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

Abstract

BackgroundGastrointestinal (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.MethodsIn 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.ResultsTwenty-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.ConclusionsAlthough 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.

Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects

“…This differentiation in GI tolerability between the two structurally related compounds can be explained by the fact that lucerastat is a galactose analog iminosugar which does not inhibit intestinal sucrase-isomaltase. Miglustat is a glucose analog iminosugar and a potent inhibitor of sucrase-isomaltase [7, 15]. …”

“…On Day 7, body weight was measured pre-dose and physical examination was conducted 48 h post-dose. Because of the well-described gastrointestinal (GI) adverse effects of miglustat [15], stool frequency and consistency were recorded by dose level, subject, and day.…”

Successful switch from enzyme replacement therapy to miglustat in an adult patient with type 1 Gaucher disease: a case report

“…In particular, simple dietary modifications such as restriction of dietary disaccharide intake, ideally commenced before initiation of treatment, has proved useful in reducing gastrointestinal side effects and in maintaining body-weight gain within normal limits in pediatric patients [40, 42, 43]. Notably, probiotics rich in Saccharomyces boulardii , combined with miglustat dose escalation, have been reported to confer further possible benefits in this respect [44]. We suggested restriction of disaccharides for our patient, and we observed acceptable gastrointestinal tolerability based on the patient’s self-reports.…”

Diagnostic workup and management of patients with suspected Niemann-Pick type C disease

“…These are the most frequent adverse effects associated with miglustat therapy and are present in up to 80% of patients during the first 6 months compared with 50-60% in the ensuing period [Remenova et al 2015]. GI disturbances have been reported as the most common reason for miglustat discontinuation [Hollak et al 2009;Belmatoug et al 2011].…”

“…Gradual dose escalation at treatment initiation may also reduce GI disturbances. Recently, a randomized double-blind, placebo-controlled study pointed towards increased miglustat GI tolerability when administered in conjunction with Saccharomyces bulardii probiotics, as the yeast produces an enzyme that breaks down sucrose [Remenova et al 2015]. Other, less commonly reported miglustat-associated side effects include tremor and peripheral neuropathy; however, these can also feature in the disease even without miglustat administration [Hollak et al 2009;Patterson et al 2015].…”