INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Idiopathic pulmonary fibrosis (IPF), a progressive clinical syndrome generally occurring in adults over 50 yr of age, poses significant challenges in clinical management (1). The syndrome is characterized by gradual onset of dyspnea, diffuse bilateral lung infiltrates as visualized on chest roentgenography, and restrictive lung disease with an increased alveolar-arterial (resting or exercise) oxygen difference P(A-a)O₂, and a reduced carbon monoxide diffusion capacity (DL_CO). It is characterized histologically by features of usual interstitial pneumonia (UIP) that include varying degrees of alveolitis, disruption of the pulmonary vascular bed, and fibrosis of the pulmonary parenchyma (4). Mortality rates from the disease are high; median survival from diagnosis is approximately 4 yr (5, 6). There is no known curative therapy.

Previously believed to be a relatively rare disorder with a prevalence of approximately three to five cases in 100,000 individuals (7, 8), IPF is now more commonly recognized, especially in older patients (9). Although the natural history of untreated patients has not been definitively described, the clinical course generally progresses to death secondary to respiratory failure. For an individual patient, however, the course is variable and unpredictable (10). Patients are often symptomatic years prior to diagnosis, with definitive medical diagnosis and treatment beginning long after initiation of the inflammatory process in the lung. Various factors, such as younger age, early disease stage, female gender, better preserved lung function, cellular lung biopsy, or lymphocytosis in bronchoalveolar lavage at diagnosis, have been associated with a better prognosis and a favorable response to therapy with corticosteroids with or without immunosuppressive agents (6, 11). Currently available medical therapy is clearly ineffective (12) and associated with significant adverse events and morbidity (13).

The U.S. Food and Drug Administration (FDA) has permitted testing of a new antifibrotic agent in this population. Pirfenidone (Deskar; MARNAC, Inc., Dallas, TX) is a pyridone molecule [5-methyl-1-phenyl-2-(1H)-pyridone]. In hamsters, pirfenidone has been shown to ameliorate bleomycin-induced pulmonary fibrosis (14). In vitro, this compound inhibits transforming growth factor beta (TGF-)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks the mitogenic effect of profibrotic cytokines in adult human lung fibroblasts derived from patients with IPF (15). Because IPF is characterized by lung fibroblast proliferation, increased connective tissue synthesis, and desposition in the lung associated with TGF- and platelet-derived growth factor (PDGF), a clinical role for an antifibrotic agent such as pirfenidone is evident.

This report describes the results of initial Phase II testing of pirfenidone in patients with advanced IPF. The aim of the study was to evaluate the clinical usefulness and tolerability of pirfenidone in this population.

	METHODS

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Study Population

This open-label, compassionate use study enrolled consecutive adult symptomatic consenting patients referred to the University of Washington Medical Center (UWMC) between March 1995 and May 1996, with a definite diagnosis of IPF. Diagnosis of IPF was based on typical clinical and histological features of UIP confirmed by surgical lung biopsy (SLB) (4, 16). Typical clinical features included radiographic progressive pulmonary infiltrates predominantly in the basilar and peripheral zones; high-resolution computed tomography (HRCT) of the chest, features of lower lobe pulmonary fibrosis with or without traction bronchiectasis, lower lobe honeycombing without ground glass opacities, and restrictive lung defect with decreased DL_CO. Patients over age 65 with long-standing typical clinical features of progressive IPF in whom transbronchial lung biopsy (TLB) had not revealed granuloma, vasculitis, infection, or malignancy were also included (16). Patients had to have demonstrated progressive deterioration of IPF (as in endpoints described subsequently) despite therapy with prednisone with or without immunosuppressives (conventional therapy) and inability to tolerate or unwillingness to try conventional therapy. There had to be no other clinical explanation for patient deterioration. Patients were excluded if they had clinical or serological evidence for collagen vascular disease, a history of exposure to known fibrogenic agents, active infection, malignancy, hemoptysis, acute or subacute hypersensitivity pneumonitis, adult respiratory distress syndrome, requirement for mechanical ventilation, congestive heart failure, or renal or hepatic dysfunction.

