Discussion
We report that the efficacy of pirfenidone in Japanese phase III trial was supported by the evaluation using the improvement ratings, PFS times and positive/negative predictive values based on 5% decline in VC. Further, the baseline characteristics of patients with ≥ 5% decline at month 3 were generally severe, and the clinical outcomes of those patients including mortality were also significantly worsened after 1 year.
According to a preceding report [
12], comparison of the distributions of the improvement ratings (improved, stable, or worsened) based on 10% change in VC did not show significant differences between pirfenidone and placebo groups. The comparison of the ratings using 5% change in VC, however, revealed significant differences between pirfenidone and placebo groups at months 3, 6, 9 and 12 (Figure
1), and approximately 35% reduction in risk in this malignant disease would support the use of pirfenidone in clinical practice. Thus, when the 5% change in VC was used as an index, efficacy of the drug was evaluated with higher sensitivity than when the 10% change in VC was used. The 5% change in VC may seem only a slight change, but the annual decline in VC in the placebo group is said to be approximately 150 to 200 mL in many recent clinical trials [
12,
21‐
25]. In the phase III trial of pirfenidone, the annual decline in VC in the placebo group was 160 mL on average [
12], and the mean baseline VC in the placebo group was 2472.3 mL, from which the annual rate of decline is calculated to be approximately 6.5%. That is, if a ≥ 10% change in VC is used as an index for evaluation over a period of a year, it may not be sensitive enough to detect efficacy of the drug, especially for changes within a shorter period of time such as 3 months and 6 months. Results of this sub analysis revealed that using a 5% change as an index improved the chances of detecting efficacy of the drug. Our results are considerably similar to those of extended analysis of the IFIGENIA study investigating the effect of N-acetylcysteine (NAC) in IPF, which also showed significance of a 5% threshold [
26]. However, it should be noted that use of a smaller change as an index may require more accurate VC measurements.
According to the preceding report, the progression of disease was defined by the ≥ 10% decline in VC or death for evaluation of progression-free survival [
12]. Results showed that the p-value of the difference between groups high-dose and placebo was 0.0280 and between groups low-dose and placebo was 0.0655. In this paper, the progression of disease was defined by the ≥ 5% decline in VC from baseline or death, and K-M plots were generated using thus defined PFS time. As a result, there were significant difference between groups high-dose and placebo and between groups low-dose and placebo (p = 0.0149 and p = 0.0034, respectively), (Figure
2-a) which seems to be more evident than those in the previous analysis by 10% decline [
12]. When the progression of disease was defined by a ≥ 5% decline in VC from baseline on two successive occasions or death, the highly significant differences were also observed (Figure
2-b), which supported the result of Figure
2-a.
Early identification of the response to therapeutic medication provides a clue in clinical decision making on treatment policy. We analyzed the positive/negative predictive values using the improvement ratings of months 3 and 12 based on 5% decline in VC. From the results of the differences of negative predictive values between placebo (50.8%) and pirfenidone (71.7%) groups, the efficacy of pirfenidone was also demonstrated (p = 0.0046). Thus, about 70% of patients assessed as non-progression at month 3 in pirfenidone group might remain in the state at 1 year. However, the results of the positive predictive values of placebo and pirfenidone groups showed that both values were very high, i.e., 86.1% and 87.1%, respectively. These results showed that the progression detected at month 3 remained (not reversed) at month 12 in most cases. These analyses suggested the possibility of identifying whether patients respond to pirfenidone or not at early phase after intervention, and of motivating patients to continue medication.
On the other hand, it will be a crucial question whether treatment should be withdrawn in patients who decline by ≥ 5% in VC at month 3. Patients with VC declined by 5% at month 3 generally had lower means of PaO2, VC, %VC, TLC, %TLC, and DLCO at baseline, and had higher means of SP-A, SP-D and dyspnea in daily living assessed with H-J classification score at baseline (Table
2). It was suggested that those patients with impairment of these baseline characteristics may lead to be corresponded to relatively "rapid progressors" in IPF, and treatment of any additional therapy would be recommended as soon as allowed. The effect of additional therapy strategies, such as combination with NAC [
22] or BIBF-1120 [
27], should be addressed in further clinical trials.
