American Journal of Respiratory and Critical Care Medicine

Rationale: An efficacious medical therapy for idiopathic pulmonary fibrosis (IPF) remains elusive.

Objectives: To explore the efficacy and safety of etanercept in the treatment of IPF.

Methods: This was a randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically progressive IPF. Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin (DlCOHb) and change in the alveolar to arterial oxygen pressure difference P(a–a)O2 at rest from baseline over 48 weeks.

Measurements and Main Results: Eighty-eight subjects received subcutaneous etanercept (25 mg) or placebo twice weekly as their sole treatment for IPF. No differences in baseline demographics and disease status were detected between treatment groups; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9% of predicted. At 48 weeks, no significant differences in efficacy endpoints were observed between the groups. A nonsignificant reduction in disease progression was seen in several physiologic, functional, and quality-of-life endpoints among subjects receiving etanercept. There was no difference in adverse events between treatment groups.

Conclusions: In this exploratory study in patients with clinically progressive IPF, etanercept was well tolerated. Although there were no differences in the predefined endpoints, a decreased rate of disease progression was observed on several measures. Further evaluation of TNF antagonists in the treatment of IPF may be warranted.

Clinical trial registered with (NCT 00063869).

Scientific Knowledge on the Subject

There is no known effective therapy for the treatment of idiopathic pulmonary fibrosis.

What This Study Adds to the Field

Although the TNF-α blocking agent, etanercept, was well tolerated, there were no differences in the predefined endpoints among patients with idiopathic pulmonary fibrosis who received etanercept or placebo.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal fibrotic lung disease of unknown etiology (1, 2) affecting up to 16 per 100,000 individuals (3). It is clinically characterized by shortened survival, declining pulmonary physiology, loss of functional status, and poor quality of life (QOL). It is a disease of older adults and afflicts individuals older than 50 years, with an increasing prevalence with advancing age. Increased awareness and routine use of high-resolution chest computed tomography (HRCT) scans has facilitated diagnosis of the disease (46).

Combination therapy with corticosteroids and cytotoxic drugs such as azathioprine is the conventional treatment for patients with IPF (1). However, the efficacy of this regimen has yet to be shown in prospective, true placebo-controlled trials. In fact, no efficacious medical treatment regimen has been shown to improve survival, physiologic outcome, or QOL compared with patients with IPF monitored without any treatment for the disease. This need for “true” placebo-controlled trials (i.e., patients receive no medications that potentially modulate pulmonary fibrosis) in patients with IPF has been recently emphasized (79).

Elevated levels of tumor necrosis factor (TNF)-α, a cytokine with inflammatory and fibrogenic properties, have been detected in the lungs of animals in experimental models of pulmonary fibrosis (1012), and in patients with IPF (13, 14). A fibrosing alveolitis develops in transgenic mice expressing high TNF-α levels in their lungs (15), and adenoviral transfer of TNF-α complementary DNA (cDNA) to lungs of normal adult rats results in the increased transforming growth factor (TGF)-β expression followed by the development of fibrosis (16). Furthermore, in animal models of pulmonary fibrosis, TNF antagonists inhibit pulmonary inflammation and fibrosis (17), suggesting that such agents could potentially diminish the fibrotic response in the lungs of patients with IPF.

Etanercept, a recombinant soluble human TNF receptor (18), which binds to TNF and neutralizes its activity in vitro (18), is indicated for the treatment of rheumatoid arthritis (1921), ankylosing spondylitis (2225), psoriatic arthritis (26, 27), and psoriasis (28, 29), and has been widely used in clinical practice. To investigate the potential efficacy of etanercept as therapy for IPF, a double-blind, multicenter exploratory clinical trial was conducted. In this study, the use of concomitant IPF medication was strictly excluded. To our knowledge, this is the first reported prospective study of IPF to include a true placebo group. Some of the results of this study have been previously reported in abstracts (3032).

Study Design

A 48-week, randomized, double-blind, placebo-controlled, multicenter, phase 2 exploratory study evaluated the potential for efficacy and assessed the safety of subcutaneous etanercept 25 mg twice weekly in subjects who met the diagnostic criteria set out in the joint American Thoracic Society/European Respiratory Society consensus statement for the diagnosis of IPF (1).

The study was conducted in accordance with the Declaration of Helsinki and is consistent with Good Clinical Practice Guidelines. The protocol and informed consent documents were approved by each institution's review board or an independent ethics committee.

Patients with IPF (1) diagnosed within 2 years of screening were eligible for enrollment if they had experienced measurable progression of dyspnea and either progressive fibrosis on chest radiograph or no improvement in lung function, despite standard-of-care therapy during the 24 months before screening. Standard-of-care therapy included corticosteroids, azathioprine, cyclophosphamide, methotrexate, colchicine, oxygen, N-acetyl cysteine, experimental agents, or no therapy, at the discretion of the physician (1). No improvement in lung function was defined as any of the following: 10% or less improvement in percentage of predicted values in FVC, 15% or less improvement in values in the diffusing capacity for carbon monoxide of lung corrected for hemoglobin (DlCOHb), or a 10-mm Hg worsening in the alveolar-arterial Po2 difference P(a–a)O2 with or without exertion (1). Concomitant treatment with any medications for IPF, including standard-of-care or experimental treatment for IPF was not allowed during the study period. Patients stopped taking all medications for the treatment of IPF, including corticosteroids for a minimum of 4 weeks before enrollment. In the event of an acute respiratory decompensation necessitating hospitalization, the use of short course (<10 d) corticosteroids were allowed at the discretion of the treating clinician.

Patients with severe physiologic impairment (FVC < 45% predicted, DlCOHb < 25% predicted, or PaO2 < 55 mm Hg [room air] or SaO2 < 88% [room air] at rest) were ineligible. Other exclusion criteria included previous treatment with a TNF antagonist such as etanercept or infliximab, clinically significant comorbid diseases, or a history of any rheumatologic disease (33).

Endpoints and Assessments

The primary endpoints were changes from baseline in FVC% predicted, DlCOHb % predicted, and P(a–a)O2 (at rest), at Week 48. Percentages of predicted normal values were calculated according to the nomogram by Crapo and colleagues (34). Secondary endpoints included overall mortality, TLC% predicted, SaO2 at rest while breathing room air, six-minute-walk distance (6MWD), QOL indices, change in dyspnea index, and radiographic progression. Dyspnea was assessed using the Mahler dyspnea scale, and QOL was assessed using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the St. George's Respiratory Questionnaire (SGRQ) (35). The effect of etanercept on radiographic progression was assessed using HRCT. The mean change from baseline in HRCT data at Week 48 or early termination was assessed for five image patterns: ground-glass attenuation, reticulation, honeycombing, emphysema, and micronodules. Digitized HRCT images were read in a blinded manner by a central reader at Synarc (Sèvres, France) who compared images from the two visits using a method of scoring that was adapted from Lynch and coworkers (36) and was based on the presence and extent of abnormalities. The extent of the abnormalities are determined for each slice and each lung (right and left) using a 5-point scale, where 0 = no involvement, 1 = 1 to 25% involvement, 2 = 26 to 50% involvement, 3 = 51 to 75% involvement, and 4 = 76 to 100% involvement.

Evaluation of all primary and secondary variables was made at baseline and at Weeks 4, 12, 24, 36, and 48 (or last visit) except for HRCT scanning, which was performed at baseline and the end of the study.

The safety profile was assessed based on reports of adverse events (AEs), medically important infections, routine physical examinations, and laboratory determinations. Medically important infections were prospectively defined as those that required hospitalization or treatment with a parenteral antimicrobial agent. Treatment-emergent AEs were AEs not present at baseline or, if present, those that worsened during the study. AEs were considered serious (SAEs) if they were life threatening, required hospitalization or prolongation of hospitalization, or resulted in cancer, congenital anomaly, or death.

Statistical Methods

An analysis of covariance (ANCOVA) model, with treatment as a factor and baseline measurements as covariates, determined within- and between-group differences. The paired t test was used for within-group comparison of the raw changes from baseline. The adjusted means and the P values are reported for between-group comparisons. The last observation carried forward approach was used to account for missing data points in the modified intent-to-treat population (all patients who received at least 1 dose of study drug). Hochberg's procedure was used to control type I error at 0.05% (37)—that is, the null hypothesis of no treatment effect was to be rejected if all three primary endpoints were significant at α < 0.05, any two of the three endpoints were significant at α < 0.025, or any one of the three primary endpoints was significant at α < 0.0167.

For this exploratory study, a sample size of 35 patients per arm was determined based on a preliminary report by Ziesche and colleagues (38). For each of the three primary efficacy variables, assuming a standard deviation (SD) of 25%, the study had approximately 80% power to detect a difference of 17.0% between the etanercept and placebo groups with a two-sided test at the 0.05 significance level.

Secondary endpoints and safety assessments were analyzed using the Fisher exact test, analysis of variance, or ANCOVA, as appropriate. HRCT data were analyzed using χ2 tests.

Study Subjects

Of 88 subjects randomly assigned, 87 received at least one dose of study medication during the period between February 2003 and March 2005. Baseline demographic data and safety outcomes are summarized for these 87 subjects. Before unblinding, two patients were excluded from the study because of Good Clinical Practice issues related to study conduct at one site; data from 85 patients are included in the efficacy analyses presented. The study population was predominantly male and white with a mean age of 65.2 years. Treatment groups were well balanced with respect to demographic and baseline disease severity characteristics (Table 1).



Etanercept (n = 46)

Placebo (n = 41)
Age, yr, mean (SD)65.2 (7.7)65.1 (7.1)
Male, n (%)35 (76.1)24 (58.5)
Weight, kg, mean (SD)86.5 (16.1)82.9 (13.9)
Disease duration, mo, mean (SD)14.7 (19.8)12.3 (13.6)
Surgical biopsy, n2823
FVC % predicted, mean (SD)64.7 (14.1)63.0 (12.7)
DlCOHb, % predicted, mean (SD)36.3 (12.6)36.9 (10.8)
P(a–a)O2, mm Hg, mean (SD)22.7 (12.6)*26.7 (12.0)
TLC predicted, %, mean (SD)62.2 (11.9)61.1 (12.7)
Mean distance for 6MWD, m, mean (SD)397.3 (108.0)396.8 (136.8)
SF-36 physical component summary score, mean (SD)36.6 (11.1)37.9 (10.3)
SF-36 mental component summary score, mean (SD)54.3 (9.3)48.9 (12.0)
SGRQ total score, mean (SD)40.8 (18.1)*42.9 (19.4)*
Mahler dyspnea index, functional impairment work2.8 (1.0)2.4 (0.9)
Mahler dyspnea index, magnitude of task2.4 (0.9)2.0 (0.8)
Mahler dyspnea index, magnitude of effort
2.3 (1.0)
2.1 (0.9)

Definition of abbreviations: DlCOHb = diffusing capacity of lung for carbon monoxide corrected for hemoglobin; P(a–a)O2 = alveolar-arterial Po2 difference; SF-36 = Short-Form 36; SGRQ = St. George's Respiratory Questionnaire; 6MWD = six-minute-walk distance.

*n = 45 for etanercept and n = 40 for placebo due to missing baseline data for one subject each.

P < 0.022 versus etanercept.

Sixty-five patients (etanercept, n = 34; placebo, n = 31) completed the 48 weeks of treatment; 12 (26%) who received etanercept and 10 (24%) who received placebo discontinued the study (Table 2). Primary reasons and the time course for withdrawal were similar between the groups. Fifteen (33%) patients receiving etanercept and 12 (29%) receiving placebo received brief periods of systemic corticosteroids during the study as permitted for acute respiratory symptoms per the protocol.



Etanercept (n = 46)

Placebo (n = 41)

P Value*
Any reason12 (26.1)10 (24.4)1.00
Adverse event7 (15.2)4 (9.8)0.53
Death1 (2.2)1 (2.4)1.00
Other nonmedical event1 (2.2)1 (2.4)1.00
Protocol violation01 (2.4)0.47
Unsatisfactory response-efficacy
3 (6.5)
3 (7.3)

*Overall P value: Fisher exact test P value (two-tail).

Efficacy Assessment

For all three primary efficacy variables, change in FVC% predicted, DlCOHb % predicted, and P(a – a)O2 (at rest) from baseline to the final visit (Week 48), there was no statistically significant difference between treatment groups (Figures 1A–1C).

Subjects in the etanercept group showed a tendency toward reduced disease progression in multiple physiologic and functional endpoints (Figure 1). At 48 weeks, after adjustment for baseline values, although not statistically significant (P = 0.1044), the difference in FVC% predicted between groups favored etanercept. Similarly, DlCOHb % predicted and P(a – a)o2 also favored etanercept (Figure 1).

At 48 weeks of follow-up, patients in the etanercept group experienced a mean decline of 0.1 (SD, 0.3) L from baseline actual FVC, compared with a mean decline of 0.2 (SD, 0.3) L experienced by patients in the placebo group (P = 0.1076). Patients in the etanercept group experienced a mean decline of 0.9 (SD, 2.6) ml/min/mm Hg from baseline in absolute measures of DlCOHb, compared with a mean decline of 1.7 (SD, 2.9) ml/min/mm Hg experienced by patients in the placebo group (P = 0.1577). TLC % predicted declined in both groups, as did oxygen saturation (Figure 1). At Week 48, patients in the etanercept group showed a reduced decline in both of these endpoints, although neither was statistically significant (Figure 1).

In the six-minute-walk test, patients in the etanercept group experienced a mean increase of 0.2 (SD, 95.8) m in the distance covered from baseline compared with a mean decline of 14.7 (SD, 112.5) m experienced by patients in the placebo group (P = 0.494) at Week 48. Mean increases at Weeks 12, 24, and 36 were 6.4 (SD, 92.9), 0.4 (SD, 95.4), and −6.6 (SD, 101.1), respectively, for patients in the etanercept group and −2.2 (SD, 65.8), 2.1 (SD, 71.7), and −22.3 (SD, 106.8), respectively, for the placebo group. Between-group differences at all three time points were not statistically significant.

There was no difference between groups in the degree of functional impairment due to dyspnea as assessed by change in the Mahler Dyspnea Scale from baseline to 48 weeks. No significant differences in the change from baseline scores were observed in any of the HCRT image patterns, or in the total scores for the five components (Table 3).


Change from Baseline % (SD)

Etanercept (n = 45)
Placebo (n = 40)
Adjusted Treatment Difference, Mean (SE)
P Value between Groups
Ground-glass attenuation−0.5 (3.6)−0.3 (3.2)0.2 (0.8)0.826
Reticulation1.2 (2.3)1.0 (3.3)0.1 (0.7)0.834
Honeycombing0.3 (1.8)0.6 (1.5)0.3 (0.4)0.480
Emphysema−0.1 (0.6)0.1 (0.3)0.2 (0.1)0.143
Micronodules−0.1 (1.1)0.6 (1.1)0.5 (0.3)0.082
Total score
0.8 (3.3)
1.9 (3.1)
1.1 (0.8)

For both of the QOL endpoints, the SF-36 and the SGRQ, none of the between-group differences in the domain-specific or summary scores achieved statistical significance.

