The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials
Authors: V Panetta
E De Stefani
A Bacchieri
S Papetti
P Navarra
Journal: European review for medical and pharmacological sciences (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: probiotic mixture; VSL#3®; safety; adverse events; clinical trials
Affiliations: L'altrastatistica S.r.l., for GB Pharma Services & Consulting S.r.l, Rome, Italy. .

Abstract:  Objective: A high-concentration of a multi-strain probiotic mixture, VSL#3® is widely used 'whenever it is useful to promote the balance of intestinal flora'. As a food supplement, VSL#3® has been so far scarcely investigated on the aspect of safety. To fill this gap, in this paper, we analyzed the adverse events (AEs) recorded during the conduct of three (3) double-blind, randomized, placebo-controlled trials carried out to explore the efficacy of VSL#3® in various clinical settings. Data from a large open-label observational trial were also considered. Materials and methods: All trials included in the analysis were carried out according to good clinical practice (GCP) rules. AEs were classified by System Organ Class (SOC), Preferred Term (PT) and frequency. Differences vs. placebo control were considered as statistically significant if the p-value was &lt; 0.05. Results: A total of 120 patients were analyzed, 70 patients being included in the randomized controlled trials. In this population, 45 patients had at least one AE, 20 (64.5%) in the placebo group and 25 (64.1%) in the VSL#3® group. 29 patients had at least one related AE, 14 (45.2%) and 15 (38.5%) in the two treatment groups, respectively. Only one AE was assessed as serious, i.e., Foetal malformation, which occurred in the placebo group and was considered unrelated. No significant difference was found between VSL#3® and placebo for any of the SOC considered, with the exception of Injury, poisoning and procedural complications, which was in favor of VSL#3®. Conclusions: Based on GCP-quality data from clinical trials, we conclude that VSL#3® is a safe and well-tolerated agent. 

Retracted: Yes

PubPeer comments:
 This paper is a purported meta-analysis of u201ct*hree (3) double-blind, randomized, placebo-controlled trials carried out to explore the efficacy of VSL#3u00ae*u201d and one (1) u201c l*arge open-label observational trial*u201d on the same probiotic brand. It appears that the three randomized placebo controlled trials were all terminated before the end for unclear reasons. Could the authors explain (if they are aware of ) why the studies were terminated? Have been these studies published in any form.? There is no mention to any of them in the reference section, suggesting that none has been published. All together the three randomized u201ctrialsu201d contribute 30 patients in the active harm and 27 in the placebo harm. The fourth study contribute 49 patients in active harm and no placebo patients. At first look the studies heterogeneity is self evident. How was this taken into account? Further on, from the method: u201cVSL#3u00ae (Actial Farmaceutica Srl, Rome, Italy) has been used in four clinical studies in different populations: obese pregnant women (ESDO study, Italy), ulcerative colitis (PROREM UC study, Italy), women with osteoporosis (PROBONE study, US) and Irritable Bowel Syndromeu201d. The patients populations were quite heterogeneous. Could the authors explain whether and how the u201cmetanalysisu201d was powered to detect a difference with such low numbers. ? The authors might want to check this conundrum on the light of the following very basic principle: u201c [the] power of tests in meta-analysis like power of any statistical test needs to be computed a priori, using assumptions about the size of an important effect in a given context, and the typical sample sizes used in a given field.u201d (From Advances in Meta-Analysis Authors: Pigott Terri). Was anyone of the authors a PI in these studies.? Finally, according to the conflict of interest : u201cThe writing of this paper was funded by Actial Farmaceutica. Initial data analyses were undertaken by GB Pharma Services Consulting S.r.l and received funding from Actial Farmaceutica.u201d Why the initial? ,