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Pirfenidone in Idiopathic Pulmonary Fibrosis

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Pirfenidone in Idiopathic Pulmonary Fibrosis Eur Respir J 2010; 35: 821–829 DOI: 10.1183/09031936.00005209 CopyrightßERS Journals Ltd 2010 Pirfenidone in idiopathic pulmonary fibrosis H. Taniguchi*, M. Ebina#, Y. Kondoh*, T. Ogura", A. Azuma+, M. Suga1, Y. Taguchie, H. Takahashi**, K. Nakata##, A. Sato"", M. Takeuchi++, G. Raghu11, S. Kudoh+ and T. Nukiwa#, and the Pirfenidone Clinical Study Group in Japanee ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven AFFILIATIONS effective therapy. *Dept of Respiratory Medicine and Allergy, Tosei General Hospital, A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was Aichi, conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of #Dept of Respiratory Medicine, pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, Tohoku University Graduate School of 1,800 mg?day-1; low-dose, 1,200 mg?day-1; or placebo groups in the ratio 2:1:2), 267 patients were Medicine, Sendai, "Dept of Respiratory Medicine, evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; Kanagawa Cardiovascular and the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the Respiratory Center, Yokohama, progression-free survival (PFS) time. +Fourth Dept of Internal Medicine, Significant differences were observed in VC decline (primary end-point) between the placebo Nippon Medical School, Tokyo, ##Nakata clinic, Tokyo, group (-0.16 L) and the high-dose group (-0.09 L) (p50.0416); differences between the two groups ++Dept of Biostatistics, Kitasato (p50.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a University, Tokyo, well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild 1Dept of Respiratory Medicine, in severity in most of the patients. Saiseikai Kumamoto Hospital, Kumamoto, Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may eDept of Respiratory Medicine, Tenri decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional Hospital, Tenri, studies are needed to confirm these findings. **Third Dept of Internal Medicine, Sapporo Medical University Hospital, Sapporo, and KEYWORDS: Idiopathic pulmonary fibrosis, pirfenidone, progression-free survival time, vital ""Kyoto Preventive Medical Center, capacity Kyoto, Japan. 11University of Washington Medical Center, Seattle, WA, USA. ee diopathic pulmonary fibrosis (IPF) is a 9 months [15]. The trial was prematurely termi- A full list of the members of the devastating, progressive fibrotic lung disease nated by the independent Data and Safety Pirfenidone Clinical Study Group in Japan and their affiliations can be with a median survival of 3–5 yrs without Monitoring Board (DSMB) because of a higher I found in the Acknowledgements proven effective therapy [1, 2]. Recent studies incidence of acute exacerbations in the placebo section. have suggested that IPF develops from chronic group than the pirfenidone group. These encoura- epithelial cell injury and aberrant activation of ging results, prompted us to undertake a phase III CORRESPONDENCE progressive fibrosis [3, 4]. Therefore, the thera- 1-yr clinical study to examine the therapeutic T. Nukiwa, peutic strategy against IPF has shifted from effects of pirfenidone on lung functional deteriora- Dept of Respiratory Medicine, corticosteroids and/or immunosuppressants to tion and disease progression in patients with IPF. Tohoku University Graduate School of antifibrotic agents, as reported in recent clinical Medicine, trials [5, 6]. MATERIALS AND METHODS Sendai 980-8574, Japan Study subjects Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; E-mail: [email protected] The diagnosis of IPF was in accordance with the Shionogi & Co., Osaka, Japan; MARNAC, Dallas, American Thoracic Society (ATS)/European TX, USA) [7–9] is a promising agent with Received: Respiratory Society (ERS) Consensus statement Jan 13 2009 therapeutic potential for IPF that has combined [16] and the fourth version of the clinical Accepted after revision: anti-inflammatory, antioxidant and antifibrotic diagnostic criteria guidelines for idiopathic inter- Nov 20 2009 effects in experimental models of pulmonary stitial pneumonia in Japan [17]. High-resolution First published online: fibrosis [10–14]. Following an open-label phase II computed tomography (HRCT) scans of the chest Dec 08 2009 pioneer study [7] and an open-label 1-yr study in were reviewed by expert chest radiologists prior Japan [9], a double-blind, placebo-controlled to randomisation; two out of six expert radiolo- clinical trial of pirfenidone in Japanese patients gists independently evaluated the HRCT images with IPF demonstrated a lesser decline of vital to agree and determine whether the pattern of capacity (VC) in patients receiving pirfenidone for usual interstitial pneumonia (UIP) was present or European Respiratory Journal not in accordance with the predetermined proto- Print ISSN 0903-1936 c For editorial comments see page 728. col (see online supplementary