5 juni 2012: recent heeft een fase III studie aangetoond dat een combinatie van Prednisone, azathioprine, and N-acetylcysteine meer sterfte geeft dan placebo. Wat nu het verschil is met eerdere juist positieve studie resultaten weet ik eerlijk gezegd niet.

Dit is de reactie van arts-bioloog Engelbert Valstar: "in de eerste studie is prednison met azathioprine plus NAC - N-acetylcysteine vergeleken slecht in vergelijking met placebo; een groep met alleen NAC - N-acetylcysteine is nog niet geëvalueerd (komt nog) ; de combinatie is dus slecht vergeleken met placebo; het zegt echter niets over NAC - N-acetylcysteine alleen ; misschien is het zonder NAC - N-acetylcysteine nog slechter

"uit het tweede onderzoek blijkt geen voordeel van azathioprine plus prednison (geen placebo-groep) ; NAC - N-acetylcysteine minder nadeel ; kortom prednison plus azathioprine dient afgeraden te worden ; NAC - N-acetylcysteine alleen zou gunstig kunnen zijn

N Engl J Med. 2012 May 24;366(21):1968-77. 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; ClinicalTrials.gov number, NCT00650091.).

[PubMed - indexed for MEDLINE]

30 november 2005: Bron: http://www.Medscape.com">Medscape en N Engl J Med. 2005;353:2229-2242, 2285-2287

Acetylcesteine toegevoegd aan prednison en azathioprine verbetert positief significant de markers voor longfibrose en daarbij significant kwaliteit van leven van mensen met een ernstige vorm van longfibrose. Dit blijkt uit een gerandomiseerde dubbelblinde studie bij 182 patiënten uitgevoerd in meerdere ziekenhuizen en de resultaten zijn gepubliceerd in de november 2005 editie van de New England Journal of Medicine. Na 12 maanden hadden patiënten die acetylcysteine namen een significant langzamere verslechtering van hun vitale capaciteit en DCLO dan de patiënten uti de placebogroep. Het absolute verschil in de veranderingen vanuit de uitgangspositie (start van de studie) tussen groep patiënten die acetylcysterine namen en de placebogroep was 0.18 L (95% confidence interval , 0.03 - 0.32) of een relatief verschil van 9% voor de vitale capaciteit (P = .02) en 0.75 mmol per minuut per kPa (95% CI, 0.27 - 1.23) en 24% voor DLCO (P = .003). Sterfte gedurende de studietijd was 9% in de acetylcysteine groep en 11% in the placebo groep (P = .69).

De onderzoekers concluderen dan ook: “Behandeling met acetylcysteine met een dosis van 600 mg drie keer per dag, toegevoegd aan prednison en azathioprine, behoudt de vitale capaciteit en DLCO beter bij patiënten met idiopathische longfibrose dan standaard therapie alleen.” “Hoge dosis acetylcysteine als aanvulling op een standaard behandeling is daarom een rationele behandelingsoptie voor patiënten met idiopathische longfibrose.”

Hier een uitgebreid artikel uit Medscape over deze studie.

N Engl J Med. 2005;353:2229-2242, 2285-2287

Nov. 23, 2005 — Acetylcysteine added to steroids and azathioprine preserves vital capacity and diffusion capacity better than standard therapy for idiopathic pulmonary fibrosis (IPF), according to the results of a randomized, double-blind study published in the Nov. 24 issue of The New England Journal of Medicine.
“An oxidant–antioxidant imbalance may contribute to the disease process in idiopathic pulmonary fibrosis,” write Maurits Demedts, MD, from the University Hospital, Katholieke Universiteit Leuven in Belgium, and colleagues from the Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine (IFIGENIA) Study Group. “Acetylcysteine, a precursor of the major antioxidant glutathione, given at a daily dose of 1,800 mg, has been shown to restore depleted pulmonary glutathione levels and to result in a statistically significant improvement in lung function in patients with fibrosing alveolitis after 12 weeks of treatment.”

This multicenter study evaluated the effectiveness for one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The main outcome measures were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DLCO).

Of 182 patients randomized, 155 (80 [87%] of 92 assigned to acetylcysteine and 75 [83%] of 90 assigned to placebo) had usual interstitial pneumonia, confirmed by high-resolution computed tomography (CT) and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Of these 155 patients, 57 (71%) of the 80 patients receiving acetylcysteine and 51 (68%) of the 75 patients taking placebo completed one year of treatment. At 12 months, patients taking acetylcysteine had slower deterioration of vital capacity and DLCO than did patients taking placebo. The absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 L (95% confidence interval , 0.03 - 0.32) or a relative difference of 9% for vital capacity (P = .02) and 0.75 mmol per minute per kPa (95% CI, 0.27 - 1.23) or 24% for DLCO (P = .003). Mortality during the study was 9% in the acetylcysteine group and 11% in the placebo group (P = .69). The type or severity of adverse events did not differ significantly between groups, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P = .03). Study limitations include withdrawal or death of about 30% of patients in the acetylcysteine group at 12 months; inability to make conclusions regarding the effects and adverse effects of treatment with prednisone plus azathioprine because there was no placebo group for these drugs; inability to determine whether acetylcysteine would have the same effects when given without standard therapy; and lack of power to detect an effect on survival. “Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DLCO in patients with idiopathic pulmonary fibrosis better than does standard therapy alone,” the authors write. “High-dose acetylcysteine in addition to standard therapy is, therefore, a rational treatment option for patients with idiopathic pulmonary fibrosis.” The Zambon Group have disclosed that it supported this study. Several of the authors have disclosed various financial relationships with Zambon, Wyeth, Roche, GlaxoSmithKline, AstraZeneca, Actelion, ALTANA, Bayer, Boehringer Ingelheim, Fujisawa, Novartis, Merck Sharpe & Dohme, Pfizer, Schering-Plough, InterMune, Centocor, Chugai Pharma Europe, SMB Pharmaceuticals, CereMedix, and/or Chiron. In an accompanying editorial, Gary W. Hunninghake, MD, from the University of Iowa and Veterans Affairs Medical Center in Iowa City, acknowledges the benefit seen in this study. However, he questions whether it is simply reversing the toxicity of the standard therapy, and whether the standard therapy should be continued pending further clinical trials. “Since there are no therapies that are clearly effective for IPF, many physicians and patients will find the use of acetylcysteine to be very seductive,” Dr. Hunninghake writes. “In many ways, if it were ultimately shown to be effective, it would be an ideal drug (i.e., beneficial with few side effects). Also, acetylcysteine is available without prescription.” N Engl J Med. 2005;353:2229-2242, 2285-2287

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