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

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 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.

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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

MethodInclusion Criteria• Children 6-36 months old hospitalised with acute

diarrhoea • Clinical signs of mild to moderate dehydration• No clinical features of hypovolaemic shock

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MethodExclusion 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.

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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

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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

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Outcome MeasuresPrimary 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

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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

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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

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CASP RCT Appraisal Tool

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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

Population Children under 3 years old with acute infectious diarrhoea

Intervention Probiotic L reuteri DSM 17938 and ORT

Comparison A placebo and ORT

Outcome Reduce duration and stool frequency in acute infectious diarrhoea.

Detailed QuestionsWere 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 & 13-36 months?• Unable to compare results with other studies (probiotics

species specific in each study)