material). In cases Online ISSN 1399-3003 EUROPEAN RESPIRATORY JOURNAL VOLUME 35 NUMBER 4 821 INTERSTITIAL LUNG DISEASE H. TANIGUCHI ET AL. of disagreement, the interpretation of the third radiologist decline in VC from baseline. When the VC data could not be influenced the final decision, and the diagnosis of patients with obtained due to worsening of respiratory symptoms, including probable UIP pattern on HRCT was confirmed by the presence acute exacerbation, the case was also classified as disease of histopathological UIP pattern in surgical lung biopsy progression. As in the phase II study conducted in Japan [15], samples. the 6MET procedure had been prespecified in the protocol (see online supplementary material). Tertiary end-points were Eligible patients were adults (20–75 yrs of age) with IPF pulmonary function tests (PFTs; arterial oxygen tension, diagnosis based on the above criteria and meeting the following alveolar–arterial oxygen tension difference at rest, total lung arterial oxygen saturation measured by pulse oximetry (Sp,O ) 2 capacity (TLC) and diffusing capacity of the lung for carbon criteria: 1) oxygen desaturation of o5% difference between monoxide (DL,CO)), acute exacerbation [20], serum levels of the resting Sp,O and the lowest Sp,O during a 6-min steady-state 2 2 markers of interstitial pneumonias (sialylated carbohydrate exercise test (6MET); and 2) the lowest Sp,O during the 6MET of 2 antigen KL-6, surfactant protein (SP)-D and SP-A; see online o85% while breathing air. The 6MET procedure was in supplementary material) and subjective/objective symptoms accordance with previous study protocols (see online supple- (cough, presence/absence of sputum and dyspnoea in daily mentary material). Exclusion criteria were: 1) a decrease in living assessed with Hugh–Jones classification). symptoms during the preceding 6 months; 2) use of immuno- -1 suppressants and/or oral corticosteroids at a dose .10 mg?day VC was measured every 4 weeks, whereas the lowest Sp,O2 during the preceding 3 months; 3) clinical features of idiopathic during the 6MET and other PFTs were determined every interstitial pneumonia other than IPF; 4) evidence of known 12 weeks. Acute exacerbation of IPF was defined according to coexisting pulmonary hypertension, asthma, tuberculosis, previous reports and revised criteria for acute exacerbation of bronchiectasis, aspergillosis or severe respiratory infection. IPF in Japan (see appendices in online supplementary material) [15, 20]. The protocol was approved by the institutional review board at each centre and written informed consent was obtained from The change in the lowest Sp,O2 during the 6MET over 52 weeks all participants prior to enrolment. The ongoing efficacy and was the original intended primary end-point for this study. safety results were reviewed by the independent DSMB. The decision was made to revise the primary end-point from the lowest Sp,O2 to VC at week 52 and assess the change in the Study design lowest Sp,O2 during the 6MET as a secondary end-point. This This study was a multicentre, double-blind, randomised, was recommended by the independent DSMB, prior to placebo-controlled, phase III clinical trial designed to deter- breaking the code. This decision was based on the evolved mine the efficacy and safety of oral administration of knowledge of assessment with objective measurements in IPF pirfenidone for 1 yr in patients with IPF. Eligible patients [21–26], as well as the lack of validation in the 6MET study -1 were allocated to three groups: high dose (1,800 mg?day ), low (unpublished data) and difficulties in reproducibility of the -1 dose (1,200 mg?day ) and placebo, in a ratio of 2:1:2, Sp,O2 measurements during the 6-min walk test (6MWT) [27]. respectively, with a modified minimisation method, including some random allocation based on biased coin design to balance Statistical analysis baseline Sp,O2 [18, 19]. The planned sample size was 250 in total: 100, 50 and 100 patients in the high-dose, low-dose and placebo groups, Treatment regimen respectively. The sample sizes of 100 for the high-dose and Pirfenidone as 200-mg tablets and matching placebo were placebo groups were determined on the basis of simulations provided for oral use by Shionogi & Co. The dose was that would provide a statistical power of 0.8 to detect assumed increased in a stepwise manner as follows: one tablet t.i.d. differences of the mean changes in the lowest Sp,O2 from orally administered for the first 2 weeks (high dose baseline to week 52 between the two groups at a significance ? -1 ? -1 ? -1 600 mg day , low dose 600 mg day and placebo 0 mg day ), level in this study of 0.1 (two-sided) (details in the online then two tablets per dose t.i.d. for the following 2 weeks (high supplementary material). Although the primary end-point was dose 1,200 mg?day-1, low dose 600 mg?day-1 and placebo altered from the lowest Sp,O to VC after the study was started, ? -1 2 0mgday ) and three tablets t.i.d.
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