Endpoints

Primary endpoints included overall survival and measurable change in lung function after 12 mo of therapy in living patients willing and able to perform repeat pulmonary function tests (PFTs). FVC, TLC, DL_CO, and oxygen saturation (resting and while walking when the patient was able to walk) were measured at baseline and during follow-up using standard criteria (17). Improvement in pulmonary function measures was defined as a 10% or greater increase in predicted value of FVC or TLC, 20% or greater increase in DL_CO, or 3% increase in oxygen saturation with the same fraction of inspired oxygen (FI_O2), resting or exertional. A decrease of similar magnitude for each measure was considered a deterioration. Patients who did not demonstrate improvement or deterioration were considered stable.

Intervention and Follow-up

Consecutive eligible patients who had refused, not tolerated, or failed conventional therapy and were willing to discontinue that therapy were approached. After obtaining informed consent, medical history and physical examination data were collected. In assessing preentry measurements, only PFTs that were obtained in a standardized and acceptable manner (17) at comparable time points were selected from data gathered from available historical records. These records were obtained from community physician offices and local hospitals. PFTs included spirometry, measurement of FVC, TLC, DL_CO, and oxygen saturation (resting and exertion if able to walk) at baseline. TLC was measured by body plethysmography and DL_CO (single-breath) was corrected for hemoglobin and not corrected for alveolar gas volume. Over a period of 15 d, oral pirfenidone was slowly increased to 40 mg/ kg/d up to a maximum of 3,600 mg/d in divided doses. Study medication was continued as long as the patient was enrolled in the study (over 2 yr for many patients). Patients were informed about anticipated side effects including nausea, abdominal discomfort, dyspepsia, fatigue, and lethargy. Adjunct immunosuppressive therapy was stopped on day 1 and prednisone was tapered over a 6- to 8-wk period at a rate of 5 mg per 5- to 7-d period. Patients were not allowed to take other concurrent medications that are currently used in the treatment of IPF (including colchicine). Oxygen supplementation was continued as needed to maintain adequate saturation ( 90%). Patients were seen in clinic weekly for 2 wk, monthly for 3 mo, and then every 3 mo. Blood chemistries and hematology were measured at each follow-up. All new symptoms other than dyspnea were recorded as adverse effects. Pulmonary function was measured in patients able to perform tests and a chest roentgenogram was obtained at baseline and quarterly. All patients were followed for survival for the duration of the study regardless of whether they continued pirfenidone or not. The study protocol and informed consent were approved by the University of Washington Human Subjects Committee.

Statistical Methods

Changes in PFTs were statistically evaluated using a one-sample t test on the difference between first and last measurement (e.g., diagnosis and study entry or study entry and last follow-up). The mean and 95% confidence interval (CI) of the mean were computed and displayed for lung function measurements. A survivorship effect on pulmonary function measures was explored by comparing baseline means for subgroups of patients grouped by the time from entry until last follow-up. Survival estimates were computed using standard Kaplan-Meier estimates with the Greenwood formula for the 95% CI for the estimate (18). SPSS (SPSS, Inc., Chicago, IL) was used for statistical tests and S-Plus (MathSoft, Seattle, WA) for graphical displays. Data were independently monitored for accuracy against original medical records.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Fifty-four patients were enrolled, 42 with confirmation of IPF by SLB, eight with diagnosis by typical clinical features of IPF (granuloma, infection, neoplasm, and vasculitis were excluded by TLB), and four by typical clinical features alone whose features included typical HRCT findings of UIP. Mean age was 62 yr, mean duration of clinical symptoms prior to entry was 4.6 yr (range 8 mo to 15 yr), and mean time since diagnosis was 3.2 yr. Most patients (n = 32) were receiving the combination of prednisone with immunosuppressives and most required oxygen supplementation (Table 1). PFTs varied greatly at entry; FVC averaged 58.8% of predicted but ranged between 26% and 108% of predicted. Similarly, DL_CO ranged between 8% and 104% of predicted, mean 34.3 (Table 2). While these patients with known IPF for several years were considered to be terminally ill based on progressive subjective and objective deterioration and estimated life expectancy of less than 18 mo, two patients had normal DL_CO measurements of greater than 80% of predicted. Although the exact reason for the apparent normal DL_CO values in these two exceptional patients is unclear, it is conceivable that these may have been the result of occult technical errors or the known lack of correlation of PFTs obtained at rest with the morphological stages of pulmonary parenchymal changes in IPF.

Forty-one of 54 patients completed the PFTs at 6 mo and 31 patients completed at 12 mo; the remainder were either dead or unable to perform tests at set intervals because of profound dyspnea. Twenty-one patients died during 25 mo of follow-up. The 1-yr survival was 78% (95% CI: 66%, 89%) and the 2-yr survival was 63% (95% CI: 50%, 76%) (Figure 1). Three patients eventually received lung transplantation after 9 mo, 11 mo, and 17 mo of follow-up and were censored from survival estimates at that time.

View larger version (11K): [in this window] [in a new window]   Figure 1.   Overall Kaplan-Meier survival curve with 95% CI.

Thirty-eight of 46 (83%) patients were able to discontinue prednisone within 2 mo after study entry. The remaining eight were able to decrease their daily dose of prednisone to 10 to 15 mg. All 32 patients who were taking immunosuppressives tolerated discontinuation of the immunosuppressive therapy at study entry.

Review of available historical data revealed that full PFTs (FVC, TLC, DL_CO, O₂ saturation) were not obtained in a standardized manner for all patients at diagnosis. Of the available PFTs that were performed in an acceptable and standardized manner (17), the individual measurements were at varying time points. Therefore, comparable and acceptable PFTs were not available for all patients during the preenrollment period. The preentry data shown in Figures 2-4 have variable numbers of available measures as expected given the inevitable difficulties of collecting appropriate historical data. Mean FVC and TLC, which decreased significantly between diagnosis and entry, stabilized after entry into the study (Figures 2 and 3). Insufficient data for DL_CO measurements during preenrollment prevented a meaningful comparison between diagnosis and study entry time points. However, DL_CO did appear to stabilize after study entry (Figure 4). The apparent increasing trend of PFT measures in Figures 2-4 is likely due to a survivorship effect. Figure 5 demonstrates that patients who have FVC data available at later follow-up visits generally had higher FVC values at study entry. TLC and DL_CO measures also demonstrated similar apparent survivorship effects.

View larger version (10K): [in this window] [in a new window]   Figure 2.   Mean FVC with pointwise 95% CI for n available measures.

View larger version (10K): [in this window] [in a new window]   Figure 3.   Mean TLC with pointwise 95% CI for n available measures.

View larger version (9K): [in this window] [in a new window]   Figure 4.   Mean diffusing capacity with pointwise 95% CI for n available measures.

View larger version (13K): [in this window] [in a new window]   Figure 5.   Survivorship effect demonstrated by mean FVC stratified by amount of available follow-up information.

Oxygen saturation during exertion as well as requirement for supplemental oxygen remained stable during the first 12 mo of follow-up (Figures 6A and 6B). In addition, three patients were able to discontinue supplemental oxygen use entirely without experiencing oxygen desaturation, one of whom became entirely asymptomatic 9 mo after initiation of pirfenidone and has remained so 28 mo later.

View larger version (13K): [in this window] [in a new window]   Figure 6.   (A) Mean oxygen saturation (peak exertion) with pointwise 95% CI. (B) Mean additional oxygen requirement with pointwise 95% CI.

At 6 mo, 29 patients demonstrated stabilized or improved lung function by FVC; 12 deteriorated. Seventeen had stabilized or improved TLC whereas seven deteriorated. Twenty-five patients had stabilized or improved DL_CO and six deteriorated. Six patients, however, had died prior to the 6-mo follow-up and PFTs were not available on a considerable number (Table 3). At 1 yr, 22 demonstrated stabilized or improved FVC and nine deteriorated; 15 stabilized or improved TLC and eight deteriorated; 20 stabilized or improved DL_CO and seven deteriorated. By that time 12 patients had died and one had undergone lung transplantation.

Analysis of factors associated with survival indicated that patients with percentage of predicted DL_CO levels less than 30% predicted (Figure 7) and advanced age (> 65 yr) were associated with decreased survival. Male gender was also moderately associated with decreased survival in Cox regression models that included DL_CO and age covariates. Other PFTs were not found to be associated with survival time. A patient's smoking history was also not found to be a significant predictor of survival (data not shown) when other important factors (age, DL_CO at entry, and gender) were examined in this advanced disease patient population. There were no improvements noted in chest radiographs during the follow-up period.

View larger version (11K): [in this window] [in a new window]   Figure 7.   Kaplan-Meier survival curve stratified by DLCO.

