A Controlled Trial of Sildenafil in Advanced Idiopathic Pulmonary Fibrosis The Idiopathic Pulmonary Fibrosis Clinical Research Network* N Engl J Med 2010 R3 채정민

 Idiopathic pulmonary fibrosis (IPF) chronic, progressive lung disease of unknown cause  Progression to end-stage respiratory insufficiency and death within 5 years after the onset of symptoms  no pharmacologic therapies have definitively been shown to improve survival or quality of life in patients with this disease  severe idiopathic pulmonary fibrosis abnormalities of the pulmonary vasculature decreased levels of nitric oxide (potent pulmonary vasodilator) Pulmonary vasoconstriction and impaired gas exchange INTRODUCTION

 Sildenafil (phosphodiesterase-5 inhibitor) stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate pulmonary vasodilatation preferentially induce vasodilatation in well-ventilated lung tissue improve ventilation–perfusion matching and gas exchange in patients with IPF  Small case series of daily treatment with sildenafil in patients with IPF improved exercise tolerance, reduced degree of dyspnea, and improved quality of life INTRODUCTION

 the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF)  hypothesis treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis  The trial was sponsored by the Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet) of the National Heart, Lung, and Blood Institute INTRODUCTION

 The study was carried out at 14 IPFnet centers  Pfizer donated sildenafil and identical tablets containing placebo  but had no role in the study design, accrual or analyses of data, or preparation of the manuscript  The Duke Clinical Research Institute served as the data-coordinating center and oversaw all aspects of the study’s conduct, data management, and statistical analysis METHODS – study oversight

 Eligibility criteria a diagnosis of IPF (defined by consensus criteria) in an advanced stage (DLCO < 35% of the predicted value)  Exclusion criteria METHODS – study patients 1. 6-minute walk distance of less than 50 m (164 ft) 2. a difference of more than 15% in the 6-minute walk distance between two prerandomization walks 3. an extent of emphysema greater than the extent of fibrotic change as determined by HRCT 4. treatment with medications containing nitrates 5. the presence of aortic stenosis or idiopathic hypertrophic subaortic stenosis 6. the initiation of pulmonary rehabilitation within 30 days after screening 7. the initiation or change in the dose of any investigational treatment for idiopathic pulmonary fibrosis within 30 days after screening 8. treatment for pulmonary hypertension with prostaglandins, endothelin-1 antagonists, or other phosphodiesterase inhibitors within 30 days after screening 9. a resting oxygen saturation of less than 92% while breathing 6 liters of supplemental oxygen 10. being listed on an active waiting list for lung transplantation

 double-blind, randomized, placebo controlled trial  oral sildenafil (20 mg three times daily)  randomly assigned in a 1:1 ratio to receive sildenafil or matched placebo  conducted in two periods period 1 : a 12-week double blind, placebo-controlled study period 2 : a 12-week open-label extension with all patients receiving sildenafil  The primary outcome was measured at the end of period 1 (12 weeks) METHODS – study design

 The primary outcome the presence or absence of an improvement of at least 20% in the 6-minute walk distance at 12 weeks, as compared with baseline  secondary outcome changes in the 6-minute walk distance changes in degree of dyspnea changes in quality of life METHODS – outcome measures

Shortness of Breath Questionnairethe Borg Dyspnea Index Dyspnea level total score ranging from 0 to 120 MID : 5 point a scale of 0 (none) to 10 (maximum) MID : 1 point

 Quality of life was measured the St. George’s Respiratory Questionnaire The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) METHODS – outcome measures 1)Over the last year, I have coughed Most 80.6 Sever 63.2 A few 29.3 Only 28.0 Not 0.0 MID : 5~8 point MID : 2~4 point MID : 0.08 point for self-report 7 point for VAS

 secondary outcomes change in forced vital capacity carbon monoxide diffusion capacity arterial partial pressure of oxygen and arterial oxygen saturation the alveolar–arterial oxygen gradient while breathing ambient air  We recorded all adverse events, hospitalizations, and deaths METHODS – outcome measures

 Screening procedures the taking of a detailed history to rule out known causes of interstitial lung disease a physical examination spirometry measurements of lung volume on plethysmography carbon monoxide diffusion capacity arterial blood gases echocardiography was performed to rule out aortic stenosis and idiopathic hypertrophic subaortic stenosis HRCT images were reviewed METHODS – study visits

 Eligible patients returned for an enrollment visit within 6 weeks after screening Taking an initial dose were monitored for 60 minutes for adverse effects  Follow-up visits: at 1 / 6 / 12 weeks  After completion of the 12-week visit all patients were started on treatment with open-label sildenafil  Visits were scheduled at 13 / 18 / 24 / 28 weeks → serious adverse events and vital status were documented  6-minute walk distance was performed screening enrollment visits at 6 / 12 / 18 / 24 weeks METHODS – study visits

 based on a chi-square test compare the rates of improvement of the 6-minute walk distance from baseline to 12 weeks  A post hoc sensitivity analysis of data from the 6-minute walk test the effect of the prerandomization reference walk and the definition of response  Analysis of longitudinal continuous end points fixed effects to reflect the change to open-label administration of sildenafil  the Kaplan–Meier method Survival curves METHODS – statistical analysis

 From September 2007 through March 2009 RESULTS

RESULTS  Improvement in the 6-minute walk distance of 20% or more 9 of 89 patients (10%) in the sildenafil group 6 of 91 patients (7%) in the placebo group (P = 0.39)  the average walk distance worsened in both groups 28.5 m in the sildenafil group 45.2 m in the placebo group at 12 weeks

 Period 2 (week 12 to 24)  patients in the placebo group who were received sildenafil during period, no significant change the 6-minute walk distance from week 12 to week 24 the partial pressure of oxygen Arterial oxygen saturation the percentage of predicted carbon monoxide diffusion capacity score on the Shortness of Breath Questionnaire score on the St. George’s Respiratory Questionnaire the SF-36 general health and vitality scores RESULTS

 no significant difference in the primary outcome  small differences in some secondary outcomes, including the degree of dyspnea and quality of life → clinically significant  Sildenafil-treated patients significant physiological stabilization at ABGA and DLCO, as compared with placebo-treated patients consistent with previously published data DISCUSSION

 We enrolled patients with advanced disease such patients have been excluded from previous clinical trials less likely to have a response to disease modifying therapies  No therapies can improve survival in patients with IPF improvements in walk distance, degree of dyspnea, and quality of life → no doubt important to patients, especially those with severe disease  Although no significant difference in the primary outcomes the patients receiving sildenafil during period 1 had symptomatic benefit → clinically meaningful DISCUSSION

 important limitations  only to patients with advanced IPF milder physiological impairment ?  insufficient subgroup analysis the treatment effect was driven by a particular subgroups ? (e.g., those with more severe pulmonary vascular disease)  Too short and enrolled too few patients the duration of the effect of sildenafil ? any potential effect of sildenafil on rates of acute respiratory worsening or death ?  Incomplete masking Possible to quality of life DISCUSSION

 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 CONCLUSION