- Email: [email protected]
Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis
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Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis
David J. Lederer, MD1, Williamson Z. Bradford, MD, PhD2, Elizabeth A. Fagan, MS, MD2, Ian Glaspole, MB BS, PhD3, Marilyn K. Glassberg, MD4, Kenneth F. Glasscock, BS2, David Kardatzke, PhD2, Talmadge E. King, Jr., MD5, Lisa H. Lancaster, MD6, Steven D. Nathan, MD7, Carlos A. Pereira, MD8, Steven A. Sahn, MD9, Jeffrey J. Swigris, DO, MS10, Paul W. Noble, MD11
1
Columbia University Medical Center, New York, NY
2
InterMune, Inc., Brisbane, CA
3
Alfred Hospital, Melbourne, Australia
4
University of Miami Miller School of Medicine, Miami, FL
5
University of California, San Francisco, San Francisco, CA
6
Vanderbilt University Medical Center, Nashville, TN
7
Inova Fairfax Hospital, Falls Church, VA
8
Paulista School of Medicine, Federal University of São Paulo, Brazil
9
Medical University of South Carolina, Charleston, SC
10
National Jewish Health, Denver, CO
11
Cedars-Sinai Medical Center, Los Angeles, CA
Running Head: Pirfenidone for IPF
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Lederer et al. Corresponding author and request for reprints: David J. Lederer, MD Columbia University Medical Center 622 W 168th Street, PH14-101 New York, NY 10032 E-mail: [email protected]
Conflict of Interest Statement: DJL, IG, MKG, EAF, LHL, TEK, SDN, CAP, SAS, JJS, and PWN served as members of the ASCEND study steering committee. DJL has served on a scientific advisory board for Boehringer-Ingelheim, Gilead, Immune Works, and InterMune, Inc. IG has received honoraria from Boehringer Ingelheim. LHL has served on a scientific advisory board for Boehringer Ingelheim and InterMune, Inc., and as a consultant to Boehringer Ingelheim. TEK has served as a consultant for Actelion, Boehringer Ingelheim, Daiichi Sankyo, Immune Works, and InterMune. SDN has served on a scientific advisory board and received research funding from Intermune, Inc.; he has also received research funding and served as a consultant for Boehringer Ingelheim, Gilead Sciences and Roche/Genentech. CAP has received a research grant from InterMune, Inc. JJS has served on a scientific advisory board and received research funding from InterMune, Inc., and served as a consultant to Boehringer Ingelheim and Roche/Genentech. PWN has served as a consultant for Boehringer Ingelheim, Bristol Meyers Squibb, InterMune, Inc., Moerae Matrix, Roche/Genentech, and Takeda. WZB, EAF, KFG, and DK are employees of InterMune, Inc.
Financial Support: This study was sponsored by InterMune Inc. (Brisbane, CA)
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ABSTRACT Background: Forced vital capacity (FVC) outcomes in clinical trials in idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary endpoint of FVC change in a Phase 3 trial evaluating pirfenidone in adults with IPF. Methods: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the ASCEND study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary endpoint of change from baseline to week 52 in FVC. Results: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. Conclusion: Our results confirm the robustness of the statistical finding on the primary endpoint of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF.
Clinical Trial Registration Number: NCT01366209 (www.clinicaltrials.gov) Key words: interstitial lung disease, idiopathic pulmonary fibrosis, clinical trial
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Abbreviations ANCOVA
Analysis of covariance
CI
Confidence interval
FVC
Forced vital capacity
HR
Hazard ratio
IPF
Idiopathic pulmonary fibrosis
LOCF
Last observation carried forward
MI
Multiple imputation
MMRM
Mixed effect model with repeated measures
RCM
Random coefficients model
SSD
Sum of squared differences
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INTRODUCTION The selection of robust and clinically meaningful primary efficacy endpoints for therapeutic clinical trials in patients with idiopathic pulmonary fibrosis (IPF) has been the subject of considerable debate.1-7 Forced vital capacity (FVC), a widely used measure of disease status and a strong independent predictor of mortality in patients with IPF, 8-14 has emerged as the most common primary endpoint in IPF clinical trials. However, it is widely recognized that the analytic strategy and the method used to handle missing data can have a substantial influence on the magnitude of change in FVC and the estimate of effect size in therapeutic clinical trials in adults with IPF.15,16
The ASCEND study was a multinational, randomized, double-blind, placebo controlled, Phase 3 trial evaluating pirfenidone in adults with IPF.17 The primary efficacy endpoint in the study was the change from baseline to week 52 in percent predicted FVC, analyzed using a non-parametric rank analysis of covariance (ANCOVA) model that tested for between-group differences in the distribution of ranked change in FVC at week 52.
The rank ANCOVA model was selected as the test statistic for the primary efficacy analysis for three primary reasons. First, unlike some tests, the rank ANCOVA model requires no assumptions regarding data structure and distribution. Second, as a landmark analysis, it minimizes assumptions about the course preceding the measurement (i.e. no assumption of linearity) and provides an estimated effect size at a clinically relevant time point. Finally, it provides a satisfactory solution to the problem of missing data due to death—a clinically important outcome—without overweighting. Since deaths are assigned the lowest ranks according to the time of death since randomization, the model
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incorporates time to death and accounts for the effect of deaths on the primary outcome without the need to rely on the assignment of an arbitrary value for missing data.18,19
Importantly, while the rank ANCOVA model tests for between-group differences in the distribution of change from baseline, it provides no clinically interpretable information regarding the magnitude of the treatment effect. Therefore, the magnitude of treatment effect in the ASCEND study was estimated by comparing the distribution of patients in the pirfenidone and placebo groups across two clinically meaningful thresholds of change at week 52: an absolute decline of ≥10% in percent predicted FVC or death, and no decline in percent predicted FVC (≥0% change from baseline).
In the rank ANCOVA analysis of change from baseline to week 52 in percent predicted FVC, there was a statistically significant between-group difference that favored treatment with pirfenidone (p<0.001). Categorical analysis of outcomes at week 52 demonstrated that the proportion of patients with a ≥10% decline in FVC or death was decreased by 47.8% and the proportion of patients with no decline was increased by 132.5% in the pirfenidone group compared with placebo.17 The mean change from baseline to week 52 in FVC was –235 ml in the pirfenidone group and –428 ml in the placebo group (relative difference, 45.1%; p<0.001).
To examine the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect in the ASCEND study, we conducted a series of sensitivity analyses of the primary endpoint of change in FVC using alternative analytic methods and approaches to managing missing data.
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METHODS Patients All study participants who were randomized to treatment with pirfenidone 2403/mg day (N=278) or placebo (N=277) in the ASCEND study were included in the analyses. Eligibility criteria for the ASCEND study have been previously described.1 Briefly, eligible patients were between the ages of 40 and 80 years with a centrally confirmed diagnosis of IPF at least 6 months prior to randomisation. Physiologic eligibility criteria included a baseline percent predicted FVC ≥50% and ≤90%, percent predicted carbon monoxide diffusing capacity ≥30% and ≤90%, and 6-minute walk test distance ≥150 m.
Statistical Analyses The protocol-defined test statistic for the primary efficacy analysis in the ASCEND trial was a rank ANCOVA model with the standardized rank change in percent predicted FVC as the outcome variable and the standardized rank baseline value as a covariate. Missing values due to death were assigned the worst ranks according to the time of death since randomization. Missing values due to reasons other than death were imputed as the average value from the 3 patients (regardless of treatment assignment) with the smallest sum of squared differences at each study visit with non-missing values.20
A series of sensitivity analyses was conducted to assess the effect of alternative statistical tests and strategies for handling missing data on the robustness of the statistical finding and the observed magnitude of treatment effect on the primary
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endpoint of FVC change at week 52. Alternative statistical tests included the following: mixed effects linear model with repeated measures analysis of the annual rate of change in FVC; random coefficients model of the annual rate of change in FVC (slope analysis); mean change in FVC volume, analyzed using an ANCOVA model; CochranMantel-Haenszel row mean score test based on 2 categories of change in percent predicted FVC (≥10% absolute decline or death and <10% absolute decline); and Cochran-Mantel-Haenszel row mean score test based on 3 categories of change in percent predicted FVC (≥10% absolute decline or death, >0% and <10% absolute decline, and no decline).
Alternative methods for handling missing data due to death included the following: last observation carried forward; replacement with the average value from the 3 patients in either treatment group with the smallest sum of squared differences at each study visit with non-missing values; assignment to the worst category (for categorical analyses); replacement with the worst observed value at week 52 in the placebo group; replacement with the worst observed value at week 52 among placebo patients who discontinued treatment prior to week 52; replacement with the worst possible value (FVC=0); replacement with an intermediate value (FVC=1500 mL); and no imputation (i.e. observed data only).
For missing data due to reasons other than death, alternative imputation methods included the following: last observation carried forward; replacement with the average value from the 3 patients in either treatment group with the smallest sum of squared differences at each study visit with non-missing data; multiple imputation using data from
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patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation; multiple imputation using data from patients in the placebo group who had a week 52 observation; and no imputation.
The ASCEND study was conducted in accordance with the modified Declaration of Helsinki. All patients provided written informed consent and the study protocol was approved by the institutional review board or the ethics committee at each participating study center.
RESULTS A total of 555 patients were included in the analysis. The proportion of patients with missing FVC data at the week 52 study visit is summarized in Table 1. A total of 482 (86.6%) patients completed an FVC assessment at the week 52 study visit (243 [87.4%] in the pirfenidone group and 239 [86.3%] in the placebo group). Fewer patients in the pirfenidone group compared with placebo had a missing value due to death (11 [4.0%] vs. 20 [7.2%]) and slightly more patients in the pirfenidone group compared with placebo had a missing value due to a reason other than death (24 [8.6%] vs. 18 [6.5%]).
The statistical results of the various sensitivity analyses are summarised in Table 2. The distribution of change in FVC was systematically different between the pirfenidone and placebo groups and favored pirfenidone in each analysis. The p-value for the comparison between pirfenidone and placebo was <0.001 for each test statistic, supporting the robustness of the statistical finding in the primary efficacy analysis in the ASCEND study.
