Does Intake of Lactose-free Milk in Infants With Acute Gastroenteritis in a Developing Country Shorten the Duration of Diarrhea? A Randomized Clinical Trial.
Phase: NA
Conditions: Acute Gastroenteritis
Sponsor: American University of Beirut Medical Center

STUDY PROTOCOL
Open Access
Lactose-free milk for infants with acute
gastroenteritis in a developing country:
study protocol for a randomized controlled trial
Mona Nabulsi1,2*, Nadine Yazbeck1 and Fatme Charafeddine1
Abstract
Background: Acute gastroenteritis is a major cause of pediatric morbidity and mortality, accounting for 15% of all
childhood deaths worldwide. In developing countries, diarrheal diseases continue to be a major public health
burden. Evidence from developed countries suggests that intake of lactose-free milk during diarrheal episodes may
reduce the duration of the illness in pediatric inpatients. It is unknown whether lactose-free milk reduces the severity
or duration of acute gastroenteritis in infants treated in outpatient settings in developing countries where diarrhea is
more severe, and results in higher morbidities and mortalities. We hypothesize that lactose-free milk intake during
acute gastroenteritis would significantly decrease the duration and severity of diarrhea in infants presenting to the
Emergency Department (ED), as compared with lactose-containing milk.
Methods/Design: An open-label randomized clinical trial. Study population: 40 infants with acute gastroenteritis, age
between 2 and 12 months, presenting to the ED, will be randomized to control or intervention group. Intervention:
Lactose-free milk, whereas the control group will continue on regular infant formula for a total of 7 days. Infants will
be followed up for 7 days. Outcome measures: Diarrhea duration, weight loss, illness clinic visits, hospitalization rate,
parental satisfaction, and time to symptom resolution. Statistical analysis: Descriptive and regression analysis will be
conducted under the intention-to-treat basis by using SPSS version 21.
Discussion: Acute gastroenteritis is a public health burden for developing countries, with a significant impact on
infant morbidity and mortality. Provision of infant formula that may reduce the duration and severity of diarrhea can
decrease this burden in countries with limited healthcare resources, like Lebanon. The findings from this study are
anticipated to provide evidence-based dietary recommendations for ambulatory infants with acute diarrhea in
developing countries.
Trial registration: ClinicalTrials.gov NCT02246010; September 2014.
Keywords: Acute gastroenteritis, Lactose-free milk, Developing world
Background
Acute diarrheal illness is a major public health burden
worldwide, and more so in developing countries. Diar-
rhea is the second cause of morbidity and mortality in
children younger than 5 years, accounting for around
15% of all childhood death, and leading to more than
1 million deaths each year [1]. The North American
Society for Pediatric Gastroenterology, Hepatology, and
Nutrition estimates the overall yearly incidence of diar-
rhea in children younger than 3 years at 1.3 episodes per
child [2]. The mean incidence rate in developing coun-
tries is almost double that reported from industrialized
countries and amounts to an average of three episodes
per child per year [3]. Diarrheal diseases are also a finan-
cial burden at the macro- (country) and micro- (family)
levels. In the United States, diarrhea leads to 2.1 to 3.7
physician visits per child each year, with an average cost
of $289 per episode [4]. Moreover, pediatric diarrhea is
known to afflict parental well-being, causing major emo-
tional distress and fatigue.
* Correspondence: mn04@aub.edu.lb
1Department of Pediatrics and Adolescent Medicine, Faculty of Medicine,
American University of Beirut, Beirut, Lebanon
2Department of Pediatrics and Adolescent Medicine, American University of
Beirut Medical Center, P.O. Box: 113-6044/C8, Beirut, Lebanon
TRIALS
© 2015 Nabulsi et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Nabulsi et al. Trials  (2015) 16:46 
DOI 10.1186/s13063-015-0565-9

Pediatric diarrhea can last for several days, leading to
dehydration, electrolyte disturbances, and malnutrition,
especially in children younger than5 years. Children who
are malnourished, or have impaired immunity are at
higher risk of life-threatening complications from diar-
rhea. The main etiology of acute diarrheal disease in
children younger than 5 years is intestinal tract infection
caused by a variety of viral, bacterial, or parasitic orga-
nisms. Acute infectious diarrhea may cause damage to
the lactase-containing epithelial cells present on the tips
of the intestinal villi, thus causing lactose malabsorption.
The new epithelial cells that replace older ones are usu-
ally immature and often lack sufficient lactase activity,
which will further exacerbate the lactose malabsorption,
with subsequent prolongation of the diarrheal episode.
Adequate nutrition and hydration during diarrheal epi-
sodes is necessary to avoid dehydration, malnutrition,
and weight loss. In a systematic review published in
1994, Brown et al. [5] reported clinical improvement
after the use of lactose-free milk products in young
children with severe dehydration. A recent Cochrane re-
view reported the results of 33 randomized or quasi-
randomized trials that assessed the effects of reducing or
avoiding lactose in young children (<5 years) with diar-
rhea on the duration and/or severity of the illness [6].
The review concluded that lactose-free products may
reduce the duration of the diarrhea by an average of
18 hours (MD, −17.77; 95% CI, −25.32 to −10.21, low-
quality evidence) as compared with lactose-containing
formula. Also, lactose-free products may reduce treat-
ment failure, such as continued diarrhea or vomiting,
continuing weight loss or need for additional rehydra-
tion treatment by around a half (RR, 0.52; 95% CI, 0.39
to 0.68, moderate quality evidence). However, all trials
were conducted in high- or middle-income countries,
and most of them included inpatients only. Hence, a
need exists for high-quality trials to be conducted in de-
veloping countries where the incidence, severity, and
consequences of diarrhea are high, including mortality
and malnutrition.
In this study, we aim to investigate the effect of
lactose-free milk on the duration and severity of diarrhea
in infants with acute gastroenteritis in the ambulatory
setting (Emergency Department). We anticipate that the
findings of this study will add to the evidence base of
dietary recommendations for infants with acute diarrhea
in developing countries who are treated in ambulatory
care.
Methods/Design
Study design
A randomized controlled open-label parallel-arm clinical
trial to investigate whether lactose-free milk will shorten
the duration and lessen the severity of diarrhea in infants
with acute gastroenteritis, when compared with lactose-
containing milk (Additional file 1).
Study population
Infants who are fed artificial milk formula (2 to 12 months
of age) with acute diarrhea, first seen in the emergency
department (ED).
Recruiting process
Inclusion and exclusion criteria
Eligible infants are those who are between 2 and
12 months of age, fed artificial milk formula, and who
present to the ED of the American University of Beirut
Medical Center with acute gastroenteritis. Diarrhea is
defined as the passage of three or more loose or liquid
stools in 24 hours, for at least 24 hours, and not excee-
ding 2 weeks from presentation, with or without fever,
vomiting, mucus, or blood per stools.
Infants with any of the following conditions will be
excluded: any breastfeeding, sepsis, chronic diarrhea,
severe dehydration, inflammatory bowel disease, cow’s
milk allergy, necrotizing enterocolitis, intussusception,
volvulus, current intake of lactose-free milk, celiac dis-
ease, immune deficiency, chronic disease, malnutrition,
or need of immediate hospitalization.
Randomization
Eligible infants will be randomly allocated to one of two
parallel groups (experimental and control, 1:1 ratio), by
using a computer-generated stratified block randomization.
Stratification will be done by age groups: <6 months
versus ≥6 months, with block sizes varying between
4 and 8. The random sequence will be generated by an
independent biostatistician. Allocation concealment will
be done to ensure that group assignments of the partici-
pants are revealed only after assessing that the inclusion/
exclusion criteria are verified and consent obtained. This
will avoid any bias that might be introduced by the inves-
tigator because of the knowledge of the allocation of the
next subject. A set of sequentially numbered opaque
sealed envelopes will be prepared with the allocation
group, as per the randomization list, specified inside.
Description of the intervention
Control group
Except for dietary instructions, subjects in the control
group will receive standard medical care, including rehy-
dration with oral rehydrating solutions, as per their phy-
sicians’ recommendations. The dietary instructions will
be provided to the family by the research team and will
consist of the infant’s regular lactose-containing milk, in
addition to the hospital’s antidiarrhea diet usually pre-
scribed to patients with acute diarrhea, and which is
composed of potatoes, rice, lean meat or chicken, apples,
Nabulsi et al. Trials  (2015) 16:46 
Page 2 of 6

bananas, and yogurt. Any additional treatment by the
primary physician including dietary change (whether
milk or solid foods) will be respected. If an infant in
the control group does not improve on the lactose-
containing milk, it will be up to his primary physician to
decide on the next step, including switching to lactose-
free milk. The infant will continue to be in the study
and will be included in the intent-to-treat analysis. All
dietary changes or medication intake during the study
period will be recorded as part of data collection.
Intervention group
Infants in the experimental group will receive standard
medical care, including rehydration with oral rehydrating
solutions, as per their physicians’ recommendations. The
dietary instructions will be provided to the family by the
research team and will consist of the same antidiarrhea
diet prescribed to the control group, as previously de-
scribed, in addition to lactose-free milk (Similac LF).
Any additional treatment by the primary physician, in-
cluding dietary change (whether milk or solid foods), will
be respected. If a baby in the intervention group does
not improve on the lactose-free milk, it will be up to his
primary physician to decide on the next step, including
switching to any other lactose-free or lactose-containing
milk.
Outcome measures
Main outcome measure
The primary outcome is the difference in diarrhea dur-
ation between the intervention and control groups, de-
fined as the number of days with loose or liquid stools,
from randomization until the day of the last diarrheic
stool passed.
Secondary outcome measures
Differences between the two groups with respect to the
following:
1. Percentage weight loss from baseline.
2. Proportion of infants with a return physician visit
because of diarrhea within 7 days from baseline.
3. Proportion of infants hospitalized within 7 days
from baseline for any cause.
4. Parental satisfaction.
5. Severity of symptoms: stool quantity and quality,
colic, lethargy, use of analgesic or antispasmodic.
Recruitment
A trained research assistant will be present in the ED all
day during regular working hours to identify eligible sub-
jects. Parents of eligible infants will be approached and in-
formed about the study, and details and procedure of the
study will be explained to the family. If inclusion criteria
are met, a written informed consent will be obtained from
parents willing to enroll their infant in the study.
Data collection
1. Baseline:
a. Obtain parental consent
b. Provide parent with dietary instructions, both
verbal and written
c. Provide parent with milk formula as per
treatment allocation
d. Provide parent with diary for data collection at
home (see Additional file 2)
e. Collect baseline data: Age, gender, number of
siblings, exposure to sick contact, day-care
attendance, maternal level of education, maternal
employment, maternal age, monthly income,
smoking status at home, infant’s diet (formula
brand, other dairy intake, oral rehydrating solution,
antibiotic intake, vitamin/mineral intake,
immunization status against Rota////virus,
laboratory test results (if requested by ED physician,
including blood, urine, or stool), number of stools
per day, number of days with diarrhea, vomiting
(number, duration), days with fever, analgesic
intake, antispasmodic intake, history of previous
breastfeeding, duration of breastfeeding, use of
probiotics, initial diagnosis, physical examination
findings.
2. Day 1 (after 24 hours): Telephone call to collect
information on admission to hospital (Yes/No),
return visit to doctor (Yes/No), and compliance
with dietary instructions; reminder to fill diary.
3. Day 3: Telephone call to collect information on
admission to hospital (Yes/No), return visit to
doctor (Yes/No), and compliance with dietary
instructions; reminder to fill diary.
4. Days 5 and 6: Reminders to fill diary.
5. Day 7: Visit to research team at AUBMC to collect
information on admission to hospital (Yes/No),
return visit to doctor (Yes/No), parental satisfaction,
drug intake, final diagnosis; obtain infant’s weight on
the same scale previously used at baseline; collect
diary from parent, collect empty formula cans to
check on compliance; pay transportation fees
(See Figure 1).
Data management and quality assurance
The research assistant (RA) will be trained on how to
approach parents, contact them for follow-up by phone
(by using a pre-paid phone card), and collect data during
the 1-week follow-up. Training will entail familiarizing him
or her with all necessary documentation, including enroll-
ment and consent forms, and consenting in accordance
Nabulsi et al. Trials  (2015) 16:46 
Page 3 of 6

with the ethical principles of informed consent. Instruc-
tions and demonstrations on how to explain the dietary
instructions and fill the diary card will also be done.
The RA will send daily reminders to parents to fill the
diary by using email, telephone messages, or communi-
cation through social media.
Sample size
We hypothesize that the lactose-free milk will shorten
the diarrhea duration by an average of 24 ± 16 hours [6],
as compared with lactose-containing milk. To detect this
difference between the two groups with 90% power and
5% type I error, 12 infants will be needed in each arm
(24 infants in total). We anticipate that 30% to 40% of
infants that will be recruited will either withdraw or will
be lost to follow-up from previous research experience.
Hence, to allow for a loss-to-follow up rate of 35%, we
will inflate the sample size to become 40 infants.
Statistical methods
We will compare continuous variables (duration of diar-
rhea, percentage weight loss, age) by using the Student
t test, and categoric variables (proportions, categories
of severity) by using a χ2 test. Nonparametric tests will
be used to analyze variables with skewed distribution or
when the number of analyzed subjects is fewer than 30.
Baseline characteristics of both groups will be compared
to assure similarity of groups at study entry, and to iden-
tify clinically significant imbalance of any variable that
needs adjustment during analysis. Risk ratios will be calcu-
lated for the outcomes of hospital admission and return
physician visit. Results will be reported as means or me-
dians when appropriate, intervals will be calculated. To as-
sess the severity of diarrhea, we will evaluate the stool
quantity and quality from the parental responses to the
questions in the diary. For the quantity evaluation, we will
consider passage of three to four stools per day as consist-
ent with mild diarrhea, five to seven stools per day as con-
sistent with moderate diarrhea, and eight or more stools
per day as consistent with severe diarrhea.
For the quality evaluation, the responses will be
assigned points ranging from a minimum of zero to a
maximum of 6. A cumulative score will be created for
the stool-quality assessment, which is the sum of points
Formula-fed infants with acute diarrhea in ED
Intervention
Collect baseline 
characteristics
Day 1-6
Data collection:
-Telephone call by 
research team
-Parental diary
Day 7
Hospital visit:
-Reweigh infant
-Collect parental 
diary and milk cans
Day 7
Hospital visit:
-Reweigh infant
-Collect parental 
diary and milk cans
Control
Collect baseline 
characteristics
Informed consent and 
randomization
Day 1-6
Data collection:
-Telephone call by 
research team
-Parental diary
Figure 1 A flow diagram of study participants.
Nabulsi et al. Trials  (2015) 16:46 
Page 4 of 6

to all responses, ranging from zero to 14. We will con-
sider that an overall qualitative score of 0 to 4 is con-
sistent with mild diarrhea, 5 to 8 as consistent with
moderate diarrhea, and a score of ≥9 as consistent with
severe diarrhea. The main analysis will be based on the
intention-to-treat principle. In addition, we will conduct
per-protocol analyses for primary and secondary out-
comes. The Statistical Package for Social Sciences (SPSS)
version 21 will be used for data management and analyses.
A P value of <0.05 will indicate statistical significance.
Ethical approval
The study is approved by the Internal Review Board of
the American University of Beirut. Written informed
consent will be obtained from the parents. Because the
study involves comparison of two types of milk formula,
we estimate that the risks to infants from participating
in this study are negligible, not exceeding those of
current standard practice. Confidentiality of participants
will be secured by storing data sheets in locked cabinets
in the principal investigator’s office. Access to SPSS data
file will be password-protected and restricted to the
principal investigator.
Discussion
This study aims at investigating whether lactose-free
milk, when compared with lactose-containing milk, will
shorten the duration and lessen the severity of diarrhea
in infants with gastroenteritis who are treated in the am-
bulatory setting (ED) of a hospital in a developing coun-
try. The World Health Organization (WHO) estimates
that 1.5 million children under the age of 5 years die
each year of diarrhea; half of those are from the develop-
ing world [7]. Exclusive breastfeeding for the first
6 months of life is one cost-effective intervention that
reduces the risk of infant death of diarrhea. Unfortu-
nately, fewer than 40% of infants younger than6 months
in developing countries are exclusively breastfed [8]. The
lack of studies from the developing world investigating
the effectiveness of lactose-free milk in reducing the dur-
ation or severity of infant diarrhea underscores the need
for high-quality trials that can address this knowledge
gap. Hence, this study may provide much-needed evidence
regarding the dietary recommendations of formula-fed in-
fants with acute gastroenteritis.
The study may have some limitations. The first limita-
tion is the sampling frame, which is the ED of one hos-
pital in an urban setting, from which a convenience
sample of infants is recruited. It can be argued that in-
fants living in rural areas may have a much more severe
illness and may respond differently to the lactose-free
milk. However, AUBMC is a major referral center for all
the country, with patients seen in its ED from different
urban and rural areas.
Another limitation is the small sample size. This is be-
cause the standard error used to calculate the sample
size is relatively large (16 hours) in comparison with the
estimated effect size (24 hours). Nevertheless, the effect
size and its standard error were those reported by the
most recent Cochrane Review about the subject.
The third limitation is the open-label design, which is
due to the difficulty in concealing the milk containers in
our setting, and to the fact that it is very likely that par-
ents will decline participation in a trial in which they
cannot know the name of the milk brand their infant
will take. Despite these limitations, we anticipate that
lactose-free milk, if proven effective, will have a signifi-
cant impact on the morbidity of formula-fed infants with
acute gastroenteritis in developing countries.
Trial status
Recruiting as of November 1, 2014.
Additional files
Additional file 1: SPIRIT Checklist. NA: Not applicable.
Additional file 2: Parental diary for the diarrhea study.
Abbreviations
AUBMC: American University of Beirut Medical Center; ED: emergency
department; SSPS: Statistical Package for Social Sciences; WHO: World Health
Organization.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MN was responsible for the conception and design of the study, questionnaires,
and data-collection instruments, wrote the first and final versions of the protocol,
and applied and received grant for the study. NY was responsible for the
conception and design of the study and questionnaires, and participated
in the writing of the initial and final protocol versions. FC participated in
study design and writing of the first version of the protocol. All authors
read and approved the final manuscript.
Acknowledgements
This study is funded by the University Research Board and the Medical
Practice Plan of the American University of Beirut.
We are grateful to Dr. Lilian Ghandour for her valuable input on the diarrhea
questionnaires.
Received: 23 October 2014 Accepted: 13 January 2015
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