Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01558440 |
| Other study ID # |
PR-10039 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
March 5, 2012 |
| Last updated |
July 26, 2015 |
| Start date |
January 2012 |
| Est. completion date |
June 2015 |
Study information
| Verified date |
June 2015 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Bangladesh: Ethical Review Committee |
| Study type |
Interventional
|
Clinical Trial Summary
Hypothesis:
During rehabilitation phase of management of severe acute malnourished Bangladeshi infants
less than 6 months old, rates of weight gain will be significantly more in children fed
F-100 and diluted F-100 compared to those fed infant formula.
Brief summary:
Until recently, severe malnutrition has been relatively rare in infants younger than 6
months, but with urbanization and the HIV/AIDS pandemic it is feared that the incidence of
severe malnutrition among young infants will rise. The question of how best to feed infants
aged <6 months has thus come to the forefront. Given the lack of published evidence
regarding the most advantageous formulations for feeding severely malnourished infants aged
<6 months, there is a need for observational studies and comparative randomized trials of
alternative formulations to guide decisions about optimum dietary management in this age
group. This area has been aptly considered a research priority during the consultation
meeting of experts from all over the world convened by the World Health Organization on
management of severe malnutrition in September 2004.
In the WHO case-management guidelines for severe malnutrition, there is no separate
provision for young infants (infants less than 6 months old). The guidelines suggest the use
of a low-solute formula (F-75) and continued breastfeeding in the initial stabilisation
phase. In the rehabilitation phase, the guidelines advise F-100 with an energy density of
100kcal/100ml to promote catch-up growth. There is a concern that the renal solute load from
using F-100 is too high for young infants, and some groups have started using diluted F-100
with an energy density of 75 kcal/100 ml.
Another related issue is the contribution of breastfeeding in dietary intakes during
rehabilitation. In severely malnourished infants, breast milk intakes are likely to be low
initially when appetite is poor, but may be substantial as the infant recovers. Uncertainty
about breast milk intakes has led to conflicting opinions and advice, weaning from the
breast as it is not providing sufficient energy (1).
The aim of this study, to be conducted in a carefully supervised Nutrition Rehabilitation
Unit (NRU), will compare three recovery diets (Infant formula, F-100 and diluted F-100) in
order to provide the evidence-base to determine if a change or add-on in terms of diet in
the WHO guidelines is needed. It will also measure the potential renal solute load
(mosmol/l), serum electrolytes and plasma osmolality of the same children. Body composition
of the infants will also be measured using stable isotope dilution technique before and
after the intervention diet is provided.
Description:
Study design: This is a randomized controlled trial comparing three recovery diets and will
be conducted at a Nutrition Rehabilitation Unit (NRU).
Duration of the study: 24 months. Study site: The trial will take place at the Dhaka
Hospital of ICDDR, Bangladesh. This hospital has a high case load, peaking during
April-October, and the WHO guidelines for the management of severely malnourished children
with minor modifications are followed. Diarrhoea is the entry point for all patients
attending the hospital including children.
Methods During the stabilization phase or the acute phase management, children will be fed
every 2 hourly with 130ml/kg/day F-75 along with other necessary management according to WHO
guidelines (8). Judgment regarding suitability for transfer to the rehabilitation phase will
be made by the regular doctors at the longer-stay ward according to set criteria: i) return
of appetite (i.e. hungry, easily finishes a feed), ii) naso-gastric feeding is not required,
iii) absent or insignificant oedema, iv) cessation of vomiting, v) less than 3 watery
stools/day, and vi) no clinical signs of infection.
When ready for the rehabilitation phase, eligible children will be transferred to the NRU
and randomized to receive any of the three diets (Infant formula, F-100 or diluted F-100).
For the first 2 days on the test diets, they will be fed 130ml/kg/day in 12 (2-hourly) feeds
and then 10ml more at each feed until some is left. This is equivalent to the transition
phase in the WHO guidelines. During these 2 days the infants' pulse and respiration rates
will be monitored 3 hourly to find out the signs of possible fluid overload. Thereafter they
will be fed at 3 hour intervals. Infants will be fed by trained research personnel and will
be encouraged to eat until full. Being 'full' will be defined as two successive refusals
when feed is re-offered. Water will be freely available between feeds. Breastfed children
will continue to be breastfed. Pulse and respiration rates and temperature will be monitored
every 8 hours. If, any of the infants shows the signs of fluid overload, they will be
transferred to longer-stay or special care ward and will be managed according to the
standardized management protocol practiced at Dhaka Hospital of ICDDR,B.
All the children who are accompanied by mothers will be counselled by professional
breastfeeding counsellor for relactation if the child is already weaned from the breast.
Measurement of the diets: All feeding episodes will take place under the supervision of
study personnel. Food portions will be weighed before and after serving using an electronic
balance with one-gram precision, and the actual amount consumed will be calculated by
subtracting leftover food from the amount offered. Pre-weighed napkins will be provided; any
food that is regurgitated, vomited or spilled will be swabbed, weighed and subtracted from
the amount offered.
Measurement of breast milk intake: If, the particular child is breastfed or the re-lactation
has been established, then the mothers will be requested to breastfeed day and night,
according to the usual feeding pattern at home prior to the study or if the child demands.
At each nursing, breast milk will be offered until the child refuses further intake, and the
amount consumed will be measured by test-weighing before and after nursing, while ensuring
that the child wears the same clothing for each weighing. Each nursing episode initiated
after taking a post-feeding weight will be considered a new episode, and the intake will be
similarly measured. Breast milk intake will be measured by recording the difference in the
child's weight before and after the feed, using an electronic balance with two-gram
precision, and the weight change will be adjusted for child-specific insensible losses,
which will be measured on the same balance for at least 30 minutes each day. The duration of
each episode of breast-feeding will be measured using a stopwatch, and the duration and
frequency of breastfeeding in 24 hours will also be recorded.
Discharge criteria: Body weight gain 15% of the admission bodyweight or as soon as the
infant becomes oedema free or if the child has an oedema free weight-for-length Z-score ≥ 2.
Follow-up: At the time of discharge, the mother/caregiver will be asked to bring his/her
child to the nutritional follow-up unit after 2 weeks, then monthly for 3 months. In every
visit the child will be measured for weight, height and mid-upper arm circumference and will
also be examined for any possible illness(s). If, any of the child fails to come for
scheduled follow-up, study personnel will visit their respective homes to know the
well-being and status of the subjects.
Deuterium Oxide Dilution Technique for the Assessment of Body composition:
The following procedure for assessment of body composition will be conducted on the day the
infant will be transferred to the NRU and repeated at the time of discharge.
Deuterium oxide (2H2O) will be used for body composition assessment. Upon enrolment,
baseline saliva samples will be collected. After collection of baseline saliva samples 5g of
deuterium oxide labelled water will be fed to the study infant. Children should avoid
drinking water during the equilibration period, i.e., 3-4 hours after ingestion of the
stable isotope dose. According to the recommendation from International atomic Energy Agency
(IAEA) field manual (9), two post-dose saliva samples will be collected at 3rd and 4th
hours. The concentration of deuterium oxide in saliva samples will be measured with Fourier
Transform Infrared Spectrometer (FTIR) and for total body water (TBW) estimation. Afterward
from measured TBW, the amount of fat free mass (FFM) can be estimated. Body fat mass (FM) is
the difference between body weight and fat free mass (10).
Therefore for each child, saliva samples will be collected 6 times (2 baseline and 4 post
dose) during the course of NRU stay.
Calculation of body composition:
The dilution space of 2H (VD) is 4.1 % higher than TBW due to exchange of H with non-aqueous
H in the body TBW (kg) = VD /1.041 Where, VD (kg) = Dose 2H2O (mg)/enrichment 2H in saliva
(mg/kg) FFM (kg) = TBW (kg) / hydration coefficient*
- Hydration factor = Hydration of FFM (%FFM)/100 Fat mass (FM) is calculated by
difference between body weight and FFM FM (kg) = body weight (kg) - FFM (kg) Results
are often expressed as % body weight FM (%) = FM (kg) / body weight (kg) x 100
- