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N Engl J Med. 2012 May 24;366(21):1968-77. doi: 10.1056/NEJMoa1113354. Epub 2012 May 20.

Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.

Collaborators (147)

Martinez FJ, Raghu G, Schwarz M, Toews GB, Hunninghake G, Zibrak J, Demersky A, Vey M, Rosas IO, Debrosse P, Culver DA, Chapman J, Olman M, Lubell S, Wehrmann R, Morrison LD, Steele MP, Haram T, Kidd R, Kallay M, Lyda E, Ryu JH, Utz JP, Limper AH, Daniels CE, Meiras K, Walsh S, Sahn S, O'Banner N, Stokes F, Brown KK, Bair C, Kervitsky D, Ettinger NA, Merli S, Criner G, Swift IQ, Satti A, Cordova F, Patel N, West K, Jones G, Lasky JA, Ditta S, de Andrade J, Thannickal VJ, Stewart M, Belperio J, Lynch JP 3rd, Calahan E, Lopez P, King TE Jr, Collard HR, Golden J, Wolters P, Eller A, Noth I, Hogarth DK, Sandbo N, Strek ME, Maleckar S, Rahimova G, Sardin L, Roman J, Perez R, Perez T, Glassberg MK, Simonet E, Martinez FJ, Baumann K, Chan K, Chughtai A, Gross B, Flaherty KR, Han ML, Hyzy R, Kazerooni E, Moore B, Myers J, Toews GB, White E, Dahlgren D, Rossman M, Kreider M, Le K, Fitzgerald J, Glazer C, Scholand MB, Brewster L, Johnson A, Raghu G, Berry-Bell P, Snydsman A, Loyd JE, Lancaster L, Lawson W, Greer R, Kinser K, Richardson R, Mason W, Kaner RJ, Bandong K, Antin-Ozerkis D, Holm C, Estrom J, Lynch DA, Colby T, Anstrom KJ, Eisenstein EL, Sundy JS, Davidson-Ray L, Dignacco P, Edwards R, Anderson R, Beci R, Calvert S, Gentry-Bumpass T, Hill D, Hwang K, Kaur J, Matti C, Meredith A, Pesarchick J, Ramey S, Roberts RS, Sharlow A, Winsor J, Yang Q, Yow E, Weinmann GG, Reynolds H, Schmetter B, Tian X, Kiley J, Davis G, Levine R, Nathan SD, Rounds S, Thompson BT, Thompson B, Bitterman PB, Franks TJ, Idell S, Piantadosi S, Rom WN, Selman M, Wilkes DS.



A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown.


In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.


When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here.


Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; number, NCT00650091.).

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