Post Hoc Analyses

The results from a post hoc analysis of death or disease progression (≥10% decline in FVC [L]) are presented in a Kaplan-Meier plot (P = 0.136 using the log-rank test; Figure 2). Events were censored 14 days after the last dose date. At 48 weeks, 55.0% of placebo-treated patients and 33.3% of etanercept-treated patients met the endpoint of death or disease progression (P = 0.052) using a two-sided Fisher exact test.

Correlation between Lung Function, Functional Status, and Health Outcomes

Change in the SGRQ scores correlated well with change in the FVC (L) (correlation coefficient, −0.52; P < 0.0001). Similarly, change in the physical component scores of the SF-36 also correlated well with change in FVC (r = 0.43, P < 0.0001). Change in the 6MWD also correlated well with change in QOL as measured by both the SGRQ (r = −0.48, P < 0.0001) and the SF-36 (r = 0.34, P < 0.0001). In general, the mental component of the SF-36 correlated to a lesser degree with both FVC (L) and 6MWD.

In Table 4, mean changes in QOL scores over the treatment period are compared between subjects (regardless of treatment arm) with and without a 10% or greater decline in FVC (L) (n = 37 and n = 48, respectively). Subjects with a 10% or greater decline in FVC (L) also experienced a statistically and clinically significant decline in QOL when compared with subjects without the decline.


QOL Domain

Subjects with ≥10% Decline in FVC

All Other Subjects

P Value*
Change in SGRQ overall scores13.70−0.58<0.001
Change in SF-36 scores
 Physical component−6.920.69<0.001
 Mental component

Definition of abbreviations: QOL = quality of life; SF-36 = Short-Form 36; SGRQ = St. George's Respiratory Questionnaire.

*Unpaired t test, two-tailed.

Safety Assessments

Overall, the rates of infectious and noninfectious AEs were similar between treatment groups with the exception of injection site reactions, which were more frequent in the etanercept group than in the control group (63 vs. 15 events, respectively; P < 0.001). Treatment-emergent AEs, including infections reported by 10% or more of patients in either treatment group are presented in Table 5.


Adverse Event

Etanercept (n = 46)

Placebo (n = 41)
Any noninfectious event
 Total*42 (91.3)37 (90.2)
 Cough increase17 (37.0)16 (39.0)
 Dyspnea12 (26.1)11 (26.8)
 Asthenia8 (17.4)11 (26.8)
 Headache7 (15.2)11 (26.8)
 Rhinitis11 (23.9)8 (19.5)
 Back pain9 (19.6)6 (14.6)
 Arthralgia7 (15.2)8 (19.5)
 Pain8 (17.4)5 (12.2)
 Rash8 (17.4)5 (12.2)
 Chest pain4 (8.7)6 (14.6)
 Accidental injury3 (6.5)6 (14.6)
 Diarrhea4 (8.7)6 (14.6)
 Injection site hemorrhage6 (13.0)4 (9.8)
 Myalgia1 (2.2)6 (14.6)
Any infectious event
 Total29 (63.0)28 (68.3)
 Upper respiratory infection15 (32.6)13 (31.7)
 Bronchitis10 (21.7)11 (26.8)
4 (8.7)
8 (19.5)

*Excluding injection site reactions.

P < 0.05.

Serious AEs occurred at similar rates between the two treatment groups; 12 patients receiving etanercept and 10 receiving placebo experienced SAEs. Withdrawals because of AEs (7 in the etanercept group and 3 in the placebo group) were not significantly different. Medically important infections occurred in four patients receiving etanercept and six patients receiving placebo. The respiratory system was involved with the largest number of medically important infections: two in the etanercept group and five in the placebo group.

National Cancer Institute grade 3 and 4 laboratory abnormalities (39) reported included the following: one grade 3 case and one grade 4 case of hypokalemia were reported by patients receiving placebo, and one case of grade 3 lymphocytopenia and one case of grade 3 neutropenia, resulting in study withdrawal, were reported in the etanercept group.

Six patients died during the study, four in the etanercept group and two in the placebo group (P = 0.41) (Table 6). Two of the six patients, one in each group, withdrew prematurely because of “unsatisfactory response” and subsequently died during the study follow-up period. None of the deaths in either group was considered by the investigator to be related to use of the study drug.




No. of Days on Therapy

No. of Days between Therapy Discontinuation and Death

Etanercept76/M5317Pulmonary fibrosis, idiopoathic pulmonary  fibrosis progression
Etanercept70/M27221Cardiac arrest
Etanercept56/M1133Dyspnea, pulmonary fibrosis, pneumonia, kidney failure, respiratory distress syndrome/acute respiratory distress syndrome, sepsis
Etanercept75/M2588Empyema, syncope
Pulmonary fibrosis

This exploratory study evaluated the tolerability and the potential therapeutic benefit of etanercept, a TNF-α blocking agent, in the treatment of patients with progressive IPF. This is the first prospective, true placebo-controlled trial in which all other treatments for IPF were disallowed in all patients during the study period. Because this study included only a modest number of subjects, it was not altogether surprising that there were no statistically significant differences between treatment groups in the three primary endpoints: changes in FVC% predicted, DlCOHb% predicted, and the P(a–a)O2 (at rest) at 48 weeks. On the basis of the observed means and pooled SD, a 3.5-fold greater sample size would have been required for the between-group differences observed in this study to be statistically significant. Etanercept was well tolerated with no unexpected safety findings in this population of older patients.

During the 48 weeks of the trial, almost 25% of patients withdrew from the study, which is similar to the dropout rates seen in the IFIGENIA (40) and BUILD-1 trials (41) and seems to be an intrinsic issue inherent to long-term IPF trials. The numbers of patients and reasons were similar between the two groups. Efficacy results analyzed by the least observation carried forward approach were similar to the observed data analysis (data not shown).

Although the primary efficacy endpoints for this study were continuous measures of lung function and oxygenation, during the period in which this study was conducted (February 2003 to March 2005) a number of reports proposed that a 10% decline in the FVC (L) represents clinically relevant progression, and that patients with IPF who experience this decline are at increased risk of death (4244). On the basis of these data, it has been proposed that agents that prevent a 10% or more decline in absolute measurements of FVC might ultimately prevent mortality among patients with IPF. In post hoc analyses, using rate of disease progression by death or absolute reduction in FVC (L), a statistically nonsignificant difference favoring etanercept was observed.

More recent evidence suggests that risk of death in patients with IPF may be associated with acute rather than a gradual decline in pulmonary function (acute exacerbations) (45). However, because these reports were published after our study was in progress, the study design had no prespecified definition for acute exacerbation and did not require that investigators record evidence regarding exacerbation. Investigators were therefore not explicitly asked if death was a result of IPF exacerbation.

Additional post hoc analyses examined the relationship between change in FVC and measures of patients' functional status (6MWD) and QOL independent of treatment assignment. Although data generated from post hoc analyses should be interpreted with caution, the results provide further insights for the concept that a 10% or greater decline in absolute measures of FVC represents clinically relevant disease progression in patients with IPF and such hypotheses need to be tested in future studies (46).

Consistent with the lack of treatment effect demonstrated on lung function endpoints, no significant between-group difference was detected for the 6MWD endpoint. These results may be due, in part, to intrinsic problems inherent to the variables measured during a 6MWD test in this population (47). In addition, it is likely that changes in 6MWD test indices are dependent on other factors in addition to change in pulmonary function status, including effects of rehabilitation, mood changes, musculoskeletal and other comorbid factors that might have a ceiling effect in patients' ability to walk. The large SD seen both at baseline and Week 48 (as well as Weeks 4, 12, 24, and 36) in this study and in the BUILD-1 trial (41) may be another factor limiting our ability to detect a statistical significant effect.

