title: A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat.
abstract: BACKGROUND
  Gastrointestinal (GI) disturbances such as diarrhea and flatulence are the most frequent adverse effects associated with miglustat therapy in type 1 Gaucher disease (GD1) and Niemann-Pick disease type C (NP-C), and the most common recorded reason for stopping treatment during clinical trials and in clinical practice settings. Miglustat-related GI disturbances are thought to arise from the inhibition of intestinal disaccharidases, mainly sucrase isomaltase. We report the effects of a co-administered dietary probiotic, S. boulardii, on the GI tolerability of miglustat in healthy adult subjects.
  
  
  METHODS
  In a double-blind, placebo-controlled, two-period, two-treatment cross-over trial, healthy adult male and female subjects were randomly allocated to treatment sequences, A-B and B-A (treatment A - miglustat 100 mg t.i.d. + placebo; treatment B - miglustat 100 mg t.i.d. + S. boulardii [500 mg, b.i.d.]). GI tolerability data were collected in patient diaries. The primary endpoint was the total number of 'diarrhea days' (≥3 loose stools within a 24-h period meeting Bristol Stool Scores [BSS] 6-7) based on WHO criteria. Secondary endpoints comprised numerous other diarrhea and GI tolerability indices.
  
  
  RESULTS
  Twenty-one subjects received randomized therapy in each treatment sequence (total N = 42), and overall, 37 (88 %) subjects completed the study. The total number of diarrhea days was <1.5 for both treatment sequences, and approximately 60 % of subjects did not experience diarrhea during either treatment period. The mean (SD) number of diarrhea days was lower with miglustat + S. boulardii (0.8 [2.4] days) than with miglustat + placebo (1.3 [2.4] days), but the paired treatment difference was not statistically significant (-0.5 [2.4] days; p = 0.159). However, a significant treatment difference (-0.7 [1.9]; p < 0.05) was identified after post hoc exclusion of a clear outlier who had a very high number of diarrhea days (n = 13) and inconsistent GI tolerability reporting. The incidence of the GI AEs was higher with miglustat + placebo (82 %) than with miglustat + S. boulardii (73 %). There were no between-treatment differences in miglustat pharmacokinetics.
  
  
  CONCLUSIONS
  Although the primary endpoint was not met, the results of the post-hoc analysis suggest that co-administration of miglustat with S. boulardii might improve GI tolerability.
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, 4123, Switzerland. tatiana.remenova@actelion.com.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Remenova
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, 4123, Switzerland. olivier.morand@actelion.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Morand
authors.affiliation: Mount Sinai Hospital, Toronto, Canada. damato@mtsinai.on.ca.
authors.forename: Dominick
authors.initials: D
authors.lastname: Amato
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, 4123, Switzerland. harbajan.chadha-boreham@actelion.com.
authors.forename: Harbajan
authors.initials: H
authors.lastname: Chadha-Boreham
authors.affiliation: Actelion Pharmaceuticals US, Inc., San Francisco, USA. scott.tsurutani@actelion.com.
authors.forename: Scott
authors.initials: S
authors.lastname: Tsurutani
authors.affiliation: Münster University Hospital, Münster, Germany. marquat@uni-muenster.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
mesh_terms: D017485:1-Deoxynojirimycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012440:Saccharomyces
chemical_list: D004791:Enzyme Inhibitors; D010919:Placebos; D017485:1-Deoxynojirimycin; C059896:miglustat