In order to translate the 5% decline in VC into a clinical relevant outcome, we compared the clinical outcomes (dyspnea in daily living assessed with H-J classification, mortality rate, and incidence of acute exacerbation) between 2 classes of patients, i.e., those with "worsened (VC ≥ 5% decrease)" and others with "non-worsened (VC < 5% decrease)" at month 3 (Table
3,
4). In short, dyspnea in daily living and mortality rate of patients with worsened at month 3 were significantly worsened after 1 year. Similar trend was also seen in the prevalence of acute exacerbation between the 2 classes of patients, which marginally supported the significance of the 5% change in VC. We speculated that the patients with 5% decline in VC at month 3 have further progression more easily; however, PFS times with origin at month 3 were not different between patients with or without 5% decline in VC at month 3 (Figure
3). Namely, it is noted that declines in VC at month 3 do not mean the possibility of further progression in next 9 months, i.e., month 3 to 12. In summary, except for the results of PFS times, it was suggested that a 5% decline in VC at month 3 is a clinically meaningful indicator in IPF and may be a useful prognostic factor. As the potential limitation, it should be addressed that these analytical results were obtained by the small number of subjects with death or prevalence of acute exacerbation within a one year study period.
Acknowledgements
The authors would like to thank M. Ando (Omotesando Yoshida Hospital, Kumamoto, Japan), S. Kitamura (Minami-Tochigi Hospital, Oyama, Tochigi, Japan), Y. Nakai (Tanpopo Clinic, Sendai, Miyagi, Japan), and A. Kondo (Niigata Tetsudo Kenshin Center, Niigata, Japan) of the independent Data and Safety Monitoring Board; K. Murata (Shiga University of Medical Science Hospital, Ohtsu, Shiga, Japan), M. Takahashi (Shiga University of Medical Science Hospital, Ohtsu, Shiga, Japan), H. Hayashi (Japanese Red Cross Okayama Hospital, Okayama, Japan), S. Noma (Tenri Hospital, Tenri, Japan), T. Johkoh (Osaka University Hospital, Osaka, Japan), H. Arakawa (Dokkyo Medical University Hospital, Shimotsuga, Tochigi, Japan) and K Ichikado (Kumamoto University Hospital, Kumamoto, Japan) of the Imaging Central Judging Panel. The authors are also grateful to E. Tsuboi (Toranomon Hospital, Minato, Tokyo, Japan) for his expert advice on 6-minute steady-state exercise test. Also, the authors thank M. Igarashi, Y. Tsuchiya, S. Kakutani, Y. Yoshida, H. Oku, and S. Yomori (all Shionogi & Co. Ltd, Osaka, Japan) for their advice and for reviewing the manuscript.
This work was supported by a grant-in-aid for and by members of interstitial lung diseases from the Japanese Ministry of Health, Labor and Welfare, also by members of the Japanese Respiratory Society's committee for diffuse lung diseases, and sponsored by Shionogi & Co., Ltd, Osaka, Japan.
The members of Pirfenidone Clinical Study Group in Japan are as follows. T. Betsuyaku (Hokkaido University Hospital, Sapporo, Hokkaido), Y. Sugawara (Kyowakai Obihiro Respiratory Hospital, Obihiro, Hokkaido), S. Fujiuchi (Dohoku National Hospital, Asahikawa, Hokkaido), K. Yamauchi (Iwate Medical University Hospital, Morioka, Iwate), K. Konishi (Morioka Tsunagi Onsen Hospital, Morioka), M. Munakata (Fukushima Medical University Hospital, Fukushima), Y. Kimura (Tohoku University Hospital, Miyagi), Y. Ishii (Dokkyo Medical University Hospital, Shimotsuga, Tochigi), K. Kudoh (International Medical Center of Japan, Shinjuku, Tokyo), T. Saito (Ibarakihigashi National