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Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis David J. Lederer, MD, Williamson Z. Bradford, MD, PhD, Elizabeth A. Fagan, MS, MD, Ian Glaspole, MB BS, PhD, Marilyn K. Glassberg, MD, Kenneth F. Glasscock, BS, David Kardatzke, PhD, Talmadge E. King, Jr., MD, Lisa H. Lancaster, MD, Steven D. Nathan, MD, Carlos A. Pereira, MD, Steven A. Sahn, MD, Jeffrey J. Swigris, DO, MS, Paul W. Noble, MD
Supplemental Material Institutional Review Board/Ethics Committee Approvals (ASCEND Study)
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Study Site
Principal Investigator
1001
James N. Allen, Jr. MD
1002
1003
1004
1005
1006
1007
1008
1009
Andrew L. Chan, MD
Francis Cordova, MD
Mark H. Gotfried, MD
IRB/Ethics Committee Name and Address
IRB/EC Approval Date
Protocol or Approval Number
July 8, 2011
1126215
UC Davis Medical Center lnstitutional Review Board CTSC Building, 2921 Stockton Blvd, Suite 1400, Room 1429 Sacramento, CA 95817 USA
November 8, 2011
258092-2
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
October 28, 2011
1128398
May 25, 2011
26042/8
September 13, 2011
1127603
August 25, 2011
201106311
University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., C1-206 Dallas, TX 75390-8843 USA
December 6, 2011
STU 072011-081
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
November 4, 2011
1128427
July 1, 2011
11-0282
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
Quorum Review lRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
John Terrill Huggins, MD (Formerly Steven Sahn, MD)
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
Tonya Russell, MD
Human Research Protection Office Washington University School of Medicine 660 South Euclid Avenue, Box 8089 St. Louis, MO 63110 USA
Carlos Girod, MD
Oksana Shlobin, MD
Mary Strek, MD
University of Chicago lnstitutional Review Board 5751 South Woodlawn Avenue, 2nd Floor Chicago, lL 60637 USA
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Our findings have two potentially important implications for the design and execution of clinical trials in IPF and the interpretation of study results. First, the influence of the data imputation methodology on the observed magnitude of change in FVC in both treatment groups in our study underscores the importance of ensuring that similar analytic methods are used when comparing FVC results across clinical trials. By way of illustration, it has been observed that the reported magnitude of decline in FVC at one year in the placebo group in the ASCEND trial (–428 ml) was substantially larger than the observed annual rate of decline in the placebo group in the recent INPULSIS trials (–223.5 ml),23 leading to speculation that this difference might be due to phenotypic differences in the study populations.7 Our analyses demonstrate that the apparent difference in the magnitude of decline in FVC in the ASCEND and INPULSIS trials is almost entirely attributable to differences in analytic methodology, including the handling of missing data due to deaths. Specifically, the reported magnitude of decline in the ASCEND trial was based on an analysis of mean change in FVC in which missing data due to death were assigned the worst possible value (FVC=0); the annual rate of decline in the INPULSIS trials was based on a slope analysis in which missing values due to death were not assigned a worst possible value. When the ASCEND data were analyzed using the methodology employed in the INPULSIS trials, the placebo rates of FVC decline were quite similar (–279.6 ml and –223.5 ml, respectively, in ASCEND and INPULSIS). Notably, the difference in the rates of decline between the placebo groups in the ASCEND and INPULSIS trials was roughly equivalent to the difference between the placebo groups in INPULSIS-1 and INPULSIS-2. Second, our results highlight the fundamental importance of study conduct in achieving robust and clinically interpretable results. Indeed, the robustness of the findings in the ASCEND study is attributable in
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part to the fact that there was minimal missing data; fully 94% of patients in both treatment groups completed the study, thereby limiting the influence of imputed data on study outcomes.
In conclusion, our results confirm the robustness of the statistical finding on the primary endpoint of change from baseline to week 52 in percent predicted FVC in the ASCEND study and corroborate the estimated magnitude of the pirfenidone treatment effect on FVC change in patients with IPF. Additionally, our findings demonstrate the effect of various analytic methods and data imputation strategies on the magnitude of change in FVC, thereby providing benchmarks to facilitate comparisons with other clinical trials.
Acknowledgments The authors thank the patients, family members, and participating staff at all study sites.
Contributions DJL, IG, MKG, EAF, LHL, DK, TEK, SDN, CAP, SAS, JJS, and PWN participated in the conception and design of the ASCEND study, as well as the acquisition and interpretation of original data. DJL, WZB, KFG, and DK were responsible for the conception and development of the plan for the analyses contained in the present report. DK performed the statistical analyses. DJL, WZB, and KFG were responsible for preparing the initial draft of the manuscript. IG, MKG, EAF, LHL, DK, TEK, SDN, CAP, SAS, JJS, and PWN participated in the review and critical revision of the manuscript for intellectual content. All authors approved the final draft and vouch for the accuracy of the overall content of the manuscript.
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REFERENCES 1. Raghu G, Collard HR, Anstrom KJ, et al. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2012;185:1044–8. 2. Rose DM, Montgomery AB. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2013;187:1269. 3. Bradford WZ, Cohen AH, Leff JA. Selection of clinically meaningful primary endpoints in phase 3 clinical trials in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2013;187:1269–70. 4. King TE Jr., Albera C, Bradford WZ, et al. All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. Am J Respir Crit Care Med 2014; 189:825–31. 5. O’Connell OJ, Egan JJ. The Burden of Disease and the Need for a Simple Staging System in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2014;189:765–7. 6. Lederer DJ. Clinical trials in idiopathic pulmonary fibrosis: a framework for moving forward. Eur Respir J 2013;42:1448–48. 7. Koczulla A. Treatments for idiopathic pulmonary fibrosis. N Engl J Med 2014;371: 781. 8. du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: Test properties and minimal clinically important difference. Am J Respir Crit Care Med 2011;184:1382–89. 9. Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538–42.
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10. Flaherty KR, Mumford JA, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:543–48. 11. Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171: 639–44. 12. King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy endpoints in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis. Chest 2005;127:171– 77. 13. Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in FVC is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 2009;35:830–36. 14. du Bois RM, Weycker D, Albera C, et al. Ascertainment of individual risk of mortality in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:459–66. 15. Richeldi L, Ryerson CJ, Lee JS, et al. Relative versus absolute change in forced vital capacity in patients with idiopathic pulmonary fibrosis. Thorax 2012;67:407–411. 16. Wells AU. Forced vital capacity as a primary end point in idiopathic pulmonary fibrosis treatment trials: making a silk purse from a sow’s ear. Thorax 2013;68: 309–310. 17. King TE, Jr., Bradford WZ, Castro-Bernadini C, et al. A Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083–92. 18. Lachin MJ. Worst-rank score analysis with informatively missing observations in clinical trials. Controlled Clinical Trials 1999;20:408–422.
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19. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med 1999;18:1341–1354. 20. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760–69. 21. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821–29. 22. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079–87. 23. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370: 2071–82. 24. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2093–101.
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Table 1. Forced vital capacity assessment at week 52*
Pirfenidone (N=278)
Placebo (N=277)
Total (N=555)
243 (87.4)
239 (86.3)
482 (86.8)
Imputed due to death
11 (4.0)
20 (7.2)
31 (5.6)
Imputed due to reasons other than death
24 (8.6)†
18 (6.5)‡
42 (7.6)
Patients, n (%) Observed
*Patients were required to complete two week 52 visits (week 52A and week 52B); the week 52 value was reported as the average value of the week 52A and week 52B assessments. †
Includes withdrawal by subject (n=7), adverse event (n=6), lung transplantation (n=6), lost to follow-up (n=2), did not complete an FVC assessment (n=1), physician decision (n=1), and other (n=1)
‡
Includes withdrawal by subject (n=7), adverse event (n=5), did not complete an FVC assessment (n=2), lost to follow-up (n=1), lung transplantation (n=1), sponsor decision (n=1), and other (n=1)
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Table 2. Effect of alternative analytic methods and data imputation strategies on the statistical finding on the primary endpoint of change from baseline to week 52 in FVC in the ASCEND study
Imputation Methodology Analysis
Missing for reasons other than death
Missing due to death
P-value*
SSD†
Worst rank†
<0.001†
SSD
SSD
<0.001
LOCF
Worst rank
<0.001
LOCF
LOCF
<0.001
MI‡
Worst observed value¶
<0.001
No imputation
No imputation
<0.001
No imputation
No imputation
<0.001
Slope
Slope
<0.001
SSD
FVC=0
<0.001
SSD
FVC=1500 ml
<0.001
Rank ANCOVA
MMRM, ml RCM (slope analysis), ml Mean change, ml (ANCOVA)
SSD
SSD
<0.001
§
SSD
Worst category
<0.001
CMH (3 categories)‖
SSD
Worst category
<0.001
CMH (2 categories)
Definition of abbreviations: ANCOVA=analysis of covariance CMH=Cochran-Mantel-Haenszel row mean score test; FVC=forced vital capacity; LOCF=last observation carried forward; MI=multiple imputation; MMRM=mixed effect model with repeated measures; RCM=random coefficients model; SSD=sum of squared differences *Pirfenidone 2403 mg/d vs. placebo †
Prespecified primary efficacy analysis
‡
Multiple imputation using data from patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation
¶
Worst observed value among placebo patients who discontinued treatment prematurely but had a week 52 observation
§
Categorical thresholds: ≥10% absolute decline and <10% absolute decline
‖
Categorical thresholds: ≥10% absolute decline, >0 to <10% absolute decline, no decline
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Table 3. Effect of alternative analytic methods and data imputation strategies on the estimated magnitude of treatment effect on change in FVC at week 52 in the ASCEND study
Imputation Methodology Analysis
Categorical analysis (Proportion of patients with ≥10% decline or death)
MMRM, ml RCM (slope), ml
Mean change, ml
Pirfenidone (N=278)
Placebo (N=277)
Relative Reduction
Worst category
16.5%
31.8%
47.9%
SSD
SSD
12.6%
29.2%
56.9%
LOCF
Worst category
16.2%
31.0%
47.9%
LOCF
LOCF
12.2%
28.5%
57.1%
No imputation
No imputation
11.1%
25.9%
57.2%
No imputation
No imputation
–149.6
–268.5
44.3%
