1. IPF Disease Management Strategies: Surveying the Landscape of Therapeutic Options
Idiopathic Pulmonary Fibrosis (IPF) Disease Management Strategies: Surveying the Landscape of Therapeutic Options

2. Learning Objectives
Employ the contemporary principles of evidence-based medicine to formulate practical patient management strategies and optimize outcomes
Critically evaluate current body of evidence regarding conventional and emerging therapies
Review and discuss current options for clinical trial enrollment
Examine the implications of the new lung transplant guidelines
Learning Objectives
The learning objective of this portion of the slide presentation is to be able to employ contemporary principles of evidence-based medicine to formulate practical patient management strategies and to optimize outcomes. This will include the ability to:
Critically evaluate the current body of evidence regarding conventional and emerging therapies
Review and discuss current options for clinical trial enrollment
Examine the implications of the new lung transplant guidelines

3. Evolution of Evidence-Based Medicine
Traditional Medicine
Original EBM
Current EBM
MD’s clinical experience
Dependable knowledge source
One tool, especially for diagnosis
MD’s understanding of physiology
Sufficient guide
Necessary, not sufficient
Authority for best practice
MD’s expertise and clinical experience
Evidence from systematic clinical outcomes studies
Synthesis of multiple factors
Patient role
Passive participant
Active participant
Evolution of Evidence-Based Medicine
Traditional medicine was based on combining clinical experience, knowledge of basic mechanisms of disease, and common sense to guide clinical practice. This paradigm valued authority and adherence to standard approaches.
In the original concept of evidence-based medicine (EBM), clinical experience and instincts were particularly important for diagnosis but could be misleading when it came to therapy. The study and understanding of basic mechanisms of disease are necessary but insufficient guides for clinical practice. Basic pathophysiologic principles may lead to inaccurate predictions about the efficacy of treatments. Finally, while information may be obtained from the scientific and medical literature, understanding rules of evidence is necessary to correctly interpret these findings. The original EBM paradigm put a much lower value on authority, but assumed that physicians whose practice is based on an understanding of the underlying evidence will provide superior patient care.
This reliance on hard evidence is a good strategy in cases where there is an abundance of published positive clinical studies. In IPF such information is not available; patients and physicians are faced with difficult choices. A current version of EBM has been developed that is applicable to this situation. It acknowledges the crucial role of patient preferences in the decision-making process. Some patients might want more aggressive plans of care, while others may opt for palliative measures. Patient tolerance for side effects, cost, and burden of therapy is variable and should be taken into account.
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:
Haynes RB, Devereaux PJ, Guyatt GH. Physicians’ and patients’ choices in evidence based practice. BMJ. 2002;324:1350.
Haynes RB, et al. BMJ. 2002;324:1350.
Guyatt G, et al. Chest. 2006;129:

4. Weighing the Research Evidence
Type of Study
Strength of Result
Adverse Events
Human RCT > Retrospective, Subgroup > Observational
Statistically significant > Trend > Not Significant
Weighing the Research Evidence
Several factors should be taken into consideration in the practice of evidence-based medicine: type of study, strength of result, adverse events. The first factor is the type of study. Primary endpoints in RCTs are more relevant than retrospective or case study results, and lab models should be considered with caution. Patient-oriented outcome endpoints of mortality or symptoms are more relevant than disease-oriented endpoints.1
The next factor is the strength of the available evidence. Many published studies give statistical significance results for subgroups. This is extremely useful for generating hypotheses for follow-up studies, but should not be construed as valid for use in EBM.
A similar critical evaluation must be applied to adverse events or side effects in weighing a particular course of action. It is this area where patient preference is most relevant.
Several other questions may be useful in critically evaluating the available research evidence2:
Is the trial in an appropriate patient group?
What are the limitations of the study?
Do the data support the conclusions? How strongly?
If the studies are observational, how convincing are the conclusions?
Sackett et al3 suggests answering the following two questions for weighing evidence:
Is the result valid? This entails elements such as study design, significance, reproducibility and consistency.
Is the result important? This addresses issues such as relevance of the result to the clinical outcome and magnitude of the result.3
Ebell MH, Siwek J, Weiss BD et al. Strength of recommendation taxonomy (SORT): A patient- centered approach to grading evidence in the medical literature. Am Fam Physician ;69:
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest ;129:
Sackett DL, Haynes RB, Rosenberg W, Richardson WS. Evidence-based Medicine: How to Practice and Teach EBM. London: Harcourt
None > Predictable > Spontaneous > Target Mediated
Guyatt G, et al. Chest. 2006;129:

5. Evidence-Based Medicine
Clinical state and circumstance
Clinical expertise
Evidence-Based Medicine
This figure summarizes the elements that influence clinical decisions:
The patient’s clinical circumstance must be assessed in order to establish what is wrong and what treatment options are available.
Relevant research evidence concerning the efficacy and efficiency of the options must be weighed.
Given the likely consequences associated with each option, the clinician must consider the patient’s preferences and likely actions, which interventions and side effects are acceptable.
Clinical expertise is needed to bring these considerations together and recommend the treatment that has the best expected outcome, the least negative effects, and acceptance by the patient.
The term “evidence-based medicine” was developed to encourage practitioners and patients to give appropriate weight to the best available evidence in making decisions in the absence of validated treatment strategies. This practice is sometimes referred to as “research-enhanced health care.”
There are currently no therapies for IPF with FDA approval or with substantial positive clinical results. Because of this, the patient’s quality of life preferences play a big role in choosing how to manage the disease. Evidence-based medicine is thus particularly relevant for IPF; since the research evidence is weak, the clinician and patient have more important decision-making roles.
Haynes RB, Devereaux PJ, Guyatt GH. Physicians’ and patients’ choices in evidence-based practice. BMJ. 2002;324:1350.
Research evidence
Patient preference
Haynes RB, et al. BMJ. 2002;324:1350.

6. Patient Management Strategies
Clinical trial enrollment
Evidence-based therapeutic management
No therapy—watch and wait
Lung transplantation
Supportive care
Patient Management Strategies
Options for patients with IPF are limited. One is enrollment in one of the clinical trials that is evaluating new therapies. Lung transplantation is an option for patients who qualify, and supportive care can be useful to alleviate symptoms. Several of these options may be appropriately combined to provide the best care.
Bouros D, Antoniou KM. Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J. 2005;26:
Bouros D, et al. Eur Respir J. 2005;26:

7. Azathioprine + Prednisone vs Prednisone Alone in IPF
Probability of Survival
Years
1.0
0.8
0.6
0.4
0.2 1 2 3 4 5 6 7 8 9
Azathioprine + Prednisone (n = 14)
Prednisone (n = 13)
P = 0.02 (age adjusted)
P = 0.16
Azathioprine + Prednisone vs Prednisone Alone in IPF
In an early trial, Raghu and colleagues evaluated the efficacy of corticosteroids and standard immunosuppressants in 27 patients with IPF. In this prospective, double-blind, placebo-controlled trial, patients were randomized to receive combined prednisone (initiated at 1.5 mg/kg/day for the first 2 weeks, then tapered to 20 mg/day) plus azathioprine (3 mg/kg) or prednisone alone. During the 9-year follow-up period, 6 of 14 patients (43%) in the prednisone/azathioprine group died compared with 10 of 13 patients (77%) in the prednisone-only group. A Cox model survival analysis showed a nonsignificant survival advantage for combination therapy (hazard ratio = 0.48; 95% CI 0.17, 1.38). However, when adjusted for age, a post-hoc analysis shows that the survival advantage of azathioprine/prednisone became statistically significant (hazard ratio 0.26; 95% CI ; P = 0.02).
This result should be interpreted with caution.
The patient groups are small
Separation between treatment survival rates is not evident at times less than 4 years
3 patients (11%) switched groups during the study (dots on left, first animation)
One of the deaths was suicide (dot on right, second animation)
Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis. 1991;144:
Raghu G, et al. Am Rev Respir Dis. 1991;144:

8. Probability of Survival
Combined Corticosteroid and Cyclophosphamide Treatment Does Not Improve Survival in IPF Patients
1.00
Expected
P = 0.58
0.75
Probability of Survival
0.50
Untreated (n = 82)
Median survival = 1431 days
0.25
Treated (n = 82)
Combined Corticosteroid and Cyclophosphamide Treatment Does Not Improve Survival in IPF Patients
Collard and colleagues performed a retrospective analysis evaluating the combination of corticosteroids plus cyclophosphamide in 164 patients with IPF. Treated and untreated patients were matched by age and percentage of predicted forced expiratory volume (FVC) at the time of the initial visit.
The Kaplan-Meier survival curve shows the probability of survival for patients treated with corticosteroid and cyclophosphamide therapy (red line; n = 82), patients not treated (blue line; n = 82), and the expected survival of 68-year-olds in the general US population (orange line). Circles and squares represent censored observations. There was no difference in survival between treated and untreated patients. The median survival was 1,431 days for treated patients and 1,665 days for untreated patients (P = 0.58). The lack of survival benefit persisted when the survival analysis was limited to only those matched patient pairs who had undergone surgical lung biopsy or patients who had a FVC  60%.
Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004;125:
Median survival = 1665
0.00
500
1000
1500
2000
2500
3000
3500
4000
Days of Follow Up
Collard HR, et al. Chest. 2004;125:

9. Interferon g-1b GIPF-001 Trial Classification Mechanisms Trial Design
Pleiotropic biologic response modifier
Mechanisms
Antifibrotic, angiostatic, antiinfective, antiproliferative
Trial Design
Multicenter, double-blind, placebo-controlled, Phase 3
Inclusion Criteria
Age 20-79, with symptoms of IPF for ≥ 3 years
Primary Endpoint
Composite: progression-free survival
Treatment Arms
200 g TIW vs placebo
Number of Patients
330 patients at 56 sites
Results
Phase 3 trial did not meet primary endpoint
Interferon -1b: GIPF-001 Trial
Interferon -1b is a pleiotropic biologic response modifier with diverse properties that include antifibrotic, angiostatic, anti-infective, anti-proliferative, and immunomodulatory effects.
Preliminary studies evaluating interferon -1b in patients with IPF demonstrated significant improvements in pulmonary ventilation and gas exchange. In contrast, GIPF-001, a randomized, double-blind, placebo-controlled trial in 330 patients with IPF did not reveal a statistically significant effect on the primary composite endpoint. However, interferon -1b tended to produce improved survival among patients with less severe impairment in lung function. Among patients with baseline FVC > 62% of predicted, 4% of the treatment group died, compared with 12% of the placebo group (P = 0.04).
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon -1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon -1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 1999;341:
Antoniou KM, Nicholson AG, Dimadi M, et al. Long-term clinical effects of IFN -1b and colchicine in idiopathic pulmonary fibrosis. Eur Respir J. 2006;28:
Raghu G, et al. N Engl J Med. 2004;350:

10. GIPF-001 Trial: Overall Survival
Lung Function (FVC)2
N = 330
1.0 75 70
0.8 65
Probability of Survival
P = 0.08 60
0.6
IFN -1b
16 IFN -1b and placebo deaths (41% relative reduction) 55
Placebo
GIPF-001 Trial: Overall Survival
This slide summarizes the discordant effect of IFN g-1b on survival and lung function (as assessed by FVC) observed in GIPF-001. A trend toward improved survival was seen among patients receiving IFN g-1b despite the absence of any discernable effect on lung function. The apparent discordance was even more pronounced in patients with less severe baseline impairment, as well as those who were treatment compliant.
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon g-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
InterMune, Inc. Data on file.
0.4 50
100
200
300
400
500
600 12 24 36 48 60 72
Day
Week
1. Raghu G, et al. N Engl J Med. 2004;350:
2. Data on file with InterMune.

11. % Reduction in Mortality
GIPF-001 Trial: Survival
0.057
64%
11 (12.9%) 85
4 (4.6%) 87
DLco  35%*
0.017
66%
20 (14.0%)
143
6 (4.8%)
126
Therapy-adherent*
0.004
71%
21 (16.4%)
128
FVC  55%
0.003
100%
8 (11.8%) 68
0 (0.0%) 71
FVC  55% and
DLco  35%
41%
% Reduction in Mortality
168 N
Placebo
28 (16.7%)
Deaths (%)
0.08
P-Value
16 (9.9%)
162
ITT*
IFN -1b
Patient Cohort
GIPF-001 Trial: Survival
While a beneficial effect on survival in the overall intention-to-treat (ITT) population was not statistically significant, analysis of several subgroups, including treatment-adherent patients, as well as those with less severe functional impairment at baseline, revealed a statistically significant survival advantage associated with interferon g-1b treatment.
It is important to note, however, that the results of the subgroup analysis are not intended to support treatment inference, but to provide a platform for subsequent clinical trials.
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon g-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:
InterMune, Inc. Data on file.
*Raghu G, et al. N Engl J Med. 2004;350:
Data on file with InterMune.

12. Interferon g-1b INSPIRE Trial Trial Design
Multinational, randomized, placebo-controlled, Phase 3
Inclusion Criteria
Age years, FVC ≥ 55% and DLCO ≥ 35% of predicted
Primary Endpoint
Survival time
Treatment Arms
200 μg TIW vs placebo, 2:1 randomization
Number of Patients
828 (enrollment complete)
Number of Sites
82 (including Europe and North America)
Treatment Duration
2 years from date of 600th patient enrollment
Interferon g-1b: INSPIRE Trial
The ongoing INSPIRE trial is a multinational, randomized, placebo-controlled, Phase 3 trial evaluating interferon -1b in the treatment of patients with IPF. Entry criteria include age 40–79 years, FVC  55% of predicted value and a DLCO  35% of predicted value. Patients are randomized in a 2:1 ratio to receive interferon -1b 200 g or placebo 3 times weekly (TIW). The primary endpoint is survival time. Eight hundred twenty-eight patients have been enrolled (enrollment complete) at 82 sites in Europe and North America. Treatment duration will continue for 2 years from the date of the 600th patient enrollment.
INSPIRE. InterMune Web site Available at: Accessed June 2006.
Accessed June 2006.

13. N-acetylcysteine IFIGENIA Trial Classification
Variant of amino acid L-cysteine, precursor for glutathione
Trial Design
Multinational, double-blind, randomized, Phase 3
Primary Endpoints
FVC and DLco change from baseline at 12 months
Secondary Endpoint
Survival
Treatment Arms
Active: NAC (600 mg TID)
+ Pred (0.5 mg/kg/day) + Aza (2 mg/kg/day)
Control: Pred (0.5 mg/kg/day) + Aza (2 mg/kg/day)
Number of Patients
182 randomized, 155 included in analysis
Treatment Duration
1 year
N-acetylcysteine: IFIGENIA Trial
Demedts and colleagues evaluated the use of N-acetylcysteine (NAC) added to prednisone and azathioprine in a multinational, double-blind, randomized, placebo-controlled trial in patients with IPF. Patients were randomized to receive NAC 600 mg 3 times daily (TID) plus prednisone 0.5 mg/kg/day and azathioprine 2 mg/kg/day or placebo plus the same dosages of prednisone and azathioprine. The dose was maintained for 12 months. The primary endpoints were the absolute changes in FVC and DLCO. Secondary endpoints included the clinical, radiologic, and physiological (CRP) score, high-resolution computed tomography (HRCT) findings, quality of life, and survival. One hundred eighty-two patients were randomized and 155 were included in the analysis.
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353:
Demedts M, et al. N Engl J Med. 2005;353:

14. IFIGENIA Study: Results
FVC
DLCO 2 2
P = 0.02
P = 0.003 -2 -2
Acetylcysteine -4
Vital Capacity (% of predicted value) -4
DLco (% predicted value)
Acetylcysteine -6 -6 -8
Placebo -8
Placebo
-10
-10
6 Months
Baseline
12 Months
6 Months
Baseline
12 Months
No. of Patients
Acetylcysteine
Placebo
IFIGENIA Study: Results
For the primary endpoints (the absolute changes in FVC and DLCO between baseline and month 12) NAC was associated with significant slowing of the rate of decline. There was a slower rate of loss of vital capacity in the group receiving NAC. The absolute difference in the vital capacity change from baseline between treatment and placebo groups was 180 mL (relative difference = 9%, P = 0.02). The same change in DLco was 0.75 mmol per minute per kilopascal (24%, P = 0.003). However, there was no significant effect of treatment on survival. There were 7 deaths in the NAC group (9%) compared with 8 deaths in the placebo group (11%) (P < 0.69).
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353: 80 75 63 60 55 51 79 74 58 59 55 51
Mortality, P = NS
NAC+Pred+Aza
7/80 (9%)
Pred+Aza+Placebo
8/75 (11%)
Demedts M, et al. N Engl J Med. 2005;353:

15. Raghu G, et al. Chest. 2005;128:496S-497S.
Etanercept Trial
Mechanism
TNF-a inhibitor
Trial Design
Randomized, placebo controlled, Phase 2
Number of Patients
87 (M = 59; F = 28)
Treatment
Etanercept 25 mg SC TIW vs placebo
Inclusion Criteria
FVC > 45% predicted (mean FVC 63.4%)
DLCO > 25% predicted
PaO2 > 55 mm Hg/SpO2 > 88%
Primary Endpoints
FVC % predicted
DLCO % predicted
A-a gradient
Results
Primary endpoint not met
Etanercept Trial
Tumor necrosis factor- (TNF-) is a pleiotropic cytokine with inflammatory and profibrotic properties. Over-expression of TNF- is thought to play a role in the pathogenesis of IPF, and preliminary evidence suggests that etanercept, a TNF-a inhibitor, might provide some benefit in patients with IPF. This was a prospective, randomized, placebo-controlled trial in 87 patients with IPF. Inclusion criteria include FVC > 45% (mean FVC 63.4%), DLCO > 25% predicted, PaO2 > 55 mg Hg, and SpO2 > 88%. The primary endpoints are change from baseline FVC % predicted, DLCO % predicted, and A-a gradient at 1 year.
No statistical difference was found between treatment groups in predefined primary endpoints. However, etanercept therapy resulted in a trend toward reduced disease progression by several measures in these patients with progressive IPF.
Raghu G, Lasky J, Costabel U, et al. A randomized placebo controlled trial assessing the efficacy and safety of etanercept in patients with idiopathic pulmonary fibrosis (IPF). Chest. 2005;128:496S-497S.
Brown KK, Raghu G. Medical treatment for pulmonary fibrosis: current trends, concepts, and prospects. Clin Chest Med. 2004;25: vii.
Walter N, Collard HR, King TE Jr. Current perspectives in the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:
Raghu G, et al. Chest. 2005;128:496S-497S.