Gastrointestinal adverse symptoms were relatively common with 44% of patients reporting nausea (Table 4). Only two patients, however, experienced symptoms severe enough to warrant discontinuation of the drug. For most, use of over-the-counter antacids relieved the symptoms. Photosensitive skin rash was experienced by 24% of patients; four of them (8%) discontinued pirfenidone because of this rash. In all cases, the rash subsided upon discontinuation of the drug and no permanent sequelae were observed. Fatigue was noted by 42% of patients. This subsided with a decreased dosage and with reminder to take the medication with food and liquid. Fatigue did not result in any patients discontinuing the drug. There were no adverse events noted in hematology or blood chemistry.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Pirfenidone is a new investigational antifibrotic agent that, prior to this study, had never been used in a clinical setting. This Phase II, open-label study evaluated pirfenidone prospectively in 54 consecutive, terminally ill patients with advanced IPF. As a compassionate use protocol, the study enrolled terminally ill patients regardless of how ill or physically limited they were at the time of enrollment. In this limited number of deteriorating patients with IPF who had failed or not tolerated conventional therapy, treatment with pirfenidone arrested further decline in the majority and improved oxygenation in a few patients. The drug was well tolerated with minimal side effects which promptly subsided after discontinuation of the drug or decrease in dosage; there were no permanent sequelae to side effects. Pirfenidone did not result in any blood count or blood chemistry abnormalities. Further, treatment with pirfenidone allowed discontinuation or tapering of prednisone and immunosuppressive therapy without further loss of lung function.

The results from this single group study are encouraging but not definitive. When compared with other reports of the natural history of IPF and survival rates for patients treated with conventional therapy (1, 5, 6, 11, 19, 20), the 22% 1-yr mortality and 37% 2-yr mortality observed among this terminally ill cohort is encouraging. It is conceivable that the patients entered into this study were among a minority of IPF patients who survive regardless of therapy. All of the patients in this cohort, however, had demonstrated progressive deterioration prior to enrollment or not tolerated conventional therapy, and 46 had tried adequate conventional therapy. The lack of appropriate controls, inconsistent historical data, and the small number of patients in this study is insufficient to accurately identify general improvement of pirfenidone on lung function. Upon initiation of pirfenidone and discontinuation of conventional therapy, however, measures of PFTs appeared to stabilize. Changes in measurements of PFTs at the end of 1 yr have been documented to predict long-term survival in this population (21, 22). Thus, the observed stabilization of lung function in this study is encouraging. Analysis of predictors of survival identified DL_CO, age, and gender to be associated with survival in this population. Female gender, relatively young age, and higher static PFTs at diagnosis have been associated with enhanced survival and response to therapy (21, 22). Perhaps of particular importance is that pirfenidone may stabilize the DL_CO measure, which in turn is predictive of a patient's survival. Further studies are necessary to establish any direct effect of pirfenidone on survival.

Current therapies focus on suppressing the inflammatory process. Corticosteroids are most commonly prescribed, although a measurable favorable response is reported in only 23% of patients (6). This may be because most patients with IPF have had the disease for an extended period, long after the initiation of the inflammatory process. Thus, most patients in current clinical practice are in the fibroproliferative phase and not the early inflammatory stage, justifying a clinical role for antifibrotic agents.

Prospective randomized clinical trials have been limited by the relatively low prevalence of the disease, its unpredictable course, and the adverse effect profile of currently available therapies. Data supporting the long-term use of corticosteroids is based primarily on retrospective, uncontrolled trials (23). More recently this drug has been combined with a second immunosuppressive agent such as azathioprine or cyclophosphamide in an attempt to use lower doses of prednisone while increasing the immunosuppressive effect of therapy. A randomized comparison of prednisone alone to the combination of prednisone and azathioprine (19) showed a benefit on survival for the combined therapy after 3 yr of follow-up. During the first year of therapy, however, there appeared to be no discernible difference. In another study comparing prednisolone alone to prednisolone in combination with cyclophosphamide, there was no difference in the therapeutic response between these two therapies (20). Significant side effects were associated with cyclophosphamide, resulting in discontinuation of therapy. The significant adverse effects associated with use of corticosteroids and immunosuppressive agents contribute to additional morbidity in these patients (13).

Recent National Institutes of Health sponsored workshops have reviewed available treatment modalities for IPF and concluded that current therapies are ineffective. They recommended development and testing, in randomized trials, of new therapeutics for IPF (12, 26). Further, the committee recommended that treatment strategies be based on evolving knowledge of the fibrotic process in addition to the inflammatory process because most cases are detected in later stages of the disease when fibrosis has already set in.

