Efficacy and safety of Bacillus clausii (O/C, N/R, SIN, T) probiotic combined with oral rehydration therapy (ORT) and zinc in acute diarrhea in children: a randomized, double-blind, placebo-controlled study in India

Abstract

Background Childhood diarrhea remains a major disease burden, particularly in developing countries, and is a leading cause of death in children aged < 5 years, worldwide. Treatment of acute diarrhea now includes probiotics to potentially reduce the duration and severity of the illness. This phase 3, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of four strains (O/C, N/R, SIN, T) of Bacillus clausii probiotic (Enterogermina®) plus oral rehydration therapy (ORT) and zinc, versus placebo plus ORT and zinc, in infants and children in India with acute moderate diarrhea. Methods Patients aged 6 months to 5 years with acute moderate diarrhea (WHO 2005 definition) of < 48 h’ duration were randomly assigned to receive one mini bottle of either polyantibiotic-resistant B. clausii (oral suspension of 2 billion spores per 5 mL bottle) or matching placebo twice daily (morning and evening) for 5 days. Exclusion criteria included known hypersensitivity to B. clausii or excipients in the study treatment, or to other probiotics. Patients were admitted to hospital from Day 1 and discharged ≥6 h after diarrhea resolution, or a maximum of 5 days. The primary endpoint was duration of acute diarrhea from randomization to recovery. Secondary endpoints included frequency of stools, diapers with stools, or dehydration status. Results In total, 457 patients were randomized; 454 were treated. Similar proportions of patients showed recovery from diarrhea over the 120 h after randomization (97.0% in the B. clausii group [n = 227]; 98.0% on placebo [n = 227]). Median time to recovery was also similar: 42.83 (95% CI: 40.90–44.90) hours for B. clausii and 42.13 (95% CI: 39.80–43.87) hours for placebo. However, no statistically significant difference was observed between groups (hazard ratio = 0.93 [95% CI: 0.77–1.13]; p = 0.6968); nor were there statistically significant differences between groups for the secondary endpoints. Treatment with B. clausii was well tolerated with incidence of adverse events (9.7%) similar to that for placebo (12.3%). Conclusions No significant difference in efficacy between B. clausii and placebo was demonstrated. Sample size may have been inadequate to allow detection of a between-group difference in efficacy, given the mild/moderate severity (only ~ 20% of patients had nausea/vomiting or abdominal pains) and short duration of disease among subjects, the relatively late start of treatment (most were already on Day 2 of their disease episode when study treatment started) and the effectiveness of the standard of care with ORT and zinc in both treatment groups. Trial registration CTRI number CTRI/2018/10/016053. Registered on 17 October 2018. EudraCT number 2016-005165-31. Registered 14 May 2020 (retrospectively registered).

Specific Probiotics for the Treatment of Pediatric Acute Gastroenteritis in India: A Systematic Review and Meta-Analysis

“…Reasons for exclusion (n = 213 studies) are provided elsewhere (see Text, Supplemental Digital Content 2, Results, http://links.lww.com/PG9/A31). Twelve trials done in India but not meeting inclusion criteria were excluded (see Table, Supplemental Digital Content 2, Excluded Trials, http://links.lww.com/PG9/A41) (31–42).…”

Efficacy and Safety of the Adjuvant Use of Probiotic Bacillus clausii Strains in Pediatric Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study

“…The type and incidence of TEAEs observed were similar between groups. B. clausii is well tolerated in studies in children with diarrhea [ 13 , 19 – 22 , 61 ].…”

Potential Complementary Effect of Zinc and Alkalihalobacillus clausii on Gut Health and Immunity: A Narrative Review

“…Participants in the treatment arm received A. clausii (oral suspension of 2 billion spores per 5 mL bottle) for 5 days plus ORT and zinc, while children in the control group received only ORT and zinc. Similar proportions of patients showed recovery from diarrhoea over 120 h after randomisation, and the combination was well-tolerated, with an incidence of adverse events of 9.7%, similar to that of children in the placebo group (12.3%) [ 15 ]. While the results from the 2015 study showed a promising role of A. clausii as an add-on therapy to ORT and zinc in the management of acute diarrhoea in children, the beneficial effects were unclear in the subsequent clinical trial.…”

“…Nevertheless, given the evidence of a well-tolerated A. clausii –zinc combination [ 15 ], hypotheses suggest that this combination may provide synergistic or complementary benefits for gut barrier integrity [ 131 ] and immunity [ 36 ], leading to greater benefits compared to using them separately. However, further research is required to understand the potential of their combined effects and mechanisms of action.…”

“…Strains of Alkalihalobacillus clausii ( A. clausii ), previously known as Bacillus clausii , are probiotics with antimicrobial and immunomodulatory properties [ 12 , 13 ]. They are useful both for the treatment and prevention of gastrointestinal [ 14 , 15 , 16 ] and non-gastrointestinal infections [ 17 , 18 ].…”