A DOUBLE BLIND, RANDOMISED, PLACEBOCONTROLLED TRIAL OF LACTOBACILLUS

ACIDOPHILUS FOR THE TREATMENT OF

ACUTE WATERY DIARRHOEA IN
VIETNAMESE CHILDREN

Tran Thi Hong Chau, MD

BACKGROUND

BACKGROUNDUND
Global heath issue (death: 7.6 milion, 1.06 milion
due to diarrhoea)
WHO VN: 23 deaths/1000 live birth, 12% diarrhoea
disease
ORS + Zinc diarrhoeal and vomiting duration

BACKGROUND (continued)
Cochrane review : duration diarrhoea , stool frequency,
risk of persistent diarrhoea.
In Vietnam:
-Probiotics widely available,
-Frequently prescribed in hospitals for a variety
of diseases (no scientific evidence).
-With or without adjunctive antimicrobial
treatment (My Phan, unpublished).

STUDY QUESTION
Are probiotics superior to placebo
in the treatment of AWD in
children?

OBJECTIVE
To study the effect of probiotics (in VN) containing
L.acidophilus on diarrheal disease duration

STUDY DESIGN
This study is a prospective, randomised double blind, placebocontrolled trial of (4 x 108 CFUs) of probiotic (L.acidophilus)
therapy compared to placebo, in Vietnamese children
admitted to CH2 with acute watery diarrhoea

Probiotic

Placebo

Acute diarrhea is defined as three or more stools per day of decreased form
from the normal

SPECIFIC ENDPOINTS
Primary endpoint:
the time from the first dose of study medication to the start
of the first 24 hour diarrhoea-free period.

Secondary endpoints:

Onset of AWD to the last diarrhoeal episode that is

followed by at least 24 hours without diarrhoea.
Total duration of AWD
Stool frequency in the first three days
Daily Norovirus and Rotavirus loads in stool
L. acidobacillus colonisation
Duration of hospitalisation

SAMPLE SIZE
Hospital duration: Median 5 days (3-6 days) SD
of log 10- duration is 0,61 and 0,27
Powered to detect 20% decrease (24hrs) in
duration of AWD
80% (5%) 123 patients 22%

300 participants (2 groups, 150 per group)

PATIENT SELECTION
Inclusion criteria:
9 60 months
AWD < 72 hrs
ICF

Exclusion criteria:
Blood or mucus stool
1 episode of diarrhoeal disease
in the month prior to AWD
Short bowel syndrome
Chronic gastrointestial disease
Systemic illnesses rendering the
patient immunocompromised
Chronic steroid therapy
Immunosuppressive therapy
Severe dehydrated (WHO)

STUDY DRUG TREATMENT

Besides receiving the standard of care those enrolled will
be assigned to one of two study groups at a ratio of 1:1:
Probiotic (4 x 108 CFUs) of L.acidophilus
2 sachets x twice/day x 5 days
OR Placebo
2 sachets x twice/day x 5 days
If vomiting within (30 minutes) of taking the
treatment, 2 sachets will be given, up to two
extra doses in four hours.

Oct 2014 Sept 2015

Figure 1: Screening and Randomization

SCREENING AND RANDOMISATION

303 patients were assessed
for eligibility
3 patients declined to
participate
300 underwent
randomization

150 were assigned to placebo in the

ITT

150 were assigned to L. acidophilus La14 probiotic in the Iintention to treat

-3 patients withdrew (2 pts took 5
and 6 doses of study drug)
-01 patient was lost to follow up
-3 patients self-prescribed probiotics
pproprobiotics (1 pt took 7 doses of
study drug)

-2 patients withdrew
(took 2 and 6 doses of
study drug)
-01 patient took 6 doses
of study drug

147 were included in

the protocol analysis

143 were included in the

protocol analysis

BASELINE CHARACTERISTIC
Characteristic

Placebo
(N=150)

Probiotic
(N=150)

155 (125,215)

156 (118,213)

Sex (female)

49/150 (33%)

52/150 (35%)

Weight [kg] median (IQR)