More recent research has shed light into the fibroblast proliferation and connective tissue synthesis by profibrotic cytokines implicated in the pathogenesis of pulmonary fibrosis (27). In vitro studies have shown that fibroblast cultures from inflammatory lung tissue can be stimulated with PDGF or serum so that they grow at a faster rate (28). The rationale to use antifibrotic agents is, thus, based on the well-known lung fibroblast proliferation associated with increased collagen synthesis and deposition of extracellular matrix components in the fibrotic human lung (27).

Currently available antifibrotic agents include colchicine, D-penicillamine, and interferon. In a recent prospective study of a small number of patients with IPF, colchicine failed to demonstrate a significant difference in the rate of decline in lung function or mortality between the colchicine group and the control group that received prednisone (31). D-penicillamine interferes with collagen cross-linking in vitro. Retrospective studies of the efficacy of D-penicillamine have showed no significant benefit for this therapy and the drug is associated with significant adverse effects (25). -interferon has been demonstrated to inhibit lung fibroblast proliferation and collagen synthesis (32). It has not been used, however, in IPF.

It has been suggested that IPF should be divided into UIP and other disorders such as nonspecific interstitial pneumonia (NSIP) (4, 33). Clinically, these two entities might be differentiated by patient age with UIP patients presenting in the sixth or later decade of life compared with a generally younger age group of patients diagnosed with NSIP. This younger cohort appears to respond better to steroid therapy than older patients with UIP. The effect of pirfenidone may have been blunted by the relative efficacy in younger patients presenting with NSIP. All 12 of the 54 patients (22%) who were younger than 55 yr of age, however, had SLB evidence of UIP. Whether there is a differential effect of pirfenidone in younger patients compared with older or UIP versus NSIP cannot be discerned from this study.

IPF is a relentless progressive disorder. First described as a fulminating case in 1933, this clinical syndrome remains fatal without effective medical therapy either to alleviate the symptoms or to improve the outcome. Corticosteroids with or without adjunct immunosuppressive regimen, although considered conventional therapy, is nonspecific, associated with significant adverse effects and poor quality of life, and response rates are only 20 to 30%. Lung transplantation is an option only for selected patients with IPF who are generally under 60 to 65 yr of age. In addition, it is associated with significant complications and the survival rates are approximately 70% at 1 yr and 50% at 5 yr,* which warrants the need for new treatment with antifibrotic agents. Currently available antifibrotics such as colchicine appear to be well tolerated but their efficacy remains to be determined. Future therapeutic strategies should continue to be based on the pathogenesis of pulmonary fibrosis, for example, looking at the effectiveness of antioxidants, cytokine inhibitors, surfactants, or other antifibrotic agents (12). In this Phase II trial, pirfenidone has shown promise despite a survivorship effect in halting the clinical decline and in reducing mortality in patients with advanced IPF. Future IPF-related clinical studies should, however, take into consideration the inherent bias associated with survivorship effect in analyzing PFTs and other objective measurements. In addition, future clinical trials investigating the efficacy of any medical regimen for IPF must be prospective, randomized, controlled, preferably double-blinded, and enroll patients early in the disease course. Such efficacy studies must enroll extremely well-defined patient populations and will require enrollment of a sufficiently large number of patients to draw definitive conclusions. Only carefully designed and well-conducted multicenter clinical trials can accomplish this. Without the joint, collaborative and concerted efforts of clinicians, patients, government, and industry, the efficacy of new treatment regimens for IPF will not be documented. Considering the high mortality rates associated with IPF and evolving clinical knowledge regarding monitoring clinical status, appropriate efficacy endpoints for such trials should include outcome measures at least at the end of 1 yr of change in static pulmonary function, oxygenation, HRCT findings, quality of life, and survival.

Pirfenidone appears to be a promising new antifibrotic drug for the treatment of IPF that deserves a well-designed randomized controlled clinical trial to adequately test the efficacy and safety of this new agent. Because patients with higher DL_CO (> 30% predicted value) at entry were associated with longer survival in this study, future trials of pirfenidone and other antifibrotic agents should focus on early treatment periods before DL_CO levels seriously decrease. Hopefully, ongoing clinical trials will document the efficacy of antifibrotic agents such as pirfenidone in IPF patients.