Hospital, Naka, Ibaragi), T. Yamaguchi (JR Tokyo General Hospital, Shibuya, Tokyo), A. Mizoo (Tokyo Kosei Nenkin Hospital, Shinjuku), A. Nagai (Tokyo Women's Medical University Hospital, Shinjuku), A. Ishizaka, K. Yamaguchi (Keio University Hospital, Shinjuku), K. Yoshimura (Toranomon Hospital, Minato, Tokyo), M. Oritsu (Japanese Red Cross Medical Center, Shibuya), Y. Fukuchi, K. Takahashi (Juntendo University Hospital, Bunkyo, Tokyo), K. Kimura (Toho University Omori Medical Center, Ota, Tokyo), Y. Yoshizawa (Tokyo Medical and Dental University Hospital, Bunkyo), T. Nagase (Tokyo University Hospital, Bunkyo), T. Hisada (Tokyo Teishin Hospital, Chiyoda, Tokyo), K. Ohta (Teikyo University Hospital, Itabashi, Tokyo), K. Yoshimori (Fukujuji Hospital, Kiyose, Tokyo), Y. Miyazawa, K. Tatsumi (Chiba University Hospital, Chiba), Y. Sasaki (Chiba-East Hospital, Chiba), M. Taniguchi (Sagamihara National Hospital, Sagamihara, Kanagawa), Y. Sugita (Saitama Cardiovascular and Respiratory Center, Kumagaya, Saitama), E. Suzuki (Niigata University Medical & Dental Hospital, Niigata), Y. Saito (Nishi-Niigata Chuo National Hospital, Niigata), H. Nakamura (Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka), K. Chida (Hamamatsu University School of Medicine, University Hospital, Hamamatsu), N. Kasamatsu (Hamamatsu Medical Center, Hamamatsu), H. Hayakawa (Tenryu Hospital, Hamamatsu), K. Yasuda (Iwata City Hospital, Iwata, Shizuoka), H. Suganuma (Shimada Municipal Hospital, Shimada, Shizuoka), H. Genma (Fukuroi Municipal Hospital, Fukuroi, Shizuoka), R. Tamura (Fujieda Municipal General Hospital, Fujieda, Shizuoka), T. Shirai (Fujinomiya City General Hospital, Fujinomiya, Shizuoka), J. Shindoh (Ogaki Municipal Hospital, Ogaki, Gifu), S. Sato (Nagoya City University Hospital, Nagoya, Aichi), O. Taguchi (Mie University Hospital, Tsu, Mie), Y. Sasaki (Kyoto Medical Center, Fushimi, Kyoto), H. Ibata (Mie Chuo Medical Center, Tsu), M. Yasui (Kanazawa University Hospital, Kanazawa, Ishikawa), Y. Nakano (Shiga Medical University Hospital, Otsu, Shiga), M. Ito, S. Kitada (Toneyama National Hospital, Toyonaka, Osaka), H. Kimura (Nara Medical University Hospital, Kashihara, Nara), Y. Inoue (Kinki-Chuo Chest Medical Center, Sakai, Osaka), H. Yasuba (Takatsuki Red Cross Hospital, Takatsuki, Osaka), Y. Mochizuki (Himeji Medical Center, Himeji, Hyogo), S. Horikawa, Y. Suzuki (Japanese Red Cross Wakayama Medical Center, Wakayama), N. Katakami (Institute of Biomedical Research and Innovation, Kobe, Hyogo), Y. Tanimoto (Okayama University Hospital, Okayama), Y. Hitsuda, N. Burioka (Tottori University Hospital, Yonago, Tottori), T. Sato (Okayama Medical Center, Okayama), N. Kohno, A. Yokoyama (Hiroshima University Hospital, Hiroshima), Y. Nishioka (Tokushima University Hospital, Tokushima), N. Ueda (Ehime Prefectural Central Hospital, Matsuyama, Ehime), K. Kuwano (Kyushu University Hospital, Fukuoka), K. Watanabe (Fukuoka University Hospital, Fukuoka), H. Aizawa (Kurume University Hospital, Kurume, Fukuoka), S. Kohno, H. Mukae (Nagasaki University Hospital of Medicine and Dentistry, Nagasaki), H. Kohrogi (Kumamoto University Hospital, Kumamoto), J. Kadota, I. Tokimatsu, E. Miyazaki (Oita University Hospital, Yufu, Oita), T. Sasaki (Miyazaki University Hospital, Miyazaki), M. Kawabata (Minami Kyushu National Hospital, Aira, Kagoshima).
Competing interests
HT, ME, AA, YT, MS, HT, KN, AS, SK, and TN have received consultancy fees for advisary board, and HT, YK, ME, TO, AA, YS, and TN have received fees for speaking from Shionogi & Co., Ltd.