The safety profile for etanercept was consistent with previous etanercept trials in other disease states; injection site reactions were reported more often in the etanercept group than in the placebo group. Treatment-emergent AEs and infections were reported by similar numbers of patients in the two treatment groups. Withdrawals from the study because of an AE or an SAE (including serious infections) were similar between treatment groups. Worsening of interstitial lung disease in association with anti–TNF therapy has been previously reported especially in rheumatoid arthritis (48, 49); no cases of worsening of IPF were attributed to etanercept therapy in this study.

In most, if not all, other prospective “placebo-controlled” studies in patients with IPF, the use of prednisone as a maintenance regimen in both the placebo and active treatment arms has been allowed. In our study, patients were not allowed to take concomitant prednisone and/or any other maintenance treatment for IPF. Approximately one-third of the patients (15 [33%] receiving etanercept and 12 [29%] receiving placebo) who received systemic corticosteroids in accordance with the protocol were treated for no more than 10 days.

Given that the natural history of IPF is not fully understood, we believe that the inclusion of a true placebo-controlled group in the study design is important in evaluating the therapeutic benefit of novel investigational agents in patients with this disease. Generally, a true placebo-controlled study would not include patients with progressive disease, such as those sought for inclusion in our study. It is noted that the rate of physiologic decline and death rates between the placebo group in this trial and that seen in IPF trials using low-dose prednisone in the placebo arm (41, 50) are similar.

Etanercept at a dose of 25 mg subcutaneously twice weekly was safe and well tolerated in this selected population of patients with very severe and progressive IPF, with a safety profile similar to that seen in clinical trials for other indications (1924, 2629). The limitations with this study need to be acknowledged when interpreting our results. The small sample size in this exploratory study may have limited our ability to detect statistically significant differences in our primary endpoints and whether etanercept might be effective in reducing all-cause mortality. Although change in lung function measures can be a useful surrogate in exploratory studies, effective therapies for IPF, which result in a reduction of all-cause mortality, are required. This study confirms the feasibility of conducting true placebo-controlled studies in patients with IPF. The results observed here support further investigation of TNF antagonists in clinical trials with adequate sample size and controls.

The authors thank Ruth Pereira, Ph.D., in the Wyeth Publications and External Communications Group, for her assistance with preparation of the manuscript. The authors are indebted to all the patients, IPF Site Investigators, and nurse coordinators for participating in this study.

The IPF Study Investigators are as follows: M. Thomeer, Leuven, Belgium; J.F. Cordier, Lyon, France; J. Behr, Munich, Germany; U. Costabel, Essen, Germany; H.C. Hoogsteden, Rotterdam, The Netherlands; R.M. du Bois, London, UK; R.P. Baughman, Cincinnati, OH; K.K. Brown, Denver, CO; J. Chapman, Cleveland, OH; M. Glassberg, Miami, FL; R. Hyzy, Ann Arbor, MI; M.C. Kallay, Rochester, MN; L. Lancaster, Nashville, TN; J.A. Lasky, New Orleans, LA; Y.N. Mageto, Dallas, TX; K.C. Meyer, Madison, WI; S.D. Nathan, Falls Church, VA; A.H. Niden, Los Angeles, CA; I. Noth, Chicago, IL; R.L. Perez, Decatur, GA; G. Raghu, Seattle, WA; M. Rossman, Philadelphia, PA; S.A. Sahn, Charleston, SC; J. Utz, Rochester, NY; G. Verghese, Charlottesville, VA.

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Correspondence and requests for reprints should be addressed to Ganesh Raghu, M.D., F.C.C.P., F.A.C.P., Division of Pulmonary and Critical Care Medicine, Campus Box 356175, University of Washington, Seattle, WA 98195-6522. E-mail:


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