101 (90,120)

102 (90,120)

Rotavirus

56/150 (37%)

64/150 (43%)

Norovirus

38/150 (25%)
18/150 (12%)

30/150 (20%)
11/150 (7%)

C. Coli

3/18 (17%)

0/11 (0%)

C. Jejuni

15/18 (83%)

11/11 (100%)

Shigella

20/150 (13%)

17/150 (11%)

Salmonella

21/150 (14%)

14/150 (9%)

Age [months] median (IQR)

Microbiology

Campylobacter

PRIMARY OUTCOME
Subgroup

Placebo (N=150)

Median (IQR)
[hours]

Probiotic (N=150)

Comparison:

Median (IQR)
[hours]

Acceleration
Factor
(95%CI); p-value

Test for effect

heterogeneity
(p-value)

All patients
(intention-totreat)

Per-Protocol
population

All patients
(intention-totreat)

150

43 (15,66)

150

35 (20,68)

109 (078,151);
p=062

Per-Protocol
population

147

43 (15,66)

143

33 (20,68)

109 (079,152);
p=060

THE MEDIAN TOTAL DURATION OF DIARRHOEA

The median total duration of diarrhoea was identical at

76 hours.

DAILY STOOL FREQUENCY AND TREATMENT FAILURE

Outcome

Placebo
(N=150)

Probiotic
(N=150)

Total stool
frequency in the
first three days
- Median (IQR)
[count]

Relative
difference in
stool frequency
7 (3,15)

8 (3 ,15)

105 (083,132);
p=068
OR of treatment
failure

Treatment failure
- Frequency [%]

Comparison
Estimate (95%
CI); p-value

11/150 (7%)

10/150 (7%)

090 (036,221);
p=082

EFFECT OF L. acidophilus La 14 ON THOSE WITH

ROTAVIRUS INFECTION
med AUC of rotavirus load (log10 copies/5l x days) was 4686 and 4658 in the placebo and the probiotic group

EFFECT OF L. acidophilus La 14 ON THOSE WITH

NOROVIRUS INFECTION
med AUC of norovirus load (log10 copies/5l x days) were 2617 and 2758 in the placebo and probiotic group

THE DYNAMICS OF L. ACIDOPHILUS COLONISATION

L. acidophilus bacteria load change in target copies after 7 days and 14 days in both arms was (-017 and -012
(log10 copies/5l) and 015 and -013 (log10 copies/5l) in the placebo and the probiotic group.

L. acidophilus La 14
The quality of the probiotic by regular quantitative
counts and via genome sequencing to identify the
strain composing the probiotic (L. acidophilus La14).

FINDINGS
L.acidophilus La-14 probiotic treatment did not reduce
the time from the first dose of study medication to the
start of the first 24- hour period without diarrhoea in
comparison to placebo.
There was no difference between intervention and
placebo in the total duration of diarrhoea, the total
duration of hospitalisation, stool frequency during the
first three days of treatment, treatment failure, or daily
rotavirus and norovirus faecal loads.

CONCLUSION
Our data add additional strong evidence
regarding the role of probiotics in treating
diarrhoeal disease and suggest that L.
acidophilus La-14 does not have a measurable
effect in this setting.

Authors: Tran Thi Hong Chau , Nguyen Ngoc Minh

Chau , Nhat Thanh Hoang Le , Hao Chung The ,
Phat Voong Vinh , Nguyen Thi Nguyen To ,
Nguyen Minh Ngoc , Ha Manh Tuan ,
Tang Le Chau Ngoc , James I Campbell , Laura
Merson , Corinne N Thompson , Ha Thanh Tuyen ,
Vo Thi Van , Nguyen Hong Van Khanh , Nguyen
Thi Hong Loan , Nguyen Thi Thu Thuy , Vo Hoang
Khoa , Nguyen Cam Tu , Nguyen Thi Thanh Tam ,
Ha Vinh , Marion-Eliette Kolader , Jeremy J
Farrar ,Marcel Wolbers , Guy E Thwaites and
Stephen Baker .

Thank you