16. Bosentan BUILD 1 Trial Classification
A nonselective endothelin-1 receptor antagonist
Mechanisms
Possible antifibrotic effects
Trial Design
12 month, double-blind, randomized, placebo-controlled study, Phase 2
Number of Patients
158 randomized, 132 included in analysis
Inclusion Criteria
IPF diagnosis < 3 years
6MWT distance limited by dyspnea
moderate restrictive lung disease
Primary Endpoint
6MWT distance change from baseline at 12 months
Results
Primary endpoint not met
Phase 3 planned based on secondary endpoints
Bosentan BUILD 1 Trial
Bosentan is a nonselective endothelin-1 (ET-1) receptor antagonist used in the treatment of pulmonary arterial hypertension. Recent observations suggest that endothelin is upregulated in the lungs of patients with IPF, providing a rationale for exploring the potential therapeutic utility of bosentan.
Preliminary results of the BUILD-1 trial suggested no benefit in terms of the primary endpoint; however, a follow-up study is being planned based on the results from secondary endpoint analyses.
Salani D, Taraboletti G, Rosano L, et al. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000;157:
O’Callaghan D, Gaine SP. Bosentan: a novel agent for the treatment of pulmonary hypertension. Int J Clin Pract. 2004;58:69-73.
Walter N, Collard HR, King TE Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:
Salani D, et al. Am J Pathol. 2000;157:
O’Callaghan D, Gaine SP. Int J Clin Pract. 2004;58:69-73.

17. Pirfenidone Classification Selective kinase inhibitor Trial Design
Randomized (2:1), double blind, placebo controlled, Phase 2
Number of Patients
107
Treatment
Pirfenidone 1800 mg/d versus placebo x 1 year
Inclusion Criteria
Confident clinical diagnosis of IPF (mild-to-moderate)
Efficacy Endpoints
Primary: Minimum SpO2 during 6MWT
Secondary: FVC, DLCO, acute exacerbations
Results
Study halted at 6 months due to increased incidence of acute exacerbations in the placebo arm
Pirfenidone
Pirfenidone is a selective inhibitor of p38g MAP kinase that exhibits antifibrotic, anti-inflammatory and antioxidant properties. Azuma and colleagues conducted a randomized (2:1 ratio), double-blind, placebo-controlled, Phase 2 trial evaluating pirfenidone in the treatment of patients with IPF. HRCT evidence of definite or probable usual interstitial pneumonia (UIP) in the appropriate clinical setting was required for inclusion; 107 patients participated. Eligible patients were 20–75 years of age, with adequate oxygenation at rest (PaO2  70 mm Hg) with oxygen saturation (SpO2) of 90% or less during exertion. Patients were randomly assigned to receive pirfenidone (titrated to 600 mg TID) or placebo for 1 year. The primary endpoint was the change in the lowest SpO2 during a 6-minute steady-state exercise test. Secondary endpoints included changes in resting pulmonary function tests, disease progression, and episodes of acute exacerbation of IPF.
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:
Azuma A, et al. Am J Respir Crit Care Med. 2005;171:

18. Pirfenidone Phase 2 Trial Results40 36 33 35 30 24
Placebo 25
Pirfenidone 18
% of Patients 20 13 15 9 10 6 5
Pirfenidone Phase 2 Trial Results
The data safety monitoring board halted the study early due to an increase in acute exacerbations in the placebo arm. At 6 months after randomization, there were 5 acute exacerbations among 35 patients in the control arm, compared to 0 acute exacerbations among 75 patients receiving pirfenidone. The primary endpoint in this trial was not met.
Despite early discontinuation of the trial, 9 months of data were available for evaluation. This figure is a secondary analysis of improving and declining patients. In the context of evidence-based medicine, this result may generate hypotheses for further study but does not support conclusions by itself.
The graph on the left illustrates the effect of treatment at 9 months on the lowest SpO2 during the 6-minute exercise test, while the graph on the right illustrates the effect of treatment on FVC. More patients receiving pirfenidone experienced an improvement in the minimum SpO2 during the 6-minute exercise test compared with placebo, while fewer patients experienced a decline in the minimum SpO2. Similarly, more patients receiving pirfenidone experienced an improvement in FVC and fewer patients experienced a decline in FVC compared with those receiving placebo.
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:
Improved
Declined
Improved
Declined
Min SpO2
FVC
Data based upon 9-month assessment due to early discontinuation of the trial.
Azuma A, et al. Am J Respir Crit Care Med. 2005;171:

19. www.capacitytrials.com. Accessed August 2006.
Pirfenidone
CAPACITY Trials
Trial Design
Randomized, double blind, placebo controlled, Phase 3
Number of Patients
CAPACITY I: 260
CAPACITY II: 325
Treatment Arms
CAPACITY I: PFD 2403 mg/d vs placebo
CAPACITY II: PFD 1197 mg/d vs PFD 2400 mg/d vs placebo
Inclusion Criteria
Age 40 – 80 years, confident IPF diagnosis
FVC ≥ 50% predicted value, DLCO  35% predicted value
Efficacy Endpoints
Primary: Change in FVC % predicted from baseline to wk 60
Secondary: Changes in symptoms, functional capacity, QOL
Treatment Duration
60 weeks
Pirfenidone CAPACITY Trials
This slide summarizes the proposed study design of the pirfenidone CAPACITY trials. These Phase 3 trials will compare the efficacy and safety of pirfenidone versus placebo. The studies will enroll approximately 580 patients at 80 sites. Patients will be randomized (2:1) to receive pirfenidone or placebo for 60 weeks. After the study, patients will be followed for a period of 4 weeks.
The dosing will be slightly different in the 2 studies. CAPACITY I participants will receive placebo or 2403 mg pirfenidone in divided doses 3 times per day, while CAPACITY II participants will receive placebo, 1197 mg pirfenidone, or 2400 mg pirfenidone in divided doses 3 times per day.
Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes. InterMune, Inc. Web site Available at: Accessed August 1, 2006.
Accessed August 2006.

20. Imatinib Mesylate Classification Tyrosine kinase inhibitor Mechanism
Inhibits activation of the platelet-derived growth factor (PDGF) receptor
Trial Design
Randomized, double blind, placebo controlled, Phase 2
Number of Patients
122
Potential Clinical Benefit
Potential reduction in the rate of decline in pulmonary function
Inclusion Criteria
Diagnosis confirmed by biopsy, FVC > 55% of predicted at baseline, DLCO > 35% of predicted at baseline
PaO2 > 60 mm Hg at rest on room air
Results
Pending
Imatinib Mesylate
Imatinib is a C-Abelson proto-oncogene (c-Abl) tyrosine kinase inhibitor that inhibits activity of platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-), which are cytokines believed to be involved in profibrotic signaling. Imatinib is currently FDA approved for the treatment of chronic myelogenous leukemia. In a mouse model of bleomycin-induced pulmonary fibrosis, imatinib was shown to produce a significant inhibition of lung fibrosis. On the basis of this observation, a Phase 2 trial involving 122 patients is currently being conducted.
Buchdunger E, O’Reilly T, Wood J. Pharmacology of imatinib (STI571). Eur J Cancer. 2002;38(Suppl 5):S28-S36.
Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF- and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114:
Buchdunger E, et al. Eur J Cancer. 2002;38(Suppl 5):S28-S36.
Daniels CE, et al. J Clin Invest. 2004;114:

21. Anticoagulation Therapy1
With Anticoagulant Therapy
0.8
n = 23
0.6
Probability of Survival
n = 33
0.4
Without Anticoagulant Therapy
0.2
N = P < 0.05
Anticoagulation Therapy
These data are from an anticoagulant therapy survival trial with 56 IPF patients. In this study, patients were assigned to receive prednisolone alone or prednisolone plus anticoagulant (warfarin or low-molecular-weight heparin). Twenty-three of the 33 patients in the control group died during follow-up compared with 5 of 23 patients in the anticoagulant group. The mortality hazard ratio was 2.9 (P = 0.04). Tick marks indicate censoring.
Mortality associated with acute exacerbations of IPF in the anticoagulant group was also significantly reduced compared to that in the non-anticoagulant group (18% vs 71%, respectively; P = 0.008). Histologic analysis performed in 3 patients who died due to an exacerbation of IPF in the control group demonstrated features of UIP and acute lung injury.
Several factors suggest caution in drawing strong conclusions from this study.
The IPF patients were not blinded to their treatment.
The incidence of acute exacerbation was higher than typical (64% in placebo group)
The median survival (399 d) of the placebo group was lower than expected
Subjects were recruited on initial hospitalization, which may have selected for more severe cases
26% of the anticoagulant treatment group withdrew prior to initiating treatment
Intention-to-treat analysis was not used, which could skew the findings
All patients were nonsmokers
Ground-glass opacity was used as part of the IPF description. It is not usually included as a criterion, thus raising questions about the initial diagnosis
Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005;128:
Walter N, Collard HR, King TE Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:
200
400
600
800
1000
1200
Time (Days)
Kubo H, et al. Chest. 2005;128:

22. Recent and Ongoing Trials for IPF
Primary Endpoints
Phase 3
Interferon gamma GIPF-001 trial
330
Progression-free survival time
Interferon gamma INSPIRE trial
826
Survival time
N-acetylcysteine (NAC) IFIGENIA trial
155
Change in FVC, DLCO
Pirfenidone CAPACITY I and II trials
535
Time to disease progression
Phase 2
Illoprost 50
Safety, 6MWT
Bosentan
132
Change in 6MWT at 1 year
Etanercept
100
FVC, DLCO, A-a gradient
Imatinib mesylate
120
Safety; efficacy
Pirfenidone (Azuma et al)
107
Minimum SpO2 during 6MWT
Recent and Ongoing Trials for IPF
This table summarizes recent and ongoing IPF clinical trials. It specifies the biological target, number of patients enrolled, and primary endpoints of each study. This summary highlights the fact that multiple targets for therapeutic intervention are being pursued, and multiple clinical trial opportunities are now available for patients with IPF.
US National Institutes of Health Web site Available at: Accessed May 2006.
Coalition for Pulmonary Fibrosis Web site Available at: Accessed April 2006.
National Heart, Lung, and Blood Institute Strategic Plan. FY
Accessed May 2006
Accessed April 2006
National Heart, Lung, and Blood Institute Strategic Plan. FY

23. Idiopathic Pulmonary Fibrosis Clinical Research Centers
University of
Washington
Mayo Clinic Foundation
University of Chicago
University of
Michigan
Cornell University
University of California, San Francisco
Vanderbilt University
Duke University
(Data Coordinating Center)
University of California, Los Angeles
Idiopathic Pulmonary Fibrosis Clinical Research Centers
In 2004, the National Institutes of Health (NIH) initiated an Idiopathic Pulmonary Fibrosis Clinical Research Network. The objective was to establish a clinical research network and data coordinating center to conduct multiple treatment trials on patients with newly diagnosed idiopathic pulmonary fibrosis. There are 12 research centers in the United States including 1 data coordinating center (Duke University). The purposes of the network are to:
Conduct multiple therapeutic trials for patients with IPF
Evaluate existing or novel medications
Define management strategies
There are also numerous non-NIH research centers throughout the United States.
National Institutes of Health Office of Extramural Research. National Institutes of Health Web site Available at: Accessed May 31, 2006.
IPF trial location. IPFnet Web site Available at: Accessed August 2, 2006.
Emory University
University of
Colorado
Louisiana State University
and University of Alabama, Birmingham
NIH-sponsored Research Centers
Non-NIH Current Research Centers

24. Nonpharmacologic Therapies
Lung transplantation
Supplemental oxygen
Pulmonary rehabilitation
Improvement in general and disease-specific health status
Increased exercise tolerance
End-of-life care
Screen for pulmonary hypertension, obstructive sleep apnea, cough, gastroesophageal reflux disease, coronary artery disease, and depression
Nonpharmacologic Therapies
Nonpharmacologic therapies have a role in the management of patients with IPF. Early evaluation for lung transplantation is recommended. Supplemental oxygen during exercise may markedly improve exercise-induced hypoxemia and exercise performance. Pulmonary rehabilitation is an important support for exercise routines; it can produce improvements in general and disease-specific health status and increase exercise tolerance.
Identification and treatment of concomitant diseases is also important. These conditions include pulmonary hypertension, obstructive sleep apnea, cough, gastroesophageal reflux disease, coronary artery disease, and depression. End-of-life care is appropriate for patients in the terminal stages of the disease.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000;161:
Khalil N, O’Connor R. Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment. CMAJ. 2004;171:
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:
Khalil N, et al. CMAJ. 2004;171:

25. Adult Lung Transplantation
Kaplan-Meier Survival for IPF (Transplants: January 1990 – June 2003)
100
Survival Comparisons
vs : P = 0.77
vs /2003: P = 0.18 75
vs /2003: P =
Survival (%) 50 25
(N =577)
(N = 681)
Adult Lung Transplantation
These data show survival of adult patients with IPF who have received a lung transplant. Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for which any follow up has been provided. There is a significant improvement in survival rates between and /2003.1
Of the 13,452 adult lung transplants recorded by the International Society for Heart and Lung Transplantation between January 1995 and June 2005, IPF was the second most common recipient indication (19%) behind COPD (38%). Cystic fibrosis patients comprised about 16%.2
Among the major indications of transplant recipients, IPF had the shortest survival half-life: 2
Indication Survival T1/2, years
Cystic fibrosis
COPD
IPF
IPF lung transplant recipients had the following survival rates: 71% at 1 year, 43% at 5 years, and 19% at 10 years2. The major causes of death in the period between 3 and 5 years were bronchiolitis (29%), non-CMV infection (19%), graft failure (19%), and other causes (18%).2
1. United Network for Organ Sharing. Data on file. May 19, 2006.
2. Trulock EP, Edwards LB, Taylor DO, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult lung and heart-lung transplant report— J Heart Lung Transplant. 2006;25:
2000-6/2003 (N = 591) 1 2 3 4 5 6 7 8 9 10
Years
Adapted from Web site: Accessed June 2006.
Trulock EP, et al. J Heart Lung Transplant. 2006;25:

26. Lung Transplant Guidelines
Old model based on first-come/first-served basis
New transplant guidelines are based on a lung allocation score (LAS)
LAS = projected pretransplant 1-year survival vs projected posttransplant 1-year survival
Consider referral for transplant evaluation at time of diagnosis for appropriate patients
Lung Transplant Guidelines
In 2005 the new US lung allocation system was established. It was designed to address issues related to extended candidate waiting time, limited organ supply, waitlist mortality, and post-transplant survival. These guidelines replaced the old model that was primarily based on a first-come/first-served criterion. The guidelines now are based on a lung allocation score (LAS), which is the end-product of an algorithm that assigns priority to lung candidates who are at higher risk of death if they do not receive a transplant (waitlist urgency) and who are likely to live longer with a transplant (transplant benefit). A variety of clinical factors are predictive of waitlist urgency. Because there is limited donor availability and waiting times sometimes exceed 2 years, clinicians should consider referring appropriate patients for transplantation evaluation at the time of diagnosis.
The new guidelines for transplant listing recommends that patients with a diagnosis of IPF should be referred early in the course of their disease. The following portend a worse prognosis and should factor into the transplant center’s decision about listing at the time of referral:
Histologic or radiographic evidence of UIP
A DLCO < 39% predicted
A 10% or greater decrement in FVC during six months of follow-up
Impaired exercise capacity
A decrease in pulse oximetry below 88% while ambulating
Honeycombing on HRCT (fibrosis score of > 2)
United Network for Organ Sharing Web site Available at: Accessed June 1, 2006.
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:
Coke M, Edwards LB. Current status of thoracic organ transplantation and allocation in the United States. Clin Transpl. 2004;
Egan TM, Murray S, Bustami RT, et al. Development of the new lung allocation system in the United States. Am J Transplant. 2006;6(5 Pt 2):
Accessed June 2006.

27. Take Home Messages
Little quality evidence supports the safety and efficacy of conventional therapies for IPF
Randomized clinical trials should be discussed as an option for all appropriate patients
The principles of evidence-based medicine should be employed to identify optimal approaches to managing patients
Early referral and evaluation for lung transplantation are recommended—new guidelines may shorten the wait time for IPF patients
Take Home Messages
Currently, there are no FDA-approved therapies for IPF. There is little quality evidence supporting the safety and efficacy of traditional therapies for IPF. Evolving concepts regarding disease pathogenesis point to the potential value of new therapeutic targets. Ongoing randomized clinical trials may lead to identification of varied new therapies. Thus, physicians should offer patients the opportunity for enrollment in appropriate studies.
Evidence-based techniques are required to identify the best approaches to managing patients for whom randomized trials are not appropriate.
Lung transplantation can significantly reduce the risk of death for IPF patients. Early referral and evaluation for lung transplantation is recommended. New transplantation guidelines may shorten the wait time for patients with IPF.