Slope
Slope
–163.6
–279.6
41.5%
SSD
FVC=0
–235.1
–427.9
45.1%
SSD
FVC=1500 ml
–175.5
–319.6
45.0%
SSD
SSD
–161.6
–274.4
41.1%
LOCF
FVC=0
–231.6
–423.2
45.3%
MI*
Worst observed†
–154.3
–266.8
42.2%
No imputation
No imputation
–144.9
–255.5
43.3%
Missing other than death
Missing due to death
SSD
Definition of abbreviations: FVC=forced vital capacity; LOCF=last observation carried forward; MI= multiple imputation; MMRM= mixed effect model with repeated measures; RCM=random coefficients model; SSD=sum of squared differences *Multiple imputation using data from patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation †
Worst observed value among placebo patients who discontinued treatment prematurely but had a week 52 observation
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Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis David J. Lederer, MD, Williamson Z. Bradford, MD, PhD, Elizabeth A. Fagan, MS, MD, Ian Glaspole, MB BS, PhD, Marilyn K. Glassberg, MD, Kenneth F. Glasscock, BS, David Kardatzke, PhD, Talmadge E. King, Jr., MD, Lisa H. Lancaster, MD, Steven D. Nathan, MD, Carlos A. Pereira, MD, Steven A. Sahn, MD, Jeffrey J. Swigris, DO, MS, Paul W. Noble, MD
Supplemental Material Institutional Review Board/Ethics Committee Approvals (ASCEND Study)
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Study Site
Principal Investigator
1001
James N. Allen, Jr. MD
1002
1003
1004
1005
1006
1007
1008
1009
Andrew L. Chan, MD
Francis Cordova, MD
Mark H. Gotfried, MD
IRB/Ethics Committee Name and Address
IRB/EC Approval Date
Protocol or Approval Number
July 8, 2011
1126215
UC Davis Medical Center lnstitutional Review Board CTSC Building, 2921 Stockton Blvd, Suite 1400, Room 1429 Sacramento, CA 95817 USA
November 8, 2011
258092-2
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
October 28, 2011
1128398
May 25, 2011
26042/8
September 13, 2011
1127603
August 25, 2011
201106311
University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., C1-206 Dallas, TX 75390-8843 USA
December 6, 2011
STU 072011-081
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
November 4, 2011
1128427
July 1, 2011
11-0282
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
Quorum Review lRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
John Terrill Huggins, MD (Formerly Steven Sahn, MD)
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
Tonya Russell, MD
Human Research Protection Office Washington University School of Medicine 660 South Euclid Avenue, Box 8089 St. Louis, MO 63110 USA
Carlos Girod, MD
Oksana Shlobin, MD
Mary Strek, MD
University of Chicago lnstitutional Review Board 5751 South Woodlawn Avenue, 2nd Floor Chicago, lL 60637 USA
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1021
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Maria L. Padilla MD
Nina M. Patel, MD
Gregory Tino, MD
Hyun J. Kim, MD
Jeffrey Golden, MD
John Belperio, MD
Kevin R. Flaherty, MD, MS
Marilyn K. Glassberg, MD
Keith C. Meyer, MD
Robert Baughman, MD
Program for the Protection of Human Subjects Icahn School of Medicine/Mount Sinai Medical Center 1 Gustave L. Levy Place, Box 1075, 3 East 101st Street New York, NY 10029 USA
December 8, 2011
11-1500
Columbia University Medical Center IRB 722 West 168th Street,4th Floor New York, NY 10032 USA
September 6, 2011
IRB-AAAI2351
University of Pennsylvania Office of Regulatory Affairs 3624 Market Street, Suite 301 S Philadelphia, PA 19104-6006 USA
September 9, 2011
814158
University of Minnesota IRB D 528 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 USA
September 22, 2011
1107M02627
October 7, 2011
028840
UCLA Office of Human Research Protection Program 11000 Kinross Avenue, Suite 211 Box 951694 Los Angeles, CA 90095-1694 USA
September 12, 2011
11-002305
University of Michigan Medical School IRB 2800 Plymouth Road Building 200, Room 2086 Ann Arbor, Ml 48109-2800 USA
September 22, 2011
HUM00053182
UM lRB c/o Human Subjects Research Office (HSRO) 1500 NW 12th Avenue, Suite. 1002 Miami, FL 33136 USA
September 12, 2011
20110402
Western lnstitutional Review Board 3535 7th Avenue SW Olympia, WA 98502 USA
October 14, 2011
1127872
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
September 13, 2011
1127168
The Committee on Human Research, UCSF 333 California Street, Suite 315 San Francisco, CA 94118 USA
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1028
1029
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1036
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1042
Ralph Panos, MD
Leo C. Ginns, MD
Harold D. Haller, Jr., MD
Deren M. Sinkowitz, MD
Danielle Antin-Ozerkis, MD
Adaani E. Frost, MD
John Pantano, MD
Sivagini Ganesh, MD, MPH
Jeremy P. Feldman, MD
Dennis P. Clifford, MD (Formerly Robert Lapidus, MD)
University of Cincinnati lnstitutional Review Board 51 Goodman Drive Suite 300 Cincinnati, OH 45221-0567 USA
October 12, 2011
11-07-18-01
August 9, 2011
2001-P-001508/1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 23, 2011
26042/7
UCLA Office of Human Research Protection Program 11000 Kinross Avenue Suite 211 Los Angelas, CA 90095-1694 USA
June 29, 2011
26042/17
Yale University School of Medicine Human lnvestigation Committee 55 College Street New Haven, CT 06520 USA
September 22, 2011
1107008775
Baylor College of Medicine Institutional Review Board for Human Subjects One Baylor Plaza, Room 600D Houston, TX 77030 USA
December 21, 2011
H-28809
May 20, 2011
26042/6
January 10, 2012
HS-11-00550
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 14, 2011
26042/16
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 9, 2011
26042/12
Partners Human Research Committee 116 Huntington Ave., Suite 1002 Boston, MA 02116 USA
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Health Sciences lnstitutional Review Board (HSlRB) University of Southern California Health Science Campus 1200 North State Street Suite 4700 Los Angeles, CA 90033 USA
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1056
Navdeep S. Rai, MD (Formerly Clifton Baylor, MD)
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Anoop Nambiar, MD
University of Texas Health Science Center San Antonio IRB Mail Code 7830, 7703 Floyd Curl Drive San Antonio, TX 78229 USA
John A. Butler, MD, FCCP
Henry D. Covelli, MD
Jacqueline Chang, MD
Murali Ramaswamy, MD
Augustine S. Lee, MD
Jay H. Ryu, MD
Alicia Gerke, MD
Maureen Horton, MD
Randolph Lipchik, MD, MPH (Formerly Rade Tomic, MD)
May 31, 2011
26042/10
January 10, 2012
HSC20110475H
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 13, 2011
26042/11
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 10, 2011
26042/1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 29, 2011
26042/14
Cone Health IRB/Committee for Human Research Protections 1200 North Elm Street Greensboro, NC 27401 USA
July 12, 2011
1485
Mayo Clinic lnstitutional Review Board 200 First Street, SW Rochester, MN 55905 USA
September 29, 2011
11-003167
Mayo Clinic lnstitutional Review Board 200 First Street, SW Rochester, MN 55905 USA
December 15, 2011
11-004690
Western lnstitutional Review Board 3535 Seventh Avenue Southwest Olympia, WA 98502-5010 USA
August 26, 2011
1126997
Johns Hopkins Institutional Review Board Reed Hall B-130,1620 McElderry Street Baltimore, MD 21205-1911 USA
October 10, 2011
NA_00051351
September 12, 2011
PRO00015985
Medical College of Wisconsin/Froedtert Hospital 8701 Watertown Plank Road HRC-MACC FUND 3040 Milwaukee, Wl 53226 USA
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Lee Morrow, MD
William P. Tillis, MD
Stephanie Eaton, MD
Daniel F. Dilling, MD
Rafael L. Perez, MD
Stuart Garay, MD
Richard Enelow, MD
Abubakr A. Bajwa, MD
Mark A. Yoder, MD
Jonathan S. llowite, MD
Creighton University IRB 2500 California Plaza Omaha, NE 68178 USA
September 6, 2011
11-16176
University of lllinois College of Medicine at Peoria IRB One Illini Drive, Box 1649 Peoria, lL 61656-1649 USA
July 14, 2011
247718-1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 16, 2011
26042/18
Loyola University Chicago Health Sciences Division IRB 2160 S. First Avenue Maywood, lL 60153 USA
July 20, 2011
203591072011
October 27, 2011
11.0455
June 22, 2011
26042/20
September 15, 2011
CPHS# 23002
Western Institutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
October 14, 2011
1128097
Research and Clinical Trials Administration Office Rush University Medical Center 1653 West Congress Parkway, Suite 439 Chicago, lL 60612 USA
November 9, 2011
11061703-IRB01
Western Institutional Review Board 3535 Seventh Avenue SW Olympia, WA 98502 USA
November 4, 2011
1128518
University of Louisville Human Subjects Protection Program MedCenter One, Suite 200, 501 E. Broadway Louisville, KY 40202 USA Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Dartmouth College Protection of Human Subjects Committee 63 South Main Street, #6254 Hanover, NH 03755 USA
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Peter LaCamera, MD
Gary Kinasewitz, MD
Donald W. Russell, MD
Mark J. Hamblin, MD
St. Elizabeth's Medical Center Institutional Review Board 736 Cambridge Street Boston, MA 02135 USA
August 8, 2011
00589
Office of Human Research Participant Protection 1000 SL Young Blvd., Lib 176 Oklahoma City, OK 73117 USA
January 3, 2012
16132
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
October 11, 2011
26042/26
Human Subjects Committee University of Kansas Medical Center 3901 Rainbow Blvd Kansas City, KS 66160 USA
January 26, 2012
13020
March 22, 2012
2012.06
January 23, 2012
26042/27
March 27, 2012
2012-0135
May 18, 2012
26042/30
September 18, 2012
40033
August 24, 2012
2012059
Christina Migliore, MD (Formerly Sean Studer, MD)
Barnabas Health lnstitutional Review Board Newark Beth lsrael Medical Center 201 Lyons Avenue Suite H-3 Newark, NJ 07112 USA
Anthony Floreani, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Paul Simonelli, MD, PhD
Dennis K. Zawadski, MD
Rebecca Bascom, MD, MPH
Timothy Evans, MD, PhD
Geisinger Institutional Review Board 100 North Acadamy Avenue Danville, PA 17822-3069 USA Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Human Subjects Protection Office/Institutional Review Board The Milton S. Hershey Medical Center 600 Centerview Drive, ASB1140 Hershey, PA 17033 USA Community Medical Centers Institutional Review Board 155 North Fresno Street Suite 290 Fresno, CA 93701 USA
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1508
1509
Jaun Sanchez, MD
Scott & White Institutional Review Board 2401 South 31st Street Temple, TX 76508 USA
August 23, 2012
120259
Low Su Ying, BA, BMBCh, MRCP
Office of Research, Singapore Health Services Pte Ltd 7 Hospital Drive, #03-01, Block A SingHealth Research Facilities Singapore 169611
August 6, 2012
2012/491/C
Joseph Parambil, MD
Cleveland Clinic Foundation Institutional Review Board Desk OS-1, 9500 Euclid Ave. Cleveland, Ohio 44195 USA
October 6, 2011
11-874
May 12, 2011
26042/3
University of Nebraska Medical Center IRB 987830 Nebraska Medical Center Omaha, NE 68198 USA
November 9, 2011
446-10-FB
National Jewish Health Institutional Review Board 1400 Jackson Street, M211 Denver, CO 80206 USA
October 27, 2011
HS-2616
Western Institutional Review Board 3535 7th Avenue SW Olympia, WA 98502-5010 USA
November 4, 2011
1128243
July 19, 2011
11-243907
August 2, 2011
21700
September 7, 2011
110982
Kevin Gibson, MD
Austin B. Thompson, MD
Jeffrey J. Swigris, DO, MS
Michael C. Kallay, MD
Joseph A. Lasky, MD
Glenn D. Rosen, MD
Lisa Lancaster, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Tulane University HRPO 1440 Canal Street Suite 1705, TW-36 New Orleans, LA 70112 USA Stanford University Administrative Panel on Human Subjects in Medical Research 1501 S. California Avenue Stanford, CA 94304 USA Vanderbilt Institutional Review Board 1313 21st Avenue South, Suite 504, Oxford House Nashville, TN 37232 USA
