised with the percent of patients with a≥10% absolute decline or death, and treatment comparison was performed using the rank ANCOVA method. Annual rate of FVC decline was estimated using the mixed-effects model. Results 170 patients (90 pirfenidone, 80 placebo) had low%DLCO (n=157) or%FVC (n=13) at baseline. Treatment with pirfenidone was associated with a 72% reduction in risk of ACM over 12 months vs. placebo (4 vs. 12 deaths; HR, 0.28; 95% CI, 0.09, 0.86; p=0.018; Table). There was a 56% relative reduction in the proportion of patients with a ³10% absolute decline in%FVC or death at 12 months vs. placebo (18.9% vs. 42.5%; p=0.0038). The annual rates of FVC decline were 150 and 278 mL in the pirfenidone and placebo arms, respectively (p=0.003). Conclusions Treatment with pirfenidone resulted in clinically meaningful benefits for ACM and FVC decline in patients with baseline%FVC <50% and/or%DLCO <35%. These data suggest that patients with more severe lung function impairment can also benefit from pirfenidone therapy. References . King TE Jr, et al. N Engl J Med2014;370:2083–2092. . Noble PW, et al. Eur Resp J2016;47:27–30. Abstract M32 Table 1 ACM and FVC outcomes at 12 months in patients with IPF with low FVC and/or low DLCO at baseline* Endpoint at 12 Months Patients With Low FVC and/or Low DLCO (n=170) All Patients (n=1247) Pirfenidone vs placeboACM: HR (95% CI) 0.28 (0.09–0.86) 0.52 (0.31–0.87) Pirfenidone vs. placebo:≥10% absolute decline in%FVC or death 18.9% vs. 42.5%(p=0.0038) 14.8% vs. 26.3%(p<0.0001) Pirfenidone vs. placebo:Annual rate of FVC decline, mL 150 vs. 278(p=0.003) 109 vs. 208(p<0.0001) *All pirfenidone-treated patients included in these analyses were randomised to receive 2403 mg/day.

M19 Differences in patient and physician viewpoints of the management of idiopathic pulmonary fibrosis (ipf)

Introduction A majority of patients with IPF do not receive antifibrotic therapy with pirfenidone or nintedanib. We investigated viewpoints about IPF care and treatment amongst patients, and amongst physicians with a ‘watch and wait’ approach (WWP) or a proactive approach (PP). Methods Participants from Europe and Canada took part in an online survey. Responses were collected from patients with IPF, and from physicians responsible for initiation of IPF treatment who had consulted with ≥5 patients with IPF within 3 months. A mixture of WWP (monitor for ≥4 months post-diagnosis in ≥50% of patients before initiating antifibrotic) and PP (initiate antifibrotic <4 months post-diagnosis in majority of patients) were recruited. Results 43 patients and 254 physicians were surveyed between September and October 2016. Only 56% of patients felt that they received enough information at diagnosis: 58% were advised that IPF is progressive; 44% discussed prognosis; and 49% were told about treatment options. Although the majority of patients (93%) preferred to receive information from their physician, most patients sought additional information about IPF (86%), treatment (81%), and/or prognosis (76%). Most patients (86%) felt that the ability of antifibrotic treatments to slow IPF progression was more important than side-effect profiles. Overall, 86% of patients who had received antifibrotic therapy felt confident in managing side effects. WWP were less likely to discuss IPF prognosis than PP, even when asked specifically by patients (Table). 62% and 38% of patients with ‘mild’ IPF were treated with an antifibrotic <4 months post-diagnosis by PP and WWP, respectively. WWP were more concerned about treatment side effects than PP (28% vs 17%, respectively); PP were more concerned about disease progression than WWP (83% vs 72%, respectively). Conclusions We identified a disparity between the information patients want at diagnosis and the information they receive from physicians. Furthermore, Results suggest that PP may be more confident with the benefit-risk profile of antifibrotic treatment than WWP. A belief in effective treatment options may aid conversation with patients regarding their IPF diagnosis, thereby enabling patients to make informed treatment decisions. Abstract M19 Table 1 Differences between physicians regarding disease prognosis and treatment decisions WWP n= 118 PP n= 136 Mention typical IPF prognosis at diagnosis 47% 59% Will avoid discussing typical prognosis/life expectancy even when patient asks 51% 33%* Comfortable discussing IPF prognosis 21% 34%* Strongly believe they can make a big difference in IPF patients’ lives post-diagnosis 29% 45%* Agree that antifibrotic therapies significantly slow the progression of IPF 36% 51%* Reasons for not treating patients with ‘mild’ IPF with an antifibrotic: Patient is asymptomatic/has few symptoms 66% 36%* Patient has stable disease 65% 33%* Patient has good lung function 58% 38%* Patient has a good quality of life 53% 27%* Patient has IPF that is progressing slowly 53% 26%* *p<0.05 for PP vs WWP.

Diseases that Mimic Idiopathic Pulmonary Fibrosis

There are number of conditions that may commonly be confused and difficult to differentiate from idiopathic pulmonary fibrosis (IPF). This chapter discusses these conditions in more detail.

Treatment of Idiopathic Pulmonary Fibrosis

The treatment of idiopathic pulmonary fibrosis (IPF) can be broadly divided into pharmacologic therapies and non-pharmacologic interventions (Chap. 8). There are two agents that have been shown to slow the rate of deterioration in lung function in IPF. These two drugs, pirfenidone and nintedanib, have been variably approved in countries around the world.

Prognosis, Clinical Course, and Monitoring of Patients with Idiopathic Pulmonary Fibrosis

The prognosis of idiopathic pulmonary fibrosis (IPF) is generally regarded as quite poor with a median survival from the time of diagnosis of anywhere from 2.5 to 4 years [1]. However, it is difficult a priori to predict the course of the disease in individual patients [2]. There are some patients who have a protracted course and survive 5 years or more, but this disease phenotype can only be recognized in retrospect. This represents about 20–25 % of all patients with IPF [3].