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Treatments for Idiopathic Pulmonary Fibrosis To the Editor: In reporting the results of the INPULSIS-1 and INPULSIS-2 trials, Richeldi et al. (May 29 issue)1 describe the use of nintedanib in the treatment of idiopathic pulmonary fibrosis. In the same issue, King et al.2 report the results of the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study of the use of pirfenidone for this condition. In the two INPULSIS trials, a significant and similar benefit with nintedanib versus placebo was observed with respect to the primary end point, the annual rate of decline in forced vital capacity (FVC). In the ASCEND trial, the primary end point was prespecified as the change from baseline to week 52 in the percentage of the predicted FVC, but the test statistic used was based on a “cutoff point” analysis. In the secondary outcome data provided in the ­ASCEND trial, the mean decline from baseline in FVC over 52 weeks in the placebo group was 428 ml, as compared with an average of 150 to 200 ml per year in contemporary trials.1,3 Can the authors provide an explanation of this inconsistency? A.-Rembert Koczulla, M.D. Philipps University Marburg Marburg, Germany [email protected] Dr. Koczulla reports receiving fees for serving on advisory boards from Almirall and Mundipharma and receiving lecture fees and travel support from Almirall, Boehringer Ingelheim, Chiesi, Grifols, Mundipharma, and Novartis. No other potential conflict of interest relevant to this letter was reported. 1. 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. 2. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92.

3. Ley B, Collard HR, King TE Jr. Clinical course and prediction

of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431-40.

DOI: 10.1056/NEJMc1407776

To the Editor: Richeldi et al. report that 178 patients in the nintedanib group had dose reductions for the management of adverse events, including 82 patients in INPULSIS-1 (26.5%) and 96 patients in INPULSIS-2 (29.2%). Nintedanib is a triple tyrosine kinase inhibitor that is currently in clinical development as a potential treatment for a number of types of cancer.1 Previous studies have suggested that improvements in overall and progression-free survival observed during treatment with epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer are associated with the development and severity of adverse events such as rash.2 Treatment with reduced doses of tyrosine kinase inhibitors could therefore produce substantial therapeutic benefits in patients who have potent adverse effects (both in patients with idiopathic pulmonary fibrosis and in patients with non–small-cell lung cancer). Can the authors provide data on the rate of decline in FVC among the patients in the nintedanib group who had dose reductions? If this decline was identical to that seen in the patients without dose reductions, there may be a

this week’s letters 781

Treatments for Idiopathic Pulmonary Fibrosis

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The Metabolic Syndrome and DYRK1B

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parallel between the treatment of various cancers and that of idiopathic pulmonary fibrosis, indicating that the potent adverse events may be a predictor of favorable outcome. Shinyu Izumi, M.D., Ph.D. Motoyasu Iikura, M.D., Ph.D. Haruhito Sugiyama, M.D., Ph.D. National Center for Global Health and Medicine Tokyo, Japan [email protected] No potential conflict of interest relevant to this letter was reported. 1. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angio-

kinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008;68:4774-82. 2. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913-21. DOI: 10.1056/NEJMc1407776

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To the Editor: We have some concerns regarding the management of missing data on FVC values and lung transplantation events in the ASCEND trial. Missing FVC values owing to death in 31 patients (5.6%) were assigned a value of 0, which decreased the mean FVC decline of the whole group, so comparison with the trial reported by Richeldi et al. is difficult. Because missing FVC values do not occur at random, an analysis ignoring the dropout process is biased. However, other methods such as a joint modeling of the FVC decline and time to death have been found to be appropriate in analyses in which data are missing not at random.1 The occurrence of transplantation precludes any subsequent meaningful assessment of vital status. Because undergoing transplantation is a strong indicator of disease worsening and treatment failure, a composite end point of death or transplantation, previously used in such studies, could be informative.2 Because transplantation occurred more frequently in the pirfenidone group than in the placebo group in the ASCEND study (six patients vs. one patient), we wonder whether pirfenidone would have had a beneficial effect on this end point in a combined analysis of the ASCEND and Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes ­(CAPACITY)3 trials.

To the Editor: King and colleagues report that among patients with idiopathic pulmonary fibrosis, pirfenidone significantly attenuated the proportion of patients who had declines of 10 percentage points or more in the percentage of the predicted FVC and the proportion of patients who had decreases in the 6-minute walk distance. They further show decreased mortality at 1 year. We wonder whether the authors can provide data on the ability of pirfenidone to prevent exacerbations of idiopathic pulmonary fibrosis defined according to the following criteria: wors- Gabriel Thabut, M.D., Ph.D. ening of dyspnea within 30 days, new findings Bruno Crestani, M.D., Ph.D. on high-resolution computed tomography, and Bichat Hospital the absence of an alternative identifiable cause Paris, France 1 such as infection. Patients with clinical deterio- [email protected] ration who do not fulfill the above criteria owing Dr. Crestani reports receiving consulting fees from Boehto missing data receive a diagnosis of suspected ringer Ingelheim, InterMune, and Sanofi and research grants Boehringer Ingelheim, InterMune, and Roche. No other acute exacerbation.1 Furthermore, can the au- from potential conflict of interest relevant to this letter was re­ thors describe their management of these events? ported. Hirotsugu Ohkubo, M.D., Ph.D. 1. Lawrence Gould A, Boye ME, Crowther MJ, et al. Joint modeling of survival and longitudinal non-survival data: curNorihisa Takeda, M.D. rent methods and issues: report of the DIA Bayesian joint modAkio Niimi, M.D., Ph.D. Nagoya City University Graduate School of Medical Sciences Nagoya, Japan [email protected] No potential conflict of interest relevant to this letter was reported. 1. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerba-

tions of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636-43. DOI: 10.1056/NEJMc1407776

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eling working group. Stat Med 2014 March 14 (Epub ahead of print). 2. King TE Jr, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009;374:222-8. 3. Nobel PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760-9. DOI: 10.1056/NEJMc1407776

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correspondence

Dr. Richeldi Replies: In response to Koczulla’s comment: when my colleagues and I compared the slope of FVC decline (which was a secondary end point in the ASCEND trial and the primary end point in the INPULSIS trials), similar effects were observed in these trials. The difference observed in FVC decline in the placebo groups of the ASCEND and INPULSIS trials is due to the way in which FVC was “scored” for patients who died in the ASCEND trial and in other InterMune studies,1 which does not provide a precise measure of FVC decline in the placebo group as a whole.2 With regard to the valuable and clinically relevant question raised by Izumi and colleagues: in the INPULSIS trials, dose reductions from 150 mg of nintedanib twice daily to 100 mg twice daily and treatment interruptions to manage adverse events were allowed. We conducted a prespecified subgroup analysis in the pooled data set from both INPULSIS trials according to dose intensity (>90% or ≤90%). Dose intensity takes into account dose reductions, as well as temporary treatment interruptions and their duration. The adjusted annual rate of decline in FVC was of similar magnitude among 484 patients who received nintedanib with a dose intensity of more than 90% as among 154 patients who received nintedanib with a dose intensity of 90% or less (mean [±SE], 112.7±12.8 vs. 72.7±24.3 ml per year), suggesting that dose reductions or interruptions had no major effect on the efficacy of nintedanib. Luca Richeldi, M.D., Ph.D.

trial, we did not evaluate acute exacerbations because of the challenges associated with its diagnosis1 and the low incidence of acute exacerbations in previous clinical trials. In the CAPACITY trials, only 1.7% of patients who received placebo had a protocol-defined acute exacerbation. This is consistent with the recent INPULSIS trials, wherein only 0.9% of patients in the pooled placebo group had confirmed acute exacerbations. Koczulla and Thabut and Crestani highlight the importance of handling missing data owing to death in analyses of change in FVC. In the ASCEND trial, the test statistic for the primary end point of change in FVC was a ranked analysis of covariance model in which missing values owing to death were assigned the worst ranks according to time to death. The model therefore accounted for the effect of death without overweighting or assigning arbitrary values for missing data.2,3 In addition, we conducted several supportive analyses in which missing values owing to death were handled differently, including an analysis of mean change in FVC in which missing values owing to death were assigned the worst possible value (FVC = 0) and a linear slope analysis (the primary analysis in the recent ­INPULSIS trials) in which deaths were ignored. Predictably, the rate of FVC decline was higher when missing values owing to death were assigned the worst possible value. In response to Koczulla: when similar methods (e.g., slope analysis) are used, the rates of FVC decline among patients who received placebo in the ASCEND and INPULSIS trials are very similar. Regardless of the analytic method used, the National Institute for Health Research Respiratory Biomedical   Research Unit magnitude of the pirfenidone treatment effect Southampton, United Kingdom (expressed as the relative between-group [email protected] Since publication of his article, Dr. Richeldi reports receiving ence) was generally consistent across analyses lecture fees from Cipla. No further potential conflict of interest and resulted in an approximate halving in the relevant to this letter was reported. rate of FVC decline. 1. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in paThabut and Crestani inquire about the effect tients with idiopathic pulmonary fibrosis (CAPACITY): two ranof lung transplantation in the population indomised trials. Lancet 2011;377:1760-9. 2. Food and Drug Administration briefing information for the cluded in our mortality analyses. We performed March 9, 2010 meeting of the Pulmonary-Allergy Drugs Advi- several sensitivity analyses in the pooled populasory Committee (http://www.fda.gov/AdvisoryCommittees/ tion from the ASCEND and CAPACITY studies. CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugs In the mortality analysis with the worst-case AdvisoryCommittee/ucm203079.htm). handling of lung transplantations (i.e., transDOI: 10.1056/NEJMc1407776 plantations that were counted as deaths), the Dr. King and Colleagues Reply: Ohkubo and risk was 37% lower at 1 year in the pirfenidone colleagues inquire about acute exacerbations of group than in the placebo group (hazard ratio, idiopathic pulmonary fibrosis. In the ASCEND 0.63; 95% confidence interval [CI], 0.40 to 0.99).

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In the mortality analysis in which patients who Williamson Z. Bradford, M.D., Ph.D. underwent transplantation were followed and InterMune the data were not censored, the hazard ratio was Brisbane, CA publication of their article, the authors report no fur0.51 (95% CI, 0.31 to 0.86), favoring pirfenidone. therSince potential conflict of interest. These findings are consistent with and corroborate the results of the prespecified analysis of 1. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbaof idiopathic pulmonary fibrosis. Am J Respir Crit Care all-cause mortality (hazard ratio, 0.52; 95% CI, tions Med 2007;176:636-43. 0.31 to 0.87). 2. Lachin JM. Worst-rank score analysis with informatively missing observations in clinical trials. Control Clin Trials 1999; Talmadge E. King, Jr., M.D. 20:408-22. 3. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med 1999;18:134154.

University of California, San Francisco San Francisco, CA

[email protected]

Paul W. Noble, M.D.

DOI: 10.1056/NEJMc1407776

Cedars–Sinai Medical Center Los Angeles, CA

The Metabolic Syndrome and DYRK1B To the Editor: Keramati et al. (May 15 issue)1 found that the gain-of-function DYRK1B variants R102C and H90P were associated with the metabolic syndrome. These findings probably reveal one end of the phenotypic spectrum associated with DYRK1B variants. The L28P variant of DYRK1B is predicted to be “damaging,”2 and we have postulated that it may be a loss-of-function variant with a protective effect against the metabolic syndrome. We performed a phenomewide association study to examine phenotypes associated with Table 1. Association of Clinical Conditions with the L28P Variant of DYRK1B, as Determined by Means of a Phenomewide Association Study. Adjusted Odds Ratio (95% CI)

Adjusted P Value*

Diabetes mellitus

0.30 (0.12–0.71)

0.002

Essential hypertension

0.52 (0.24–1.10)

0.09

Disorders of lipid metabolism

0.68 (0.30–1.53)

0.36

Overweight and obesity

0.91 (0.36–2.29)

0.85

Hypertensive heart disease

1.32 (0.39–4.41)

0.66

Myocardial infarction

0.36 (0.05–2.66)

0.24

Pulmonary heart disease

1.71 (0.52–5.64)

0.41

Heart failure

1.59 (0.65–3.87)

0.32

Symptoms involving cardiovascular system

1.34 (0.46–3.95)

0.60

Condition

* P values were adjusted for age, sex, and study group. CI denotes confidence interval.

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the L28P variant of DYRK1B in a cohort of 7800 Geisinger MyCode Project participants for whom existing genotype data (obtained with the use of the Illumina HumanExome BeadChip) were available and linked to electronic medical record data. Phenotypes associated with cardiometabolic disease were identified with the use of previously validated phenomewide association study codes.3 Our study revealed a significant protective effect of L28P (in 42 heterozygotes) against type 2 diabetes and a trend toward a protective effect against hypertension (Table 1). Two DYRK1B variants (G352A and P578S) that were predicted to be benign had no significant associations in the phenomewide association study. Some DYRK1B variants are associated with autosomal dominant protective effects. Electronic medical records linked to existing genomic data sets can be used to rapidly identify populationlevel genotype–phenotype associations. Tooraj Mirshahi, Ph.D. Michael F. Murray, M.D. David J. Carey, Ph.D. Geisinger Clinic Danville, PA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Keramati AR, Fathzadeh M, Go G-W, et al. A form of the

metabolic syndrome associated with mutations in DYRK1B. N Engl J Med 2014;370:1909-19.

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Treatments for idiopathic pulmonary fibrosis.

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