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Thomas Schaumberg, MD
Mary Beth Scholand, MD
Robert Sussman, MD
Mark L. Wencel, MD
Neil Ettinger, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 20, 2011
26042/19
November 23, 2011
IRB_00045185
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 20, 2011
26042/5
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 13, 2011
26042/4
St. Luke's Hospital IRB 232 South Woods Mill Road Chesterfield, MO 63017 USA
July 20, 2011
2011.021
The University of Utah lnstitutional Review Board Building 512 Room 140, 75 South 2000 East Salt Lake City, UT 84112 USA
Charles E. Rose Jr., MD (Formerly G. Verghese, MD)
UVA IRB-HSR One Morton Drive Suite 400, Box 5 Charlottesville, VA 22908 USA
November 8, 2011
15727
Lewis J. Wesselius, MD
Mayo Clinic Institutional Review Board 200 First Street SW Rochester, MN 55905 USA
October 28, 2011
11-004133
June 8, 2011
26042/13
August 23, 2011
Pro00031436
September 16, 2011
1127461
October 11, 2011
11-0645-03
Daniel G. Lorch, Jr., MD, CPl
Lake Daniel Morrison, MD
Joao M. De Andrade, MD
Wei Shen, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Duke University Health System Institutional Review Board Hock Plaza,Suite 405, 2424 Erwin Road Durham, NC 27705 USA Western Institutional Review Board 3535 7th Avenue SW Olympia, WA 98502 USA Southern Arizona VA Health Care Systems IRB 3601 South 6th Avenue (0-151) Tucson, AZ 85723
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1534
1541
1543
4001
4002
4003
Todd K. Horiuchi, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 15, 2011
26042/9
October 28, 2011
1128496
July 8, 2011
11-594
Baystate Medical Center Institutional Review Board 759 Chestnut Street Springfield, MA 01199 USA
September 7, 2011
244064-3
University of Vermont Research Protections Office 227 Waterman Building Burlington, VT 05401 USA
August 10, 2011
M11-245
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
October 2, 2012
26042/36
Spectrum Health, Office of the Institutional Review Board 100 Michigan, MC 38 Grand Rapids, Ml 49503 USA
October 15, 2012
2012-218
The Alfred Hospital Ethics Committee 55 Commercial Road Melbourne VlC 3004 Australia
September 8, 2011
276/11
Monique Malouf, MBBS FRACP
St. Vincent's Hospital Human Research Ethics Committee Level 6, de Lacy Building, 390 Victoria Street Darlinghurst NSW 2010 Australia
September 21, 2011
11/103
Huw Davies, MBBS FRACP
Southern Adelaide Clinical Research Ethics Committee Human Research Ethics Room 2A 221 Flinders Medical Centre Level 2 Bedford Park SA 5042 Australia
November 10, 2011
352.11
Daniel Grinnan, MD
Mark Yagan, MD
John Landis, MD
Gerald S. Davis, MD
Philip R. Foti, MD
Reda E. Girgis, MD
lan Glaspole, MBBS, FRACP
Western Institutional Review Board (WlRB) 3535 7th Avenue SW Olympia, WA 98502 USA Saint Luke's Institutional Review Board 4401 Wornall Road Kansas City, MO 64111 USA
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4502
4504
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Francis Thien, MBBS FRACP
Eastern Health Research and Ethics Committee 5 Arnold Street Box Hill VIC 3128 Australia
October 24, 2011
E09-1112
November 30, 2011
2011089
St. Vincent's Hospital Human Research Ethics Committee 390 Victoria Street Darlinghurst NSW 2010 Australia
January 20, 2012
X12-0001
Elizabeth Veitch, MBBS FRACP
St. Vincent's Hospital Human Research Ethics Committee 390 Victoria Street Darlinghurst NSW 2010 Australia
November 28, 2011
CH62/6/2011-169
Mark Holmes, MBBS FRACP MD
Royal Adelaide Hospital Research Ethics Committee Level 3, Hanson lnstitute North Terrace Adelaide, South Australia 5000 Australia
October 5, 2011
110723
Michael Musk, MBBS FRACP
Royal Perth Hospital Ethics Committee Level 5 Colonial House Wellington Street Perth WA 6000 Australia
August 11, 2011
EC 2011/071
Prince Charles Hospital Metro North Health Service District Human Research Ethics Committee Administration Building, Lower Ground, Rode Road Chermside, QLD 4032 Australia
July 28, 2011
HREC/11/QPCH/10 5
Mater Health Services Human Research Ethics Committee Room 235, Level 2, Aubigny Place Mater Adult Hospital Raymond Terrace South Brisbane QLD 4101 Australia
September 20, 2011
1766A
August 31, 2011
URB/11/07/026
Antony Veale, MBBS FRACP
Tamera Corte, MBBS FRACP
Peter Hopkins, MBBS FRACP
David Serisier, MBBS FRACP
Margaret Wilsher, MD MB ChB FRACP
Adelaide Health Service Human Research Ethics Committee Queen Elizabeth Hospital 28 Woodville Road Woodville South SA 5011 Australia
Northern B Health and Disability Ethics Committee, c/- Ministry of Health 1 The Terrace Wellington New Zealand
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5201
5203
5204
5206
5207
6101
6105
7002
Lutz Erwin Lothar Beckert, MD FRACP
Northern B Health and Disability Ethics Committee, c/-Ministry of Health 1 The Terrace Wellington New Zealand
Moises E. Selman Lama, MD
Comite de Ciencia y Bioetica en Investigacion del Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas Tlalpan 4502, Col. Secci6n XVl Mexico, D.F., Del Tlalpan. 14080 Mexico
Roberto Perea Sanchez, MD
Jesus Diaz Castafion, MD
Uriel Chavarria Martinez, MD
Rodolfo Posadas Valay, MD
August 31, 2011
URB/11/07/026
June 30, 2011
DI/CCB/161/11
September 5, 2011
N/A
July 12, 2011
N/A
Comite de Etica de la Facultad de Medicina de la UANL y Hospital Universitario 'Dr. Jose Eleuterio Gonzalez' Av. Francisco Madero Pte. y Dr. E. Aguirre Pequefio, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon Mexico
November 8, 2011
NM11-012
Comite de Etica lndependiente en lnvestigacion Cientifica Capitan Aguilar Sur 669, Colonia Obispado, 64060 Monterrey, Nuevo Leon Mexico
September 13, 2011
N/A
Comite de Investigacion y Etica, Hospital Central Universitario Calle Rosales No. 3302 Col. Obrera C.P. 31350 Chihuahua, Chihuahua, Mexico Comite de Etica Hospital Dr. Angel Leafio Av. Dr. Angel Leafio 500 C.P. 45200 Zapopan, Jalisco, Mexico
Tatjana Peros-Golubicic, MD, PhD
Central Ethics Committee Agency of Medicinal Products and Medical Devices Ksaverska cesta 4 10000 Zagreb, Croatia
October 30, 2012
381-15/60-12-08
Neven Tudoric, MD, PhD
Agency of Medicinal Products and Medical Devices Ksaverska cesta 4 10000 Zagreb, Croatia
July 11, 2012
381-15/60-12-04
February 29, 2012
085/2011
Elie Fiss, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
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7004
7006
7008
7009
8001
8002
8003
Adalberto Sperb Rubin, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
February 15, 2012
3697/12
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 26, 2011
CE0984.11
Rogerio Lopes Rufino Alves, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 2, 2012
3180/2012
Maria Eunice Morales de Oliveira, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
April 16, 2012
496/11
Carlos Ribeiro de Carvalho, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 9, 2012
0004/12
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
January 19, 2012
CE0036.12
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
May 26, 2011
CE0984.11
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
May 26, 2011
CE0983.11
Carlos Pereira, MD
Carlos lberico Barrera, MD
Socorro Castro Bernardini, MD
Luis Enrique Pun Leon, MD
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8005
8006
8007
8008
Danilo Joel Salazar Ore, MD
Comite Institucional de Etica en la lnvestigacion del Hospital Nacional Cayetano Heredia Av. Honorio Delgado 262, Urb. Ingenieria. San Martin de Porres Lima 31 Lima - Peru
January 19, 2012
N/A
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1157.11
Alfredo Guerreros Benavides, MD
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1206.11
Alberto Fuchigami, MD
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1199.11
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1212.11
September 6, 2012
0312-12-HMO
Jose William Torres Sales, MD
Andres Calderon, MD
9001
Raphael Breuer, MD
Helsinki Committee of Hadassah Hebrew University Medical Center Jerusalem, 91120 lsrael
9002
Yehuda A. Schwarz, MD
Helsinki Committee of Tel Aviv Sourasky Medical Center 6 Weizman St. Tel Aviv, 64239 lsrael
August 19, 2012
0407-12-TLV
October 11, 2012
9672-12-SMC
July 16, 2012
6919
September 2, 2012
0242-12-RMB
9003
Ben-Dov lssahar, MD
Helsinki Committee of The Chaim Sheba Medical Center Tel Hashomer, 52621 lsrael
9004
Mordechai Kramer, MD
Rabin Medical Center - Belinson Campus 39 Jabotinsky Street- 49100 Petach - Tikva, lsrael
9005
Mordechai Yigla, MD
Helsinki Committee of Rambam Health Care Campus POB 9602 Haifa, 31096 lsrael
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ONLINE FIRST This is an Online First, unedited version of this article. The final, edited version will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication. http://journal.publications.chestnet.org/
Online First articles are not copyedited prior to posting. ©American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
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Word count Text:
2230
Abstract:
241
Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis
David J. Lederer, MD1, Williamson Z. Bradford, MD, PhD2, Elizabeth A. Fagan, MS, MD2, Ian Glaspole, MB BS, PhD3, Marilyn K. Glassberg, MD4, Kenneth F. Glasscock, BS2, David Kardatzke, PhD2, Talmadge E. King, Jr., MD5, Lisa H. Lancaster, MD6, Steven D. Nathan, MD7, Carlos A. Pereira, MD8, Steven A. Sahn, MD9, Jeffrey J. Swigris, DO, MS10, Paul W. Noble, MD11
1
Columbia University Medical Center, New York, NY
2
InterMune, Inc., Brisbane, CA
3
Alfred Hospital, Melbourne, Australia
4
University of Miami Miller School of Medicine, Miami, FL
5
University of California, San Francisco, San Francisco, CA
6
Vanderbilt University Medical Center, Nashville, TN
7
Inova Fairfax Hospital, Falls Church, VA
8
Paulista School of Medicine, Federal University of São Paulo, Brazil
9
Medical University of South Carolina, Charleston, SC
10
National Jewish Health, Denver, CO
11
Cedars-Sinai Medical Center, Los Angeles, CA
Running Head: Pirfenidone for IPF
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Lederer et al. Corresponding author and request for reprints: David J. Lederer, MD Columbia University Medical Center 622 W 168th Street, PH14-101 New York, NY 10032 E-mail: [email protected]
Conflict of Interest Statement: DJL, IG, MKG, EAF, LHL, TEK, SDN, CAP, SAS, JJS, and PWN served as members of the ASCEND study steering committee. DJL has served on a scientific advisory board for Boehringer-Ingelheim, Gilead, Immune Works, and InterMune, Inc. IG has received honoraria from Boehringer Ingelheim. LHL has served on a scientific advisory board for Boehringer Ingelheim and InterMune, Inc., and as a consultant to Boehringer Ingelheim. TEK has served as a consultant for Actelion, Boehringer Ingelheim, Daiichi Sankyo, Immune Works, and InterMune. SDN has served on a scientific advisory board and received research funding from Intermune, Inc.; he has also received research funding and served as a consultant for Boehringer Ingelheim, Gilead Sciences and Roche/Genentech. CAP has received a research grant from InterMune, Inc. JJS has served on a scientific advisory board and received research funding from InterMune, Inc., and served as a consultant to Boehringer Ingelheim and Roche/Genentech. PWN has served as a consultant for Boehringer Ingelheim, Bristol Meyers Squibb, InterMune, Inc., Moerae Matrix, Roche/Genentech, and Takeda. WZB, EAF, KFG, and DK are employees of InterMune, Inc.
Financial Support: This study was sponsored by InterMune Inc. (Brisbane, CA)
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ABSTRACT Background: Forced vital capacity (FVC) outcomes in clinical trials in idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary endpoint of FVC change in a Phase 3 trial evaluating pirfenidone in adults with IPF. Methods: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the ASCEND study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary endpoint of change from baseline to week 52 in FVC. Results: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. Conclusion: Our results confirm the robustness of the statistical finding on the primary endpoint of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF.
Clinical Trial Registration Number: NCT01366209 (www.clinicaltrials.gov) Key words: interstitial lung disease, idiopathic pulmonary fibrosis, clinical trial
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Abbreviations ANCOVA
Analysis of covariance
CI
Confidence interval
FVC
Forced vital capacity
HR
Hazard ratio
IPF
Idiopathic pulmonary fibrosis
LOCF
Last observation carried forward
MI
Multiple imputation
MMRM
Mixed effect model with repeated measures
RCM
Random coefficients model
SSD
Sum of squared differences
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INTRODUCTION The selection of robust and clinically meaningful primary efficacy endpoints for therapeutic clinical trials in patients with idiopathic pulmonary fibrosis (IPF) has been the subject of considerable debate.1-7 Forced vital capacity (FVC), a widely used measure of disease status and a strong independent predictor of mortality in patients with IPF, 8-14 has emerged as the most common primary endpoint in IPF clinical trials. However, it is widely recognized that the analytic strategy and the method used to handle missing data can have a substantial influence on the magnitude of change in FVC and the estimate of effect size in therapeutic clinical trials in adults with IPF.15,16
The ASCEND study was a multinational, randomized, double-blind, placebo controlled, Phase 3 trial evaluating pirfenidone in adults with IPF.17 The primary efficacy endpoint in the study was the change from baseline to week 52 in percent predicted FVC, analyzed using a non-parametric rank analysis of covariance (ANCOVA) model that tested for between-group differences in the distribution of ranked change in FVC at week 52.
The rank ANCOVA model was selected as the test statistic for the primary efficacy analysis for three primary reasons. First, unlike some tests, the rank ANCOVA model requires no assumptions regarding data structure and distribution. Second, as a landmark analysis, it minimizes assumptions about the course preceding the measurement (i.e. no assumption of linearity) and provides an estimated effect size at a clinically relevant time point. Finally, it provides a satisfactory solution to the problem of missing data due to death—a clinically important outcome—without overweighting. Since deaths are assigned the lowest ranks according to the time of death since randomization, the model
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incorporates time to death and accounts for the effect of deaths on the primary outcome without the need to rely on the assignment of an arbitrary value for missing data.18,19
Importantly, while the rank ANCOVA model tests for between-group differences in the distribution of change from baseline, it provides no clinically interpretable information regarding the magnitude of the treatment effect. Therefore, the magnitude of treatment effect in the ASCEND study was estimated by comparing the distribution of patients in the pirfenidone and placebo groups across two clinically meaningful thresholds of change at week 52: an absolute decline of ≥10% in percent predicted FVC or death, and no decline in percent predicted FVC (≥0% change from baseline).
In the rank ANCOVA analysis of change from baseline to week 52 in percent predicted FVC, there was a statistically significant between-group difference that favored treatment with pirfenidone (p<0.001). Categorical analysis of outcomes at week 52 demonstrated that the proportion of patients with a ≥10% decline in FVC or death was decreased by 47.8% and the proportion of patients with no decline was increased by 132.5% in the pirfenidone group compared with placebo.17 The mean change from baseline to week 52 in FVC was –235 ml in the pirfenidone group and –428 ml in the placebo group (relative difference, 45.1%; p<0.001).
To examine the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect in the ASCEND study, we conducted a series of sensitivity analyses of the primary endpoint of change in FVC using alternative analytic methods and approaches to managing missing data.
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METHODS Patients All study participants who were randomized to treatment with pirfenidone 2403/mg day (N=278) or placebo (N=277) in the ASCEND study were included in the analyses. Eligibility criteria for the ASCEND study have been previously described.1 Briefly, eligible patients were between the ages of 40 and 80 years with a centrally confirmed diagnosis of IPF at least 6 months prior to randomisation. Physiologic eligibility criteria included a baseline percent predicted FVC ≥50% and ≤90%, percent predicted carbon monoxide diffusing capacity ≥30% and ≤90%, and 6-minute walk test distance ≥150 m.
Statistical Analyses The protocol-defined test statistic for the primary efficacy analysis in the ASCEND trial was a rank ANCOVA model with the standardized rank change in percent predicted FVC as the outcome variable and the standardized rank baseline value as a covariate. Missing values due to death were assigned the worst ranks according to the time of death since randomization. Missing values due to reasons other than death were imputed as the average value from the 3 patients (regardless of treatment assignment) with the smallest sum of squared differences at each study visit with non-missing values.20
A series of sensitivity analyses was conducted to assess the effect of alternative statistical tests and strategies for handling missing data on the robustness of the statistical finding and the observed magnitude of treatment effect on the primary
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endpoint of FVC change at week 52. Alternative statistical tests included the following: mixed effects linear model with repeated measures analysis of the annual rate of change in FVC; random coefficients model of the annual rate of change in FVC (slope analysis); mean change in FVC volume, analyzed using an ANCOVA model; CochranMantel-Haenszel row mean score test based on 2 categories of change in percent predicted FVC (≥10% absolute decline or death and <10% absolute decline); and Cochran-Mantel-Haenszel row mean score test based on 3 categories of change in percent predicted FVC (≥10% absolute decline or death, >0% and <10% absolute decline, and no decline).
Alternative methods for handling missing data due to death included the following: last observation carried forward; replacement with the average value from the 3 patients in either treatment group with the smallest sum of squared differences at each study visit with non-missing values; assignment to the worst category (for categorical analyses); replacement with the worst observed value at week 52 in the placebo group; replacement with the worst observed value at week 52 among placebo patients who discontinued treatment prior to week 52; replacement with the worst possible value (FVC=0); replacement with an intermediate value (FVC=1500 mL); and no imputation (i.e. observed data only).
For missing data due to reasons other than death, alternative imputation methods included the following: last observation carried forward; replacement with the average value from the 3 patients in either treatment group with the smallest sum of squared differences at each study visit with non-missing data; multiple imputation using data from
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patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation; multiple imputation using data from patients in the placebo group who had a week 52 observation; and no imputation.
The ASCEND study was conducted in accordance with the modified Declaration of Helsinki. All patients provided written informed consent and the study protocol was approved by the institutional review board or the ethics committee at each participating study center.
RESULTS A total of 555 patients were included in the analysis. The proportion of patients with missing FVC data at the week 52 study visit is summarized in Table 1. A total of 482 (86.6%) patients completed an FVC assessment at the week 52 study visit (243 [87.4%] in the pirfenidone group and 239 [86.3%] in the placebo group). Fewer patients in the pirfenidone group compared with placebo had a missing value due to death (11 [4.0%] vs. 20 [7.2%]) and slightly more patients in the pirfenidone group compared with placebo had a missing value due to a reason other than death (24 [8.6%] vs. 18 [6.5%]).
The statistical results of the various sensitivity analyses are summarised in Table 2. The distribution of change in FVC was systematically different between the pirfenidone and placebo groups and favored pirfenidone in each analysis. The p-value for the comparison between pirfenidone and placebo was <0.001 for each test statistic, supporting the robustness of the statistical finding in the primary efficacy analysis in the ASCEND study.
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Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis David J. Lederer, MD, Williamson Z. Bradford, MD, PhD, Elizabeth A. Fagan, MS, MD, Ian Glaspole, MB BS, PhD, Marilyn K. Glassberg, MD, Kenneth F. Glasscock, BS, David Kardatzke, PhD, Talmadge E. King, Jr., MD, Lisa H. Lancaster, MD, Steven D. Nathan, MD, Carlos A. Pereira, MD, Steven A. Sahn, MD, Jeffrey J. Swigris, DO, MS, Paul W. Noble, MD
Supplemental Material Institutional Review Board/Ethics Committee Approvals (ASCEND Study)
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Study Site
Principal Investigator
1001
James N. Allen, Jr. MD
1002
1003
1004
1005
1006
1007
1008
1009
Andrew L. Chan, MD
Francis Cordova, MD
Mark H. Gotfried, MD
IRB/Ethics Committee Name and Address
IRB/EC Approval Date
Protocol or Approval Number
July 8, 2011
1126215
UC Davis Medical Center lnstitutional Review Board CTSC Building, 2921 Stockton Blvd, Suite 1400, Room 1429 Sacramento, CA 95817 USA
November 8, 2011
258092-2
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
October 28, 2011
1128398
May 25, 2011
26042/8
September 13, 2011
1127603
August 25, 2011
201106311
University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., C1-206 Dallas, TX 75390-8843 USA
December 6, 2011
STU 072011-081
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
November 4, 2011
1128427
July 1, 2011
11-0282
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
Quorum Review lRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
John Terrill Huggins, MD (Formerly Steven Sahn, MD)
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
Tonya Russell, MD
Human Research Protection Office Washington University School of Medicine 660 South Euclid Avenue, Box 8089 St. Louis, MO 63110 USA
Carlos Girod, MD
Oksana Shlobin, MD
Mary Strek, MD
University of Chicago lnstitutional Review Board 5751 South Woodlawn Avenue, 2nd Floor Chicago, lL 60637 USA
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Our findings have two potentially important implications for the design and execution of clinical trials in IPF and the interpretation of study results. First, the influence of the data imputation methodology on the observed magnitude of change in FVC in both treatment groups in our study underscores the importance of ensuring that similar analytic methods are used when comparing FVC results across clinical trials. By way of illustration, it has been observed that the reported magnitude of decline in FVC at one year in the placebo group in the ASCEND trial (–428 ml) was substantially larger than the observed annual rate of decline in the placebo group in the recent INPULSIS trials (–223.5 ml),23 leading to speculation that this difference might be due to phenotypic differences in the study populations.7 Our analyses demonstrate that the apparent difference in the magnitude of decline in FVC in the ASCEND and INPULSIS trials is almost entirely attributable to differences in analytic methodology, including the handling of missing data due to deaths. Specifically, the reported magnitude of decline in the ASCEND trial was based on an analysis of mean change in FVC in which missing data due to death were assigned the worst possible value (FVC=0); the annual rate of decline in the INPULSIS trials was based on a slope analysis in which missing values due to death were not assigned a worst possible value. When the ASCEND data were analyzed using the methodology employed in the INPULSIS trials, the placebo rates of FVC decline were quite similar (–279.6 ml and –223.5 ml, respectively, in ASCEND and INPULSIS). Notably, the difference in the rates of decline between the placebo groups in the ASCEND and INPULSIS trials was roughly equivalent to the difference between the placebo groups in INPULSIS-1 and INPULSIS-2. Second, our results highlight the fundamental importance of study conduct in achieving robust and clinically interpretable results. Indeed, the robustness of the findings in the ASCEND study is attributable in
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part to the fact that there was minimal missing data; fully 94% of patients in both treatment groups completed the study, thereby limiting the influence of imputed data on study outcomes.
In conclusion, our results confirm the robustness of the statistical finding on the primary endpoint of change from baseline to week 52 in percent predicted FVC in the ASCEND study and corroborate the estimated magnitude of the pirfenidone treatment effect on FVC change in patients with IPF. Additionally, our findings demonstrate the effect of various analytic methods and data imputation strategies on the magnitude of change in FVC, thereby providing benchmarks to facilitate comparisons with other clinical trials.
Acknowledgments The authors thank the patients, family members, and participating staff at all study sites.
Contributions DJL, IG, MKG, EAF, LHL, DK, TEK, SDN, CAP, SAS, JJS, and PWN participated in the conception and design of the ASCEND study, as well as the acquisition and interpretation of original data. DJL, WZB, KFG, and DK were responsible for the conception and development of the plan for the analyses contained in the present report. DK performed the statistical analyses. DJL, WZB, and KFG were responsible for preparing the initial draft of the manuscript. IG, MKG, EAF, LHL, DK, TEK, SDN, CAP, SAS, JJS, and PWN participated in the review and critical revision of the manuscript for intellectual content. All authors approved the final draft and vouch for the accuracy of the overall content of the manuscript.
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REFERENCES 1. Raghu G, Collard HR, Anstrom KJ, et al. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2012;185:1044–8. 2. Rose DM, Montgomery AB. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2013;187:1269. 3. Bradford WZ, Cohen AH, Leff JA. Selection of clinically meaningful primary endpoints in phase 3 clinical trials in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2013;187:1269–70. 4. King TE Jr., Albera C, Bradford WZ, et al. All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. Am J Respir Crit Care Med 2014; 189:825–31. 5. O’Connell OJ, Egan JJ. The Burden of Disease and the Need for a Simple Staging System in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2014;189:765–7. 6. Lederer DJ. Clinical trials in idiopathic pulmonary fibrosis: a framework for moving forward. Eur Respir J 2013;42:1448–48. 7. Koczulla A. Treatments for idiopathic pulmonary fibrosis. N Engl J Med 2014;371: 781. 8. du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: Test properties and minimal clinically important difference. Am J Respir Crit Care Med 2011;184:1382–89. 9. Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538–42.
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10. Flaherty KR, Mumford JA, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:543–48. 11. Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171: 639–44. 12. King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy endpoints in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis. Chest 2005;127:171– 77. 13. Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in FVC is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 2009;35:830–36. 14. du Bois RM, Weycker D, Albera C, et al. Ascertainment of individual risk of mortality in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:459–66. 15. Richeldi L, Ryerson CJ, Lee JS, et al. Relative versus absolute change in forced vital capacity in patients with idiopathic pulmonary fibrosis. Thorax 2012;67:407–411. 16. Wells AU. Forced vital capacity as a primary end point in idiopathic pulmonary fibrosis treatment trials: making a silk purse from a sow’s ear. Thorax 2013;68: 309–310. 17. King TE, Jr., Bradford WZ, Castro-Bernadini C, et al. A Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083–92. 18. Lachin MJ. Worst-rank score analysis with informatively missing observations in clinical trials. Controlled Clinical Trials 1999;20:408–422.
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19. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med 1999;18:1341–1354. 20. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760–69. 21. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821–29. 22. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079–87. 23. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370: 2071–82. 24. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2093–101.
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Table 1. Forced vital capacity assessment at week 52*
Pirfenidone (N=278)
Placebo (N=277)
Total (N=555)
243 (87.4)
239 (86.3)
482 (86.8)
Imputed due to death
11 (4.0)
20 (7.2)
31 (5.6)
Imputed due to reasons other than death
24 (8.6)†
18 (6.5)‡
42 (7.6)
Patients, n (%) Observed
*Patients were required to complete two week 52 visits (week 52A and week 52B); the week 52 value was reported as the average value of the week 52A and week 52B assessments. †
Includes withdrawal by subject (n=7), adverse event (n=6), lung transplantation (n=6), lost to follow-up (n=2), did not complete an FVC assessment (n=1), physician decision (n=1), and other (n=1)
‡
Includes withdrawal by subject (n=7), adverse event (n=5), did not complete an FVC assessment (n=2), lost to follow-up (n=1), lung transplantation (n=1), sponsor decision (n=1), and other (n=1)
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Table 2. Effect of alternative analytic methods and data imputation strategies on the statistical finding on the primary endpoint of change from baseline to week 52 in FVC in the ASCEND study
Imputation Methodology Analysis
Missing for reasons other than death
Missing due to death
P-value*
SSD†
Worst rank†
<0.001†
SSD
SSD
<0.001
LOCF
Worst rank
<0.001
LOCF
LOCF
<0.001
MI‡
Worst observed value¶
<0.001
No imputation
No imputation
<0.001
No imputation
No imputation
<0.001
Slope
Slope
<0.001
SSD
FVC=0
<0.001
SSD
FVC=1500 ml
<0.001
Rank ANCOVA
MMRM, ml RCM (slope analysis), ml Mean change, ml (ANCOVA)
SSD
SSD
<0.001
§
SSD
Worst category
<0.001
CMH (3 categories)‖
SSD
Worst category
<0.001
CMH (2 categories)
Definition of abbreviations: ANCOVA=analysis of covariance CMH=Cochran-Mantel-Haenszel row mean score test; FVC=forced vital capacity; LOCF=last observation carried forward; MI=multiple imputation; MMRM=mixed effect model with repeated measures; RCM=random coefficients model; SSD=sum of squared differences *Pirfenidone 2403 mg/d vs. placebo †
Prespecified primary efficacy analysis
‡
Multiple imputation using data from patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation
¶
Worst observed value among placebo patients who discontinued treatment prematurely but had a week 52 observation
§
