Discussion
Our exploratory analyses using changes in VC, categorical changes in VC, PFS time, and scores on subjective symptoms as outcomes suggested that pirfenidone was more effective in patients with mild-to-moderate lung function impairment (baseline %VC ≥ 70 and the lowest SpO2 < 90; Subgroup A). In addition, pirfenidone had significant effects on some of these outcomes in Subgroup B (baseline PaO2 ≥ 70 and the lowest SpO2 < 90). In the population of patients with mild-to-moderate disease, pirfenidone is especially effective in patients with desaturation during exercise which typically corresponds to the lowest baseline SpO2 < 90.
To evaluate temporal changes in subjective symptoms in the phase III trial, means of the changes in cough and in F, H-J classification scores were calculated. In FAS, pirfenidone tended to prevent the elevation of these scores more consistently in high- and low-dose groups than in the placebo group, but no significant differences were detected. Additional analysis in the present study, however, showed that compared to placebo, pirfenidone significantly prevented elevation of these scores at week 52 and significantly lowered dyspnea score as early as week 12 especially in Subgroup A. These results suggest that pirfenidone can be expected to prevent worsening of subjective symptoms such as dyspnea and exert this effect at a very early stage in the same patient population shown to have reduced impairment of respiratory functions such as VC. We additionally compared the incidence of acute exacerbation between pirfenidone and placebo groups in Subgroup A. The incidence in the pirfenidone group (1.82% [1/55]) was lower than that in the placebo group (8.33% [3/36]), although the difference was not statistically significant (data not shown).
In the 'responsive' subgroup, i.e., patient subgroup with baseline %VC of ≥70 and the lowest SpO
2 of <90, lung function is better preserved though oxygen saturation is deteriorated. These are mutually conflicting characteristics. As pulmonary fibrosis progresses at the early stage of the disease, interstitial septa between the alveoli and capillaries, which are the major sites of gas exchange, become thickened and gas exchange and diffusion become impaired. Hypoxemia is thought to be caused by pulmonary-diffusion impairment and ventilation-perfusion ratio mismatching. The ventilation-perfusion ratio mismatching is more likely during exercise due to dynamic change of pulmonary circulation and increased flow, irrespective of PaO
2 status at rest [
20]. In this way, the thickening of the lung interstitial septa leads to desaturation and dyspnea during exercise at an early stage of the disease progression. The results showing that pirfenidone tended to be more effective in patients with %VC ≥70 and the lowest SpO
2 <90 than in patients with %VC <70 and the lowest SpO
2 <90 (Table
1) suggest that the desaturation exhibited by the subgroup with more preserved lung function may have been due to developing fibrosis with inflammatory edema and not to established fibrosis. Pirfenidone could be more effective in treating such 'young' fibrosis and therefore able to inhibit progression of fibrosis during the early stage. Furthermore, pirfenidone, which also has anti-inflammatory activity [
3], may be effective in improving dyspnea by reducing inflammatory edema and vascular permeability. Above explanations are speculative, and therefore a future prospective clinical study is necessary to confirm the better response to this drug by this subgroup.
Recent clinical trials of drugs for IPF tend to include mild-to-moderate cases while totally excluding severe cases, as in the clinical trials of IFN-γ [
21]. This is probably because the inclusion of severe cases can bias the evaluation of treatment effectiveness. In the phase II trial of pirfenidone for Japanese patients [
7], mean decline in VC was 130 mL in the placebo group and 30 mL in pirfenidone-treated groups with a p-value of 0.0356 at week 36. The reduction in decline by pirfenidone was greater than that obtained in the phase III trial in Japan [
13]. The entry criteria of the phase II trial included PaO
2 at rest of ≥70 torr and the lowest SpO
2 during 6MET of ≤90%, while criteria of the phase III trial were broader (i.e., 1] oxygen desaturation of >5% difference between resting SpO
2 and the lowest SpO
2, and 2] the lowest SpO
2 >85% while breathing air). These characteristics were similar in patients enrolled in the phase II trial and in the Subgroup B patients of the phase III trial enrolled in this study. Pirfenidone was shown to have a more marked effect on both the patients with the lowest SpO
2 ≤ 90% in Subgroup B as those in the phase II trial (data not shown). Possibly, the phase II trial might have enrolled a population of patients who were more responsive to the drug. The broader criteria for inclusion into the phase III trial might have resulted in a more heterogeneous population and more variable data.
In Japan, the severity of idiopathic interstitial pneumonia (IIPs) is classified on the basis of baseline PaO
2 value at rest, and categories are defined by 10-torr intervals. The grade of IIPs in patients with SpO
2 of < 90 on exertion is increased by one (except for grade I) as described in the online supplemental materials of our previous report of the Phase III trial [
13]. In the phase III trial, patients were grouped based on severity to identify the subpopulation that was more responsive to pirfenidone. Pirfenidone was found to be more effective in grade-III patients
(data not shown). A more detailed analysis revealed that the population of patients with PaO
2 ≥ 70 and < 80 included many grade-III patients when SpO
2 was < 90% on exertion
(data not shown). These findings also may support the efficacy of pirfenidone in patients with desaturation during exercise.
Identifying those patients clinically responsive to pirfenidone is very important. The present analyses revealed that pirfenidone was more effective in populations of patients with relatively favorable baseline %VC and PaO
2, especially in those with desaturation on exertion. Since pirfenidone was more effective in Subgroup A than in Subgroup B, baseline %VC may be a more appropriate index than PaO
2. In addition, patients presenting desaturation during exercise may be comparable to those complaining of dyspnea on exertion. For more beneficial use of pirfenidone, the factors--baseline %VC and the presence/absence of complaints of dyspnea on exertion--may be used to select candidate patients. However, since responsiveness in this study depended on the stage of the disease as determined by respiratory function tests, these factors cannot be regarded as indicative of a responsive phenotype but rather as indicative of a responsive "phenostage" (coinage by the authors). (A 'Phenotype' determining response to therapy, for example to anti-cancer therapy, is generally characterized by expression of a specific gene, whereas the 'responsiveness' of the subgroup identified in this study may be due to the timing of treatment during disease progression rather than a specific gene.) A sub-analysis of data from the CAPACITY trials [
14] yielded similar results. The FVC change at week 72 showed that a subpopulation of patients given oxygen during 6MWT at baseline responded favorably to pirfenidone [
22]. To determine whether this observation and our findings are equivalent, a detailed sub-analysis of data from the CAPACITY trials or further prospective studies will be needed.
To support the results obtained from the analyses described in preceding sections, we used respiratory function tests at baseline to determine the factors associated with the efficacy of pirfenidone. Thus, we included percentage predicted total lung capacity (%TLC), %DLco in addition to the lowest SpO
2, %VC, and PaO
2. Then, we used the change in VC from baseline to week 52 as the efficacy parameter and evaluated the effects of the 5 function tests on this efficacy parameter in pirfenidone and placebo groups. At first, correlation coefficients among the 5 respiratory tests were calculated in the pirfenidone and placebo groups. The correlation coefficients between %VC and %TLC were very high in both groups (0.811 and 0.826, respectively). Thus, we subsequently omitted %TLC from the evaluation, and retained %VC since %VC behaves like VC (which was the primary endpoint in the phase III trial) and was considered indispensable in the additional analysis. Then, we applied a multiple regression model letting the change in VC serve as the response variable and the four respiratory function tests as explanatory variables in the two groups (Table
3). From the Tables, the regression coefficient of %VC in the pirfenidone group was significant (p = 0.0018), and it was suggested that in patients with relatively low baseline %VC, the tendency to prevent the decline in VC was greater in the pirfenidone group than in the placebo group.
Table 3
Effects of respiratory tests on the change in VC in Pirfenidone and Placebo groups
Pirfenidone | Intercept | -0.3543 | 0.7428 | -0.48 | 0.6340 |
(n = 155) | The lowest SpO2 | 0.0029 | 0.0091 | 0.32 | 0.7514 |
| %VC | 0.0035 | 0.0011 | 3.17 | 0.0018 |
| %DLco | -0.0011 | 0.0011 | -0.97 | 0.3361 |
| PaO2 | -0.0025 | 0.0021 | -1.19 | 0.2378 |
Placebo | Intercept | -2.0951 | 1.2726 | -1.65 | 0.1029 |
(n = 102) | The lowest SpO2 | 0.0217 | 0.0146 | 1.48 | 0.1412 |
| %VC | 0.0008 | 0.0017 | 0.49 | 0.6279 |
| %DLco | -0.0017 | 0.0017 | -0.99 | 0.3248 |
| PaO2 | 0.0003 | 0.0033 | 0.10 | 0.9172 |
Further, three dichotomized variables (the lowest SpO
2, %VC, and PaO
2 with boundary values of 90%, 70%, and 70 torr, respectively) were used in the stratification, and the effects of the variables on the change in VC were evaluated with a multiple regression model. In the pirfenidone group, the coefficients of %VC and PaO
2 were significant (p-values, 0.0002 and 0.0483, respectively, see Table
4). In the placebo group, the coefficients were not significant. This seems to support the findings presented in the previous sections, namely that the most favorable response to pirfenidone relative to placebo was in patients with %VC ≥70% and SpO
2 <90 (Subgroup A). Notably, when patients were stratified using 70% as the boundary value of %VC, decline in VC was reduced in patients with %VC ≥70 after pirfenidone treatment but not after placebo treatment. In addition, although the coefficient of SpO
2 was not significant, the decline of VC in patients with SpO
2 <90% tended to be relatively small in the pirfenidone group and large in the placebo group. Accordingly, patients with %VC ≥70% and SpO
2 <90 (Subgroup A) received more benefit from pirfenidone than did other patients. For patients with PaO2 ≥70% and <70, the change in VC differed less between the pirfenidone and placebo groups as indicated by the negative signs of both regression coefficients of the dichotomized PaO
2. Therefore, it was suggested that efficacy of pirfenidone was less clear in Subgroup B than in Subgroup A.
Table 4
Effects of respiratory function tests (values dichotomized) on the change in VC in pirfenidone and placebo groups
Pirfenidone | Intercept | -0.0857 | 0.0523 | -1.64 | 0.1039 |
(n = 155) | The lowest SpO2: <90 vs ≥90 | -0.0090 | 0.0381 | -0.24 | 0.8133 |
| %VC: <70 vs ≥70 | 0.1447 | 0.0386 | 3.75 | 0.0002 |
| PaO2: <70 vs ≥70 | -0.1111 | 0.0558 | -1.99 | 0.0483 |
Placebo | Intercept | -0.1196 | 0.0923 | -1.30 | 0.1982 |
(n = 103) | The lowest SpO2: <90 vs ≥90 | 0.0628 | 0.0566 | 1.11 | 0.2701 |
| %VC: <70 vs ≥70 | 0.0302 | 0.0585 | 0.52 | 0.6067 |
| PaO2: <70 vs ≥70 | -0.0977 | 0.0878 | -1.11 | 0.2685 |
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), M. Takeuchi (Kitasato University, Tokyo, 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 the 6-minute steady-state exercise test. Also, the authors thank M. Igarashi, Y. Tsuchiya, S. Kakutani, Y. Yoshida, S. Inagaki, H. Oku, and S. Yomori (all from 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), Y. Sugiyama (Jichi 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, Mie), 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).