Aliment Pharmacol Ther 2012:36 (4):363-369 R. Francavilla et al 16 th July 2013 Shamshad Shah

1. Randomised Clinical Trial: Lactobacillus reuteri DSM 17938 vs. Placebo in Children With Acute Diarrohea Aliment Pharmacol Ther 2012:36 (4):363-369 R. Francavilla et al 16th July 2013 Shamshad Shah

2. Question Is there clinical evidence supporting the therapeutic effects of probiotics in children with acute diarrhoea?

3. Background • Viewed from a global perspective gastroenteritis in children is of great public health importance • The use of ORT contributed to a marked reduction in death rates globally • In developed countries 30% hospital admissions for gastroenteritis due to rotavirus • Probiotics are live micro organisms which when administered in adequate amounts confer a health benefit to the host • Cochrane review; 56 trials concluded specific probiotics reduce duration diarrhoea 24 hours and frequency stools

4. Literature Search [clinical trial] AND [diarrhoea] AND [probiotics] AND [children]. Limited to [child 0 – 36 months AND English language]

5. Aim of Study To test the efficacy and safety of a new strain Lactobacillus reuteri DSM 17938 derived from L reuteri ATCC 55730 in children with acute diarrhoea Primary outcomes were the rate of unresolved diarrhoea after 3 days of treatment and duration of diarrhoea. Event Title If Required (Change Text in Footer)

6. Method Children 6 – 36 months old were recruited from 3 wards across 3 hospitals in S Italy from Jan –July 2009 Diagnosed with acute diarrhoea with clinical signs dehydration Randomised to receive in a double blind fashion either L reuteri or a placebo Symptoms were recorded in a diary 1 week

7. Method Inclusion Criteria • Children 6-36 months old hospitalised with acute diarrhoea • Clinical signs of mild to moderate dehydration • No clinical features of hypovolaemic shock Event Title If Required (Change Text in Footer)

8. Method Exclusion criteria • Included underlying chronic disease • Bloody stools at first examination • Current use of probiotic/antibiotics • Demonstration of bacterial cause for diarrhoea • Use of parenteral rehydration. Event Title If Required (Change Text in Footer)

9. Method Approved by ethics committee Randomly assigned to receive either L reuteri or placebo All enrolled children were entered sequentially to receive the assigned treatment First dose was given immediately after informed consent The study preparation was administered for 7 days At start of treatment stool sample to test for rotavirus /adenovirus was collected Dehydration was corrected in line with WHO recommendations Event Title If Required (Change Text in Footer)

10. Method The active L reuteri and placebo preparation were based in mixture of sunflower oil and MCT Both mixtures were presented in same shaped bottles Dose 5 drops bd administered by nurse Study was blinded for investigators and patients Group assignments were concealed from participants and investigators Codes were revealed after the study Event Title If Required (Change Text in Footer)

11. Outcome Measures Primary Outcomes • The rate of unresolved diarrhoea after 3 days treatment • Duration of diarrhoea Secondary outcomes • Duration of hospitalisation • Total intake of oral rehydration solution

12. Statistics Calculated a sample of 34 children per group required for study to have 80% power with a type 1 error =0.05 (two tailed test) Assumption is based on similar trials (references not quoted) SPSS Variables were tested for normal distribution and compared using Mann-Whitney U test Intention to treat analysis was performed Statistical significance accepted at p<0.05 Event Title If Required (Change Text in Footer)

13. Results 96 children enrolled Out of 64 children 10 children prompt recovery 43 children identified with rotavirus 10 children identified with adenovirus 11 children – no aetiology found Baseline characteristics similar in both groups L reuteri significantly reduced the duration of watery diarrhoea compared with placebo p<0.03 Effect of L reuteri mostly seen day 2 or 3 of treatment Event Title If Required (Change Text in Footer)

14. Enrolled Assigned Intervention and Follow up

15. % patients with persisting watery diarrhoea in the groups receiving placebo (grey) andL reuteri (white)

16. Conclusion L reuteri is efficaceous and safe alongside rehydration therapy shortening the duration and reducing stool frequency in acute infectious diarrhoea in young children Event Title If Required (Change Text in Footer)

17. CASP RCT Appraisal Tool Event Title If Required (Change Text in Footer)

18. Are the results of the trial valid?

19. Clinical Question

20. Detailed Questions

21. What are the Results?

22. Will the results help locally?

23. Discussion • Results relevant to Biogaia .Conflict of Interest ? • Small sample size but strong power 80% and no confidence intervals quoted – reliable recommendation to change practice in hospital setting? • If used in primary care setting would it reduce hospital admissions and costs? • Would a shorter duration of diarrhoea episode prevent secondary lactose intolerance? • Subgroups needed 6-12 months & 13-36 months? • Unable to compare results with other studies (probiotics species specific in each study)