Categorical thresholds: ≥10% absolute decline and <10% absolute decline
‖
Categorical thresholds: ≥10% absolute decline, >0 to <10% absolute decline, no decline
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Table 3. Effect of alternative analytic methods and data imputation strategies on the estimated magnitude of treatment effect on change in FVC at week 52 in the ASCEND study
Imputation Methodology Analysis
Categorical analysis (Proportion of patients with ≥10% decline or death)
MMRM, ml RCM (slope), ml
Mean change, ml
Pirfenidone (N=278)
Placebo (N=277)
Relative Reduction
Worst category
16.5%
31.8%
47.9%
SSD
SSD
12.6%
29.2%
56.9%
LOCF
Worst category
16.2%
31.0%
47.9%
LOCF
LOCF
12.2%
28.5%
57.1%
No imputation
No imputation
11.1%
25.9%
57.2%
No imputation
No imputation
–149.6
–268.5
44.3%
Slope
Slope
–163.6
–279.6
41.5%
SSD
FVC=0
–235.1
–427.9
45.1%
SSD
FVC=1500 ml
–175.5
–319.6
45.0%
SSD
SSD
–161.6
–274.4
41.1%
LOCF
FVC=0
–231.6
–423.2
45.3%
MI*
Worst observed†
–154.3
–266.8
42.2%
No imputation
No imputation
–144.9
–255.5
43.3%
Missing other than death
Missing due to death
SSD
Definition of abbreviations: FVC=forced vital capacity; LOCF=last observation carried forward; MI= multiple imputation; MMRM= mixed effect model with repeated measures; RCM=random coefficients model; SSD=sum of squared differences *Multiple imputation using data from patients in the same treatment group who discontinued treatment prematurely but had a week 52 observation †
Worst observed value among placebo patients who discontinued treatment prematurely but had a week 52 observation
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Sensitivity Analyses of the Change in Forced Vital Capacity in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis David J. Lederer, MD, Williamson Z. Bradford, MD, PhD, Elizabeth A. Fagan, MS, MD, Ian Glaspole, MB BS, PhD, Marilyn K. Glassberg, MD, Kenneth F. Glasscock, BS, David Kardatzke, PhD, Talmadge E. King, Jr., MD, Lisa H. Lancaster, MD, Steven D. Nathan, MD, Carlos A. Pereira, MD, Steven A. Sahn, MD, Jeffrey J. Swigris, DO, MS, Paul W. Noble, MD
Supplemental Material Institutional Review Board/Ethics Committee Approvals (ASCEND Study)
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Page 22 of 35
Study Site
Principal Investigator
1001
James N. Allen, Jr. MD
1002
1003
1004
1005
1006
1007
1008
1009
Andrew L. Chan, MD
Francis Cordova, MD
Mark H. Gotfried, MD
IRB/Ethics Committee Name and Address
IRB/EC Approval Date
Protocol or Approval Number
July 8, 2011
1126215
UC Davis Medical Center lnstitutional Review Board CTSC Building, 2921 Stockton Blvd, Suite 1400, Room 1429 Sacramento, CA 95817 USA
November 8, 2011
258092-2
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
October 28, 2011
1128398
May 25, 2011
26042/8
September 13, 2011
1127603
August 25, 2011
201106311
University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., C1-206 Dallas, TX 75390-8843 USA
December 6, 2011
STU 072011-081
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
November 4, 2011
1128427
July 1, 2011
11-0282
Western lnstitutional Review Board 3535 Seventh Ave SW Olympia, WA 98502-5010 USA
Quorum Review lRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
John Terrill Huggins, MD (Formerly Steven Sahn, MD)
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
Tonya Russell, MD
Human Research Protection Office Washington University School of Medicine 660 South Euclid Avenue, Box 8089 St. Louis, MO 63110 USA
Carlos Girod, MD
Oksana Shlobin, MD
Mary Strek, MD
University of Chicago lnstitutional Review Board 5751 South Woodlawn Avenue, 2nd Floor Chicago, lL 60637 USA
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1010
1012
1013
1014
1015
1016
1018
1020
1021
1026
Maria L. Padilla MD
Nina M. Patel, MD
Gregory Tino, MD
Hyun J. Kim, MD
Jeffrey Golden, MD
John Belperio, MD
Kevin R. Flaherty, MD, MS
Marilyn K. Glassberg, MD
Keith C. Meyer, MD
Robert Baughman, MD
Program for the Protection of Human Subjects Icahn School of Medicine/Mount Sinai Medical Center 1 Gustave L. Levy Place, Box 1075, 3 East 101st Street New York, NY 10029 USA
December 8, 2011
11-1500
Columbia University Medical Center IRB 722 West 168th Street,4th Floor New York, NY 10032 USA
September 6, 2011
IRB-AAAI2351
University of Pennsylvania Office of Regulatory Affairs 3624 Market Street, Suite 301 S Philadelphia, PA 19104-6006 USA
September 9, 2011
814158
University of Minnesota IRB D 528 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 USA
September 22, 2011
1107M02627
October 7, 2011
028840
UCLA Office of Human Research Protection Program 11000 Kinross Avenue, Suite 211 Box 951694 Los Angeles, CA 90095-1694 USA
September 12, 2011
11-002305
University of Michigan Medical School IRB 2800 Plymouth Road Building 200, Room 2086 Ann Arbor, Ml 48109-2800 USA
September 22, 2011
HUM00053182
UM lRB c/o Human Subjects Research Office (HSRO) 1500 NW 12th Avenue, Suite. 1002 Miami, FL 33136 USA
September 12, 2011
20110402
Western lnstitutional Review Board 3535 7th Avenue SW Olympia, WA 98502 USA
October 14, 2011
1127872
Western lnstitutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
September 13, 2011
1127168
The Committee on Human Research, UCSF 333 California Street, Suite 315 San Francisco, CA 94118 USA
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1042
Ralph Panos, MD
Leo C. Ginns, MD
Harold D. Haller, Jr., MD
Deren M. Sinkowitz, MD
Danielle Antin-Ozerkis, MD
Adaani E. Frost, MD
John Pantano, MD
Sivagini Ganesh, MD, MPH
Jeremy P. Feldman, MD
Dennis P. Clifford, MD (Formerly Robert Lapidus, MD)
University of Cincinnati lnstitutional Review Board 51 Goodman Drive Suite 300 Cincinnati, OH 45221-0567 USA
October 12, 2011
11-07-18-01
August 9, 2011
2001-P-001508/1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 23, 2011
26042/7
UCLA Office of Human Research Protection Program 11000 Kinross Avenue Suite 211 Los Angelas, CA 90095-1694 USA
June 29, 2011
26042/17
Yale University School of Medicine Human lnvestigation Committee 55 College Street New Haven, CT 06520 USA
September 22, 2011
1107008775
Baylor College of Medicine Institutional Review Board for Human Subjects One Baylor Plaza, Room 600D Houston, TX 77030 USA
December 21, 2011
H-28809
May 20, 2011
26042/6
January 10, 2012
HS-11-00550
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 14, 2011
26042/16
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 9, 2011
26042/12
Partners Human Research Committee 116 Huntington Ave., Suite 1002 Boston, MA 02116 USA
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Health Sciences lnstitutional Review Board (HSlRB) University of Southern California Health Science Campus 1200 North State Street Suite 4700 Los Angeles, CA 90033 USA
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1045
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1049
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1053
1055
1056
Navdeep S. Rai, MD (Formerly Clifton Baylor, MD)
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Anoop Nambiar, MD
University of Texas Health Science Center San Antonio IRB Mail Code 7830, 7703 Floyd Curl Drive San Antonio, TX 78229 USA
John A. Butler, MD, FCCP
Henry D. Covelli, MD
Jacqueline Chang, MD
Murali Ramaswamy, MD
Augustine S. Lee, MD
Jay H. Ryu, MD
Alicia Gerke, MD
Maureen Horton, MD
Randolph Lipchik, MD, MPH (Formerly Rade Tomic, MD)
May 31, 2011
26042/10
January 10, 2012
HSC20110475H
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 13, 2011
26042/11
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 10, 2011
26042/1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 29, 2011
26042/14
Cone Health IRB/Committee for Human Research Protections 1200 North Elm Street Greensboro, NC 27401 USA
July 12, 2011
1485
Mayo Clinic lnstitutional Review Board 200 First Street, SW Rochester, MN 55905 USA
September 29, 2011
11-003167
Mayo Clinic lnstitutional Review Board 200 First Street, SW Rochester, MN 55905 USA
December 15, 2011
11-004690
Western lnstitutional Review Board 3535 Seventh Avenue Southwest Olympia, WA 98502-5010 USA
August 26, 2011
1126997
Johns Hopkins Institutional Review Board Reed Hall B-130,1620 McElderry Street Baltimore, MD 21205-1911 USA
October 10, 2011
NA_00051351
September 12, 2011
PRO00015985
Medical College of Wisconsin/Froedtert Hospital 8701 Watertown Plank Road HRC-MACC FUND 3040 Milwaukee, Wl 53226 USA
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1072
Lee Morrow, MD
William P. Tillis, MD
Stephanie Eaton, MD
Daniel F. Dilling, MD
Rafael L. Perez, MD
Stuart Garay, MD
Richard Enelow, MD
Abubakr A. Bajwa, MD
Mark A. Yoder, MD
Jonathan S. llowite, MD
Creighton University IRB 2500 California Plaza Omaha, NE 68178 USA
September 6, 2011
11-16176
University of lllinois College of Medicine at Peoria IRB One Illini Drive, Box 1649 Peoria, lL 61656-1649 USA
July 14, 2011
247718-1
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 16, 2011
26042/18
Loyola University Chicago Health Sciences Division IRB 2160 S. First Avenue Maywood, lL 60153 USA
July 20, 2011
203591072011
October 27, 2011
11.0455
June 22, 2011
26042/20
September 15, 2011
CPHS# 23002
Western Institutional Review Board 3535 7th Ave SW Olympia, WA 98502 USA
October 14, 2011
1128097
Research and Clinical Trials Administration Office Rush University Medical Center 1653 West Congress Parkway, Suite 439 Chicago, lL 60612 USA
November 9, 2011
11061703-IRB01
Western Institutional Review Board 3535 Seventh Avenue SW Olympia, WA 98502 USA
November 4, 2011
1128518
University of Louisville Human Subjects Protection Program MedCenter One, Suite 200, 501 E. Broadway Louisville, KY 40202 USA Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Dartmouth College Protection of Human Subjects Committee 63 South Main Street, #6254 Hanover, NH 03755 USA
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1093
Peter LaCamera, MD
Gary Kinasewitz, MD
Donald W. Russell, MD
Mark J. Hamblin, MD
St. Elizabeth's Medical Center Institutional Review Board 736 Cambridge Street Boston, MA 02135 USA
August 8, 2011
00589
Office of Human Research Participant Protection 1000 SL Young Blvd., Lib 176 Oklahoma City, OK 73117 USA
January 3, 2012
16132
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
October 11, 2011
26042/26
Human Subjects Committee University of Kansas Medical Center 3901 Rainbow Blvd Kansas City, KS 66160 USA
January 26, 2012
13020
March 22, 2012
2012.06
January 23, 2012
26042/27
March 27, 2012
2012-0135
May 18, 2012
26042/30
September 18, 2012
40033
August 24, 2012
2012059
Christina Migliore, MD (Formerly Sean Studer, MD)
Barnabas Health lnstitutional Review Board Newark Beth lsrael Medical Center 201 Lyons Avenue Suite H-3 Newark, NJ 07112 USA
Anthony Floreani, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Paul Simonelli, MD, PhD
Dennis K. Zawadski, MD
Rebecca Bascom, MD, MPH
Timothy Evans, MD, PhD
Geisinger Institutional Review Board 100 North Acadamy Avenue Danville, PA 17822-3069 USA Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Human Subjects Protection Office/Institutional Review Board The Milton S. Hershey Medical Center 600 Centerview Drive, ASB1140 Hershey, PA 17033 USA Community Medical Centers Institutional Review Board 155 North Fresno Street Suite 290 Fresno, CA 93701 USA
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1201
1501
1502
1503
1504
1505
1506
1508
1509
Jaun Sanchez, MD
Scott & White Institutional Review Board 2401 South 31st Street Temple, TX 76508 USA
August 23, 2012
120259
Low Su Ying, BA, BMBCh, MRCP
Office of Research, Singapore Health Services Pte Ltd 7 Hospital Drive, #03-01, Block A SingHealth Research Facilities Singapore 169611
August 6, 2012
2012/491/C
Joseph Parambil, MD
Cleveland Clinic Foundation Institutional Review Board Desk OS-1, 9500 Euclid Ave. Cleveland, Ohio 44195 USA
October 6, 2011
11-874
May 12, 2011
26042/3
University of Nebraska Medical Center IRB 987830 Nebraska Medical Center Omaha, NE 68198 USA
November 9, 2011
446-10-FB
National Jewish Health Institutional Review Board 1400 Jackson Street, M211 Denver, CO 80206 USA
October 27, 2011
HS-2616
Western Institutional Review Board 3535 7th Avenue SW Olympia, WA 98502-5010 USA
November 4, 2011
1128243
July 19, 2011
11-243907
August 2, 2011
21700
September 7, 2011
110982
Kevin Gibson, MD
Austin B. Thompson, MD
Jeffrey J. Swigris, DO, MS
Michael C. Kallay, MD
Joseph A. Lasky, MD
Glenn D. Rosen, MD
Lisa Lancaster, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
Tulane University HRPO 1440 Canal Street Suite 1705, TW-36 New Orleans, LA 70112 USA Stanford University Administrative Panel on Human Subjects in Medical Research 1501 S. California Avenue Stanford, CA 94304 USA Vanderbilt Institutional Review Board 1313 21st Avenue South, Suite 504, Oxford House Nashville, TN 37232 USA
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Thomas Schaumberg, MD
Mary Beth Scholand, MD
Robert Sussman, MD
Mark L. Wencel, MD
Neil Ettinger, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 20, 2011
26042/19
November 23, 2011
IRB_00045185
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 20, 2011
26042/5
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
May 13, 2011
26042/4
St. Luke's Hospital IRB 232 South Woods Mill Road Chesterfield, MO 63017 USA
July 20, 2011
2011.021
The University of Utah lnstitutional Review Board Building 512 Room 140, 75 South 2000 East Salt Lake City, UT 84112 USA
Charles E. Rose Jr., MD (Formerly G. Verghese, MD)
UVA IRB-HSR One Morton Drive Suite 400, Box 5 Charlottesville, VA 22908 USA
November 8, 2011
15727
Lewis J. Wesselius, MD
Mayo Clinic Institutional Review Board 200 First Street SW Rochester, MN 55905 USA
October 28, 2011
11-004133
June 8, 2011
26042/13
August 23, 2011
Pro00031436
September 16, 2011
1127461
October 11, 2011
11-0645-03
Daniel G. Lorch, Jr., MD, CPl
Lake Daniel Morrison, MD
Joao M. De Andrade, MD
Wei Shen, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA Duke University Health System Institutional Review Board Hock Plaza,Suite 405, 2424 Erwin Road Durham, NC 27705 USA Western Institutional Review Board 3535 7th Avenue SW Olympia, WA 98502 USA Southern Arizona VA Health Care Systems IRB 3601 South 6th Avenue (0-151) Tucson, AZ 85723
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4002
4003
Todd K. Horiuchi, MD
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
June 15, 2011
26042/9
October 28, 2011
1128496
July 8, 2011
11-594
Baystate Medical Center Institutional Review Board 759 Chestnut Street Springfield, MA 01199 USA
September 7, 2011
244064-3
University of Vermont Research Protections Office 227 Waterman Building Burlington, VT 05401 USA
August 10, 2011
M11-245
Quorum Review IRB 1601 Fifth Avenue, Suite 1000 Seattle, WA 98101 USA
October 2, 2012
26042/36
Spectrum Health, Office of the Institutional Review Board 100 Michigan, MC 38 Grand Rapids, Ml 49503 USA
October 15, 2012
2012-218
The Alfred Hospital Ethics Committee 55 Commercial Road Melbourne VlC 3004 Australia
September 8, 2011
276/11
Monique Malouf, MBBS FRACP
St. Vincent's Hospital Human Research Ethics Committee Level 6, de Lacy Building, 390 Victoria Street Darlinghurst NSW 2010 Australia
September 21, 2011
11/103
Huw Davies, MBBS FRACP
Southern Adelaide Clinical Research Ethics Committee Human Research Ethics Room 2A 221 Flinders Medical Centre Level 2 Bedford Park SA 5042 Australia
November 10, 2011
352.11
Daniel Grinnan, MD
Mark Yagan, MD
John Landis, MD
Gerald S. Davis, MD
Philip R. Foti, MD
Reda E. Girgis, MD
lan Glaspole, MBBS, FRACP
Western Institutional Review Board (WlRB) 3535 7th Avenue SW Olympia, WA 98502 USA Saint Luke's Institutional Review Board 4401 Wornall Road Kansas City, MO 64111 USA
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4502
4504
4601
Francis Thien, MBBS FRACP
Eastern Health Research and Ethics Committee 5 Arnold Street Box Hill VIC 3128 Australia
October 24, 2011
E09-1112
November 30, 2011
2011089
St. Vincent's Hospital Human Research Ethics Committee 390 Victoria Street Darlinghurst NSW 2010 Australia
January 20, 2012
X12-0001
Elizabeth Veitch, MBBS FRACP
St. Vincent's Hospital Human Research Ethics Committee 390 Victoria Street Darlinghurst NSW 2010 Australia
November 28, 2011
CH62/6/2011-169
Mark Holmes, MBBS FRACP MD
Royal Adelaide Hospital Research Ethics Committee Level 3, Hanson lnstitute North Terrace Adelaide, South Australia 5000 Australia
October 5, 2011
110723
Michael Musk, MBBS FRACP
Royal Perth Hospital Ethics Committee Level 5 Colonial House Wellington Street Perth WA 6000 Australia
August 11, 2011
EC 2011/071
Prince Charles Hospital Metro North Health Service District Human Research Ethics Committee Administration Building, Lower Ground, Rode Road Chermside, QLD 4032 Australia
July 28, 2011
HREC/11/QPCH/10 5
Mater Health Services Human Research Ethics Committee Room 235, Level 2, Aubigny Place Mater Adult Hospital Raymond Terrace South Brisbane QLD 4101 Australia
September 20, 2011
1766A
August 31, 2011
URB/11/07/026
Antony Veale, MBBS FRACP
Tamera Corte, MBBS FRACP
Peter Hopkins, MBBS FRACP
David Serisier, MBBS FRACP
Margaret Wilsher, MD MB ChB FRACP
Adelaide Health Service Human Research Ethics Committee Queen Elizabeth Hospital 28 Woodville Road Woodville South SA 5011 Australia
Northern B Health and Disability Ethics Committee, c/- Ministry of Health 1 The Terrace Wellington New Zealand
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5201
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5204
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5207
6101
6105
7002
Lutz Erwin Lothar Beckert, MD FRACP
Northern B Health and Disability Ethics Committee, c/-Ministry of Health 1 The Terrace Wellington New Zealand
Moises E. Selman Lama, MD
Comite de Ciencia y Bioetica en Investigacion del Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosio Villegas Tlalpan 4502, Col. Secci6n XVl Mexico, D.F., Del Tlalpan. 14080 Mexico
Roberto Perea Sanchez, MD
Jesus Diaz Castafion, MD
Uriel Chavarria Martinez, MD
Rodolfo Posadas Valay, MD
August 31, 2011
URB/11/07/026
June 30, 2011
DI/CCB/161/11
September 5, 2011
N/A
July 12, 2011
N/A
Comite de Etica de la Facultad de Medicina de la UANL y Hospital Universitario 'Dr. Jose Eleuterio Gonzalez' Av. Francisco Madero Pte. y Dr. E. Aguirre Pequefio, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon Mexico
November 8, 2011
NM11-012
Comite de Etica lndependiente en lnvestigacion Cientifica Capitan Aguilar Sur 669, Colonia Obispado, 64060 Monterrey, Nuevo Leon Mexico
September 13, 2011
N/A
Comite de Investigacion y Etica, Hospital Central Universitario Calle Rosales No. 3302 Col. Obrera C.P. 31350 Chihuahua, Chihuahua, Mexico Comite de Etica Hospital Dr. Angel Leafio Av. Dr. Angel Leafio 500 C.P. 45200 Zapopan, Jalisco, Mexico
Tatjana Peros-Golubicic, MD, PhD
Central Ethics Committee Agency of Medicinal Products and Medical Devices Ksaverska cesta 4 10000 Zagreb, Croatia
October 30, 2012
381-15/60-12-08
Neven Tudoric, MD, PhD
Agency of Medicinal Products and Medical Devices Ksaverska cesta 4 10000 Zagreb, Croatia
July 11, 2012
381-15/60-12-04
February 29, 2012
085/2011
Elie Fiss, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
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7004
7006
7008
7009
8001
8002
8003
Adalberto Sperb Rubin, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
February 15, 2012
3697/12
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 26, 2011
CE0984.11
Rogerio Lopes Rufino Alves, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 2, 2012
3180/2012
Maria Eunice Morales de Oliveira, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
April 16, 2012
496/11
Carlos Ribeiro de Carvalho, MD
Comissao Nacional de Etica em Pesquisa Esplanada dos Ministerios, Ministerio da Saude Bloco G, Anexo B - sala 436b Brasilia/DF 70058-900, Brazil
May 9, 2012
0004/12
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
January 19, 2012
CE0036.12
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
May 26, 2011
CE0984.11
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
May 26, 2011
CE0983.11
Carlos Pereira, MD
Carlos lberico Barrera, MD
Socorro Castro Bernardini, MD
Luis Enrique Pun Leon, MD
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8005
8006
8007
8008
Danilo Joel Salazar Ore, MD
Comite Institucional de Etica en la lnvestigacion del Hospital Nacional Cayetano Heredia Av. Honorio Delgado 262, Urb. Ingenieria. San Martin de Porres Lima 31 Lima - Peru
January 19, 2012
N/A
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1157.11
Alfredo Guerreros Benavides, MD
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1206.11
Alberto Fuchigami, MD
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1199.11
Comite Institucional de Etica en Investigacion de la Asociacion Benefica Prisma Calle Carlos Gonzalez 251, Urb. Maranga Lima 32 Lima - Peru
June 30, 2011
CE1212.11
September 6, 2012
0312-12-HMO
Jose William Torres Sales, MD
Andres Calderon, MD
9001
Raphael Breuer, MD
Helsinki Committee of Hadassah Hebrew University Medical Center Jerusalem, 91120 lsrael
9002
Yehuda A. Schwarz, MD
Helsinki Committee of Tel Aviv Sourasky Medical Center 6 Weizman St. Tel Aviv, 64239 lsrael
August 19, 2012
0407-12-TLV
October 11, 2012
9672-12-SMC
July 16, 2012
6919
September 2, 2012
0242-12-RMB
9003
Ben-Dov lssahar, MD
Helsinki Committee of The Chaim Sheba Medical Center Tel Hashomer, 52621 lsrael
9004
Mordechai Kramer, MD
Rabin Medical Center - Belinson Campus 39 Jabotinsky Street- 49100 Petach - Tikva, lsrael
9005
Mordechai Yigla, MD
Helsinki Committee of Rambam Health Care Campus POB 9602 Haifa, 31096 lsrael
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