Respiratory Medicine CME
Volume 1, Issue 2 , Pages 75-81, 2008

Novel therapy for idiopathic pulmonary fibrosis—How to evaluate the efficacy?

Internal Medicine of Nippon Medical School, Division of Pulmonary, Infectious disease and Oncology, Tokyo, Japan

Article Outline

Summary 

As disease concepts have changed, the treatment of idiopathic interstitial pneumonias (IIPs) has become focused on idiopathic pulmonary fibrosis (IPF), which has the most adverse prognosis. Since 1998, large-scale multicenter trials have evolved, and clinical trials using novel therapeutic drugs such as interferon-γ in US and N-acetylcysteine in Europe and pirfenidone in Japan, have been organized. Most of these trials were evaluated using 1-year FVC or VC changes as the therapy endpoint, with significant differences obtained for non-progressive stage IPF. However, no significant differences were obtained in the progressive stages for any of the trials, and whether or not they contribute to improvement in life prognosis has been left to the post-market evaluation. A debate has begun in Europe and the US as to the value of assessment evaluation indicator done during activity since constant speed treadmill walking tests were introduced in the pirfenidone clinical trials carried out in Japan. Until now, therapy evaluations for IIPs have been compared using diagnostic imaging, pulmonary function tests, and pathology. In the future, therapeutic efficacy and prognosis will be discussed in terms not only of resting respiratory function evaluation, but also of systemic evaluation using exercise endurance, which is also recognized as an ADL evaluation indicator. In recent years, acute exacerbation of IPF has been the focus of global concern. A joint perspective by ATS/ERS was published, and standardized diagnosis and treatment have been provided. Acute exacerbation is an adverse prognosis factor, as are lung cancer complications, and treatments for improving life prognosis are being explored. This paper presents therapeutic drugs and treatments whose introduction is awaited, and discusses the relationship between indicators of therapy evaluation and disease concepts.

Keywords: Idiopathic pulmonary fibrosis, Interferon-γ, Pirfenidone, N-acetylcysteine, Exercise endurance test, Progression free survival interval

 

Educational aims:

•To review the therapy for Idiopathic Pulmonary Fibrosis.

•To familiarize the reader with how to Evaluate the Efficacy.

•To look at drug trials which have been carried out in Japan.

Back to Article Outline

Introduction 

Idiopathic interstitial pneumonia (IIP) is the generic name for the rare group of diseases constituting interstitial pneumonias of unknown etiology. Currently they are classified into seven different patho-morphologies. In Japan they are recognized as intractable diseases and 4400 cases have been registered (to quality for medical care subsidy, severity of PaO2<70Torr in resting state or SpO2<90% after 6-min walking).1 In the US, the number of affected individuals estimated is 83,000. Among these, idiopathic pulmonary fibrosis (IPF) is chronic and progressive, and most resistant to treatment.2 Therefore, a continuous stream of novel therapeutic drug clinical trials are being carried out in response to the continued demand for IPF therapeutic drug development. Since 1994, when nonspecific interstitial pneumonia (NSIP) was excluded as a separate disease concept,3 IPF has been seen as a treatment-resistant interstitial pneumonia. Nevertheless, based upon pathologic recognition of the inflammation as pre-existing, comparatively small-scale clinical trials have been developed according to treatment concepts focusing on immune suppression. After reporting hopeful results from interferon-γ clinical trials,4 several large-scale multicenter trials have been funded. However, due to the variability of the disease trajectory across individuals and the lack of established gold standard of success, the main endpoints for each trial differs and thus efficacy results also differ. Unfortunately, no drug has demonstrated improvement in survival, which is the desired absolute indicator of success. If there is no outcome of improved survival, issues have been raised regarding the evaluation measures of pirfenidone, which has been developed and tested in Japan. In that context, this paper assesses the future prospects of novel drug development, focusing on global IPF clinical trials.

Back to Article Outline

Progression of novel therapies for IPF 

Clinical trials of interferon-γ 

With regard to interferon-γ, which appeared to great fanfare after small-scale randomized unblinded trial results4 were reported in 1999, a large-scale randomized double blind multicenter clinical trial was carried out in North America on 330 IPF patients. The results showed no significant difference between those cases and the placebo group when comparing the main intent-to-treat (ITT) endpoint, “progression free survival interval”.5 However, an improved prognosis was suggested in non-advanced cases where %VC>55%. Meanwhile, in clinical trials carried out on IPF cases in the progressive stage, respiratory function deterioration was prevented in none of the cases,6, 7 and there were reports of confirmed exacerbated pathology accompanying IFNγ therapy.8 However, a synthesis of post-analyses of randomized IFNγ therapy results suggests the possibility of its contribution to mortality ratio reduction over the long-term prognosis9 (Table 1).

Table 1. Effect of IFN-g1b treatment in total three study
PeriodHazard ratio95% CIp
All0.4180.253–0.6900.0003
1yr0.08610.0244–0.14780.0063
1.5yr0.16820.1065–0.2299<0.0001
1.78yr0.19390.1386–0.2494<0.0001
2yr0.26520.1652–0.3652<0.0001

n=390, reduced mortality. Post-analysis synthesis of interferon-γ therapy trial.9 The possibility of contribution to lowering the long-term mortality ratio is indicated.

Based on these lessons, late phase III clinical trials on non-advanced cases were planned and carried out in Europe and the US, with a trial period of 2 years and target case number of more than 800 IPF patients and “survival ratio” as main endpoint. In particular, the trial design entailed non-progressive cases with 90%>FVC>55%, and 90%>DLco/TLC>35%.10 However, the results published in March 2007 reported it as a “negative study.” The main endpoint was changed, but ultimately the efficacy of interferon-γ was rejected.11

European trial of N-acetylcysteine (NAC) 

There is anoxidant/antioxidant imbalance in the lungs of IPF patients, and glutathione is low in the bronchoalveolar lavage fluid (BALF).12 The clinical efficacy of high-dose orally administered NAC for IPF patients was reported from Europe in 1997. Its antioxidant effect on interstitial pneumonia was noted, resulting in a pilot clinical study where NAC was administered orally 600mg three times a day for 12 weeks.13 The results showed that plasma total glutathione increased slightly from before to after NAC therapy, while BAL and epithelial lining fluid total glutathione increased demonstrably from before to after NAC therapy. Auscultatory findings confirmed a 22% reduction in crackle intensity and distribution, while breathing difficulty improved by 50%. Results of the respiratory function continue to decline during the pre-treatment observation period, with improvement seen after the 12-week NAC therapy. Based on the above results, it was reported that high-dose NAC oral therapy was an effective adjunctive therapy for IPF patients.

At the 2004 European Respiratory Society (ERS) meeting, a randomized clinical trial with prednisolone (progressive reduction starting from 0.5mg/kg/day) and azathioprine (2mg/kg/day) as the intervention arm therapy.

Overall, 184 IPF patients (155 cases available for final analysis) were divided into the NAC (internal dose of 1800mg/day) and placebo groups and compared. After 12 months, VC and DLco showed less reduction among the intervention group14 (Figure 1). However, survival was not improved.

In Japan, NAC, as a precursor of glutathione, is used as an inhaled expectorant drug for bronchial asthma and chronic bronchitis, with expectations of preventive effects for pulmonary damage caused by oxidants.

A pilot trial on NAC inhalation therapy for IPF was reported by a Ministry of Health and Welfare study group.15 Since 2005, physician-led multicenter research (part of “Clinical Research on Landmark Therapy for Idiopathic Interstitial Pneumonias” by a Ministry of Health and Welfare study group) has been carried out as the first publicly financed clinical trial in Japan, and we await the results. The subjects were those with severity degree I or II (PaO2 more than 70Torr when resting; SpO2 more than 90% after 6-min walking test) for the NAC inhalation therapy test.

Clinical trial of pirfenidone 

Based on the results of an unblinded open label trial of pirfenidone in the US,16 a phase II clinical trial was carried out in Japan starting in December 2000.17 Based on the diagnostic criteria at that time, 107 adults with “chronic idiopathic interstitial pneumonia” (IPF, under current diagnostic criteria) were studied (72 in the pirfenidone group, 35 in the placebo group). This study differed from the American clinical trial in that subjects were not advanced cases of IPF, and those on immunosuppressive drugs or steroids in excess of 10mg/day PSL equivalent units were excluded. In addition, to more sensitively and critically assess improvements in dyspnea during exertion, a unique evaluation method showing blood oxygen saturation level (minimum SpO2) improvement after 6min of constant speed treadmill walking test was employed. The conventional “6-min walking test” is highly effort-dependent. Because walking speed and walking distance change independently as respiratory function improves, it has been difficult to assess this efficacy outcome before and after therapy. However, the constant speed exercise tolerance evaluation should be able to more objectively reflect oxygen consumption for the same task volume. The remaining evaluation indicators analyzed were the same as those in the American clinical trial, but secondary endpoints were added. These were the interstitial pneumonia markers KL-6 and SP-D, often used in Japan, and acute exacerbation incidence,18 which is frequently recognized in reports from Japan.

After 6 months, the interim analysis reported five cases of acute exacerbation out of 107 (4.5%), and as all cases were skewed toward the placebo group (14.3%), based on the efficacy safety evaluation committee's report, the results were broken 9 months after the start of the trial and analysis was conducted.

For cases in which the main endpoint was completion of the 6-min constant speed walking test, the results showed a significantly higher degree of progression prevention for the pirfenidone group as compared to the placebo group, with better minimum SpO2 during the 6-min walking test both 6 and 9 months after starting administration. Further, after 6 months the minimum SpO2 during the 6-min walking test showed significant correlation with the SpO2 dropping area (Figure 2), with significant improvement shown by the pirfenidone group as compared to the placebo group.

With regard to secondary endpoints, in terms of changes in respiratory function test values, VC and TLC deterioration were significantly prevented in the pirfenidone group as compared to the placebo group both 6 and 9 months after starting administration. However, no significant differences were observed between the two groups for PaO2 changes when resting, and serum KL-6 or SP-D marker value changes. Meanwhile, although image analysis did not show the reduction or disappearance of honeycomb lung, in some cases in the pirfenidone group, the ground-glass appearance of the lung parenchyma was reduced, suggesting that pirfenidone may have an inhibiting effect on the early fibrotic stage. This was also felt to be the reason for the inhibition of exercise endurance decline.

The same as in the clinical trials conduced in the US, adverse events associated with pirfenidone administration included photosensitivity (49.3%) and digestive complaints (lack of appetite: 27.4%, gastric discomfort: 23.3%, nausea: 21.9%). However, all of these were dosage-dependent, and temporary cessation or dose reduction enabled the trial to be continued. Photosensitivity was seen in about half the cases, which highlighted the importance of advising pirfenidone patients to take sufficient care with regard to daylight exposure.

The same as the US clinical trials, the results of the phase II clinical trial carried out in Japan showed that respiratory function deterioration was inhibited, and further the frequency of acute exacerbation was reduced.

Based on these results, a phase III clinical trial was carried out with three groups. A total of 275 patients were randomly assigned to high-dose (1800mg/day) of pirfenidone group (H), low dose (1200mg/day) of pirfenidone group (L), and the placebo group (P) (H:L:P=2:1:2).19 The main endpoint was VC changes, and a key secondary endpoints progression free survival interval (definition of progression: death or 10% or greater drop in VC). Of 275 patients, 267 were included in the full analysis set (108 assigned to Group H, 55 to Group L, and 104 to Group P). Pirfenidone significantly affected the change in VC; at week 52, the difference in the adjusted mean change in VC from baseline between Group H and P was 0.07l (p=0.0416). Pirfenidone significantly affected the secondary endpoint of progression free survival: the difference between Groups H and P was statistically significant (p=0.0280, Log-rank test). The most common adverse events reported in patients treated with pirfenidone were photosensitivity in the skin and appetite loss. No significant difference in the serious adverse events was noted among three groups. The phase II and phase III studies demonstrated that pirfenidone therapy stabilized lung function and improved progression free survival in patients with IPF. With the safety and tolerability established, we conclude that pirfenidone therapy is useful for treating patients with IPF.

Beneficial role of PMX hemoperfusion therapy for acute exacerbation of IPF 

Acute exacerbation of IPF is a pathology with an extremely adverse prognosis and produces acute respiratory failure during the course of IPF. Activated neutrophilic inflammation damages the lung tissue, pathologically showing diffuse alveolar damage, and the fatality ratio is said to be as high as 80%. In recent years, global attention has focused on acute exacerbation of IPF,20 with many reports thus far from Japan,21 suggesting that the frequency differs according to race.18

When the authors experimented with polymixicin (PMX) adsorption therapy on IPF-AE patients, for whom improvement was not seen with steroid pulse and immune suppression therapies, improvement was verified for A-aDO2, and in some cases patients succeeded in coming off the respirator.22 Originally the PMX column was widely used clinically for the purpose of endotoxin adsorption.23 After the experience with these cases, PMX adsorption therapy was carried out on five cases of steroid pulse- and immune suppression-resistant acute exacerbation of IIPs. In four cases, success was achieved in the area of respiratory failure, and temporary improvement in A-aDO2 was verified in two cases.4 In all of these cases, serum endotoxins were negative, images showed infiltrative shadows with sclerotic images in both lungs as the main and most of those with P/F ratio of 300 or less manifested acute respiratory failure. Adsorption of activated neutrophils might be a possible mechanism of the column in the promising therapy for exacerbation of IPF.

Back to Article Outline

Recent trends in IPF clinical studies 

As mentioned at the beginning, the world is moving toward large-scale, multicenter (including multiple countries) in IPF clinical studies. Nonetheless, several issues remain to be overcome. The main issues are those of “diagnostic accuracy” and “disease diversity”. IPF is one of the pathological categories of IIPs, but there is a diversity of life expentancy even within the same pathomorphology disease category.

Even actual comparison of UIP and NSIP shows a poor life prognosis for cases with DLco deterioration for each pathomorphology.24 Also, it is clear that IPF cases with pulmonary hypertension complication have a poorer life prognosis than uncomplicated cases.25 In either case, the existence of prognostic factors that cannot be determined by pathomorphology alone is suggested.

It is difficult to judge statistical significance without carrying out analysis based on large-scale trials, but variation arises due to sampling because of the rarity. There is also the possibility of change in prognostic factors between the initial and progressive stages.26 The second issue is “validity of therapy evaluation indicators.” Complete recovery cannot be expected when the disease progresses, and it can be analogized to the change in brunt of therapy indicators, as when QOL evaluation was introduced as a lung cancer therapy evaluation indicator.

Overall, the speed of decline in VC predicted is gradual in the initial stages, but it becomes precipitous in the progressive stages and the chance of acute exacerbation also increases. Therefore, life prognosis also becomes poorer. The results of clinical trials in recent years show that VC and FVC percentages are much used as the best prognostic indicators. However, as can be seen from the results of massive dose NAC therapy, although a significant difference in FVC percentage was found as compared to the placebo group, no improvement in life prognosis was seen. This suggests that FVC percentage is not the only factor that contributes to improvement in survival.

In pirfenidone clinical trials carried out in Japan, it is thought that oxygen saturation minimum SpO2 during exercise endurance reflects drug efficacy, and plainly indicates the relationship between pulmonary microcirculation and oxygen consumption. As interstitial pneumonia and pulmonary fibrosis advance, the alteration in dynamic structure results in the appearance of a remarkable effect on pulmonary circulation resistance, retaining the possibility of changing prognostic factors. This kind of change in prognostic factors can occur for anyone as the disease advances, but although pulmonary circulation resistance may be an important prognostic factor from the initial stages for some patients (IPF patients with pulmonary hypertension complications), in some IPF patients it never has an effect. Because factors that depend on the host and external factors (environment, smoking, treatment, etc.) are qualified separately, life prognosis is difficult to assess based only on pathological classification and respiratory function indicators in a resting state, and it was seen that differences in minimum SpO2 during walking resulted in noticeable differences in prognosis.27, 28 In addition, even for the same IPF, a high correlation was seen between pulmonary hypertension and 6-min walking distance and minimum SpO2, and the mortality ratio was significantly high in cases of pulmonary hypertension complications.25 Further, life prognosis differed markedly depending on the existence of microthromboembolism (evaluated by increased D-dimer).29

These prognostic factors present the necessity of analysis as composite parameters in the future. In the same way as the BODE index was presented for COPD, the authors believe that it is necessary to introduce and develop useful prognosis indicators for IPF.

Back to Article Outline

Prospects for the future 

Until now, IIPs depended on pathological diagnosis classification. There is no question that IPF has the worst prognosis. However, the prognosis even for the same IPF is affected by a variety of factors (Figure 3). Currently, VC or FVC percentage is thought to be the most reliable prognosis indicator. However, FVC percentage in interstitial pneumonia complicated by the monogenic disease Hermansky–Pudlak syndrome by no means continues the same type of decrease.30 The indicators of secondary pulmonary hypertension and pulmonary microcirculation are very much implicated in “exercise endurance,” first introduced in pirfenidone clinical trials, and show the possibility of being independent prognostic factors as the disease progresses. Actually, regardless of image findings and lung capacity in a resting state, the prognosis was extremely poor in cases of reduced oxygen saturation while walking. Therefore, there is a need for indicators that provide an overall link between respiratory function and pulmonary circulation and gas exchange, hitherto difficult to evaluate, and prognosis evaluation.

  • View full-size image.
  • Figure 3. 

    IPF clinical course. Reduction in living activity accelerates as the disease progresses. Precipitous deterioration may also occur in AE-IPF. A variety of prognostic factors are involved, including inflammation, oxidative stress, pulmonary hypertension (PAH), and progression of microvascular coagulation. Composite parameters that can comprehensively evaluate these prognostic factors are required.

In fact, evaluating these indicators, not only at the time of the initial pathological diagnosis, but as they change over time, would appear to be most in line with clinical classification.

The efficacy of interferon-γ was indicated in the first small-scale clinical trials,4 but the results of a large-scale trial with 330 subjects were judged negative, with no significant statistical difference in the primary endpoint.5 With the possibility of better therapeutic efficacy in cases of VC%>55%, a further INSPIRE phase three clinical trial was carried out with 826 IPF subjects having VC%>55%. Once again no significant difference was obtained (Figure 4). From this series of trial results, it became clear that the expansion to large-scale trials completely overturned all predictions. It is not clear at this point whether or not unknown prognostic factors intervene and dilute the impact of randomization as the scale of trials grows larger. As can be seen from the walking trial analysis by Flaherty et al.26 the possibility that prognostic factors change with disease stage must be borne in mind. In the progressive stage where VC percentage dropped, the prognosis can be computed by focusing on 6-min walking distance, but the possibility that multiple indicators may define the prognosis must be taken into consideration in the non-progressive stage. The authors consider that influential prognostic factors should at least be seen as “allocated factors” for clinical trials. Then, while there is room for development of therapeutic drugs relative to each prognostic factor, intervention to prevent progression is important from an early stage.

  • View full-size image.
  • Figure 4. 

    Transition of interferon-γ clinical trials. With the introduction of large-scale trials, significant difference in main endpoint could no longer be obtained. What does this result mean? It means that there is no treatment that can improve the overall IPF prognosis. It is possible that factors influencing the prognosis effected a disequilibrium in allocation in large-scale trials. It is hoped that the analysis of effective cases will lead to the evolution of order-made therapies.

At the present time in Japan, in addition to arterial blood gas in a resting state, the higher ranked indicator used for IIPs seriousness in Japan is SpO2 decrease (<90%) during 6-min walking. It would appear necessary to start with a detailed evaluation of prognostic factors, go on to establish validity and reproducibility of indicators, and then progress to evaluate improvement in indicators for promising treatment methods.

Currently, the possibility of IPF life prognosis improvement is anticipated from the endothelin-1 inhibitor (Bosentan) being promoted in Europe and the US, not only through its inhibition of fibrosis progression, but also through its beneficial effect on pulmonary hypertension.

Back to Article Outline

Summary 

Drugs for the treatment of interstitial pneumonias continue to be developed and tested yet none has yet proven to be effective in the early stages of the disease. Outcome measures for these studies may be able to use standard imaging and pulmonary function techniques. However, once the disease has moved to the progressive stages, a different type of drug may be required to delay progression rather than prevent initial fibrosis. Outcome measures at that stage may be different and may include survival duration, slower progression in functional decline, and improved or maintained quality of life. These outcomes must be defined a priori so that comparable studies can be designed and results combined in useful meta-analyses.

CME Section 

This article has been accredited for CME learning by the European Board of Accreditation in Pneumology (EBAP). You can receive 1 CME credit by successfully answering these questions online.

(a)Visit the journal CME site at http://www.resmedcme.com.

(b)Complete the answers online, and receive your final score upon completion of the test.

(c)Should you successfully complete the test, you may download your accreditation certificate (subject to an administrative charge).

Educational questions 

Answer the following questions:

1. What factors make it difficult to study drugs for IPF?
a. Disease has several apparent subtypes
b. Patients all die before outcomes can be assessed
c. Pulmonary function results do not change significantly over time
d. The main outcomes are based on complex imaging studies
e. Progression is very slow
2. There is a clear and widely agreed upon definition of IPF
True
False
3. The 6-min walk test is the only available test for functional outcomes in clinical trials of people with
IPF?
True
False
4. It is important to develop standardized outcome measures in clinical trials to facilitate:
a. Better funding opportunities
b. Meta-analysis opportunities
c. Opportunities for new equipment to be used
d. Better collaborative opportunities
e. 2 and 4

Back to Article Outline

References 

  1. The Japanese Respiratory Society, Committee for Formulation of Diffuse Pulmonary Disease Diagnosis and Treatment Guidelines: Idiopathic Interstitial pneumonias—guide to diagnosis and treatment. Tokyo, Nankodo, 2004.
  2. American thoracic society: idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. ATS and ERS. Am J Respir Crit Care Med. 2000;161:646–664
  3. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136–147
  4. Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 1999;341(17):1264–1269
  5. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, et al. Idiopathic Pulmonary Fibrosis Study Group. A placebo–controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350(2):125–133
  6. Kalra S, Utz JP, Ryu JH. Mayo Clinic Interstitial Lung Diseases Group. Interferon gamma-1b therapy for advanced idiopathic pulmonary fibrosis. Mayo Clin Proc. 2003;78(9):1082–1087
  7. Selman M. A dark side of interferon—in the treatment of idiopathic pulmonary fibrosis?. Am J Respir Crit Care Med. 2003;167:945–946
  8. Honore I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, et al. Acute respiratory failure after interferon—therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med. 2003;167:953–957
  9. Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-g1b therapy in idiopathic pulmonary fibrosis. Chest. 2005;128:203–206
  10. 〈www.investor.intermune.com/〉, Company Announces Plans for Pivotal Phase III Trial of Actimmune in IPF. July 29, 2003.
  11. http://www.bloomberg.com/apps/news?pid=20601202&sid=ahj9UbSLuSSA&refer=healthcare
  12. Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J. 1994;7:431–436
  13. Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med. 1997;156(6):1897–1901
  14. Maurits Demedts MD, Juergen Behr MD, Roland Buhl, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229–2242
  15. Ishii Y, Kitamura S, Sugiyama Y. NAC adsorption therapy for idiopathic interstitial pneumonias: analysis of effective examples from open clinical trials. Health Science Research Specified Diseases Research Project, Diffuse Pulmonary Disease Study Group, 2000 Research report of Ministry of Health, Welfare and Labor of Japan.
  16. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med. 1999;159:1061–1069
  17. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo–controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171:1040–1047
  18. Azuma A, Hagiwara K, Kudoh S. Letter; Basis of acute exacerbation of idiopathic pulmonary fibrosis in Japanese. Am J Respir Crit Care Med xx(x). 2008;177:1397–1398
  19. Ogura T, Ebina M, Taniguchi H, Azuma A, Suga M, Taguchi Y, Pirfenidone Clinical Study Group. A Phase III, double-blind, placebo–controlled clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis in Japan. Mini-symposium (interstitial lung disease). International conference of American thoracic society (ATS2008. in Toronto, Canada), 2008, p. 5.20.
  20. Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE, et al. Idiopathic pulmonary fibrosis clinical research network investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):636–643
  21. Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest. 1993;103:1808–1812
  22. Seo Y, Abe S, Kurahara M, Okada D, Saito Y, Usuki J, et al. Beneficial effect of polymyxin B-immobilized fiber column (PMX) hemoperfusion treatment on acute exacerbation of idiopathic pulmonary fibrosis. Inter Med. 2006;45(18):1033–1038
  23. Kojika M, Sato N, Yaegashi Y, Suzuki Y, Suzuki K, Nakae H, et al. Endotoxin adsorption therapy for septic shock using polymyxin B-immobilized fibers (PMX): evaluation by high-sensitivity endotoxin assay and measurement of the cytokine production capacity. Ther Apher Dial. 2006;10(1):12–18
  24. Latsi PI, du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D, Nikolakopoulou A, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;168:531–537
  25. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746–752
  26. Flaherty KR, Andrei AC, Murray S, Fraley C, Colby TV, Travis WD, et al. Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med. 2006;174(7):803–809
  27. Lama VN, Flaherty KR, Toews GB, Colby TV, Travis WD, Long QI, et al. Prognostic Value of Desaturation during a 6-Minute Walk Test in Idiopathic Interstitial Pneumonia. Am J Respir Crit Care Med. 2003;168:1084–1090
  28. Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G. The timed walk test as a measure of severity and survival in idiopathic pulmonary fiborsis. Eur Respir J. 2005;25:96–103
  29. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005;128(3):1475–1482
  30. Gahl WA, Brantly M, Troendle J, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Padluck syndrome. Mol Genet Metab. 2002;76:234–242

PII: S1755-0017(08)00046-8

doi:10.1016/j.rmedc.2008.06.001

Respiratory Medicine CME
Volume 1, Issue 2 , Pages 75-81, 2008

Article Tools

* Image Usage & Resolution