A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat

Remenova et al. Orphanet Journal of Rare Diseases (2015) 10:81 DOI 10.1186/s13023-015-0297-7 RESEARCH Open Access A double-blind, randomized, placebocontrolled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat Tatiana Remenova1*, Olivier Morand1, Dominick Amato2, Harbajan Chadha-Boreham1, Scott Tsurutani3 and Thorsten Marquardt4 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. Keywords: Type 1 Gaucher disease, Niemann-Pick disease type C, Diarrhea, S. boulardii, Miglustat * Correspondence: 1 Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil 4123, Switzerland Full list of author information is available at the end of the article © 2015 Remenova et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Remenova et al. Orphanet Journal of Rare Diseases (2015) 10:81 Background The reversible glucosylceramide synthase inhibitor, miglustat (Zavesca®; Actelion Pharmaceuticals Ltd, Switzerland), is approved in the EU, the US, and other countries for the treatment of adult patients with mild or moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option [1, 2]. Miglustat is also indicated for the treatment of progressive neurological manifestations in adult and pediatric patients with Niemann-Pick type C disease (NP-C) in the EU, Japan, and other countries [2]. Safety and tolerability monitoring during clinical trials in both GD1 [3–6] and NP-C [7–10] has consistently shown gastrointestinal (GI) disturbances such as diarrhea, flatulence, abdominal discomfort, nausea and vomiting as the most frequent adverse effects associated with miglustat therapy. These GI adverse effects occurred primarily during the first 6 months of treatment, and were observed in 80 % of patients during the first 6 months compared with 50–60 % thereafter [2], and have been reported as the most common reason for miglustat discontinuation [11, 12]. GI tolerability is therefore an important matter as it can have an impact on treatment compliance (particularly among young patients with NP-C), thereby reducing treatment benefits. GI disturbances during miglustat treatment are thought to arise from the inhibition of intestinal disaccharidases, mainly sucrase isomaltase [11, 13–15]. Miglustat (1,5 (butylimino)-1,5-dideoxy-D-glucitol) – a glucose analog – inhibits the human disaccharidase, sucrase, which cleaves sucrose at the O-C (glucose) bond [14, 16, 17]. Furthermore, relatively little inhibition of intestinal lactase, and down-regulation of sucrase expression in gastrointestinal epithelium have been observed [11, 13–15]. Together, these effects lead to maldigestion of sucrose [11], preventing the release of the monosaccharides, glucose and fructose, for further intestinal absorption. Undigested sucrose that is not absorbed subsequently causes osmotic diarrhea [11, 18]. Bacterial fermentation of unabsorbed material can also lead to flatulence and abdominal distension/ discomfort [18]. Adaptations within the GI system, such as an enhanced capacity for fermentation in the cecum via adaptation of the microflora, are considered to account for partial resolution of GI disturbances in miglustat-treated patients over time. Additionally, anti-propulsive medications (e.g., loperamide) can help to ameliorate GI disturbances such as diarrhea [3, 18–22]. Dietary modifications at or before initiation of miglustat therapy (e.g., adoption of a low-carbohydrate diet, alongside changes to maintain adequate caloric intake) have also been shown to have some positive impact on GI tolerability [11, 23], and a gradual increase in dose up to the full Page 2 of 9 dose during the first 3 weeks of therapy has been found to be helpful (Amato D, personal communication). Other methods to improve the GI tolerability of miglustat have been suggested, but as yet there are few published data to support their use. The probiotic delivery of additional sucrase activity to the lower intestine during either initial or ongoing miglustat therapy has been suggested as a way to enhance GI adaptation. A purified formulation of the saccharomyces cerevisiae-derived invertase, sacr (...truncated)