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

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

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

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

Aim of Study To test the efficacy and safety of a new strain Lactobacillus reuteri DSM derived from L reuteri ATCC 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)

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

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)

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)

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)

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)

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

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)

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)

Enrolled Assigned Intervention and Follow up

% patients with persisting watery diarrhoea in the groups receiving placebo (grey) and L reuteri (white)

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)

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

Are the results of the trial valid? Did the trial address a clearly focused issue? An issue can be 'focused' in terms of - the population studied - the intervention given - the comparator given - the outcomes considered Yes PICO Was the assignment of patients to treatments randomized? Yes randomly assigned to receive L reuteri or placebo Were all of the patients who entered the trial properly accounted for at its conclusion Was follow up complete? Were patients analysed in groups to which they were randomised? Yes 27 children became ineligible due to non compliance or refused to participate or had commenced antibiotics

Clinical Question P opulation Children under 3 years old with acute infectious diarrhoea I ntervention Probiotic L reuteri DSM and ORT C omparison A placebo and ORT O utcome Reduce duration and stool frequency in acute infectious diarrhoea.

Detailed Questions Were patients, health workers and study personnel ‘blind’ to treatment? - were the patients - were the health workers - were the study personnel Yes Study was blinded for investigators and patients Were the groups similar at the start of the trial? In terms of other factors that might effect the outcome such as age, sex, social class Results are reported on those that completed the trial not the number recruited Aside from the experimental intervention, were the groups treated equally? Not specifically stated

What are the Results? How large was the treatment effect? What outcomes are measured? Not stated numerically in paper NNT 10 people Experimental Event Rate 40% Control Event Rate 50% Absolute Risk Reduction 10% How precise was the estimate of the treatment effect? What are its confidence limits? No confidence limits reported P< 0.03

Will the results help locally? Can the results be applied to the local population? Do you think that the patients covered by the trial are similar enough to your population? Applicable to local community Were all clinically important outcomes considered? If not, does this affect the decision? Yes Are the benefits worth the harms and costs? This is unlikely to be addressed by the trial. But what do you think? Cost ORT £2.52 for 20 sachets Cost Biogaia £11.10 bottle Cost LF formula £12 /week

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 & months? Unable to compare results with other studies (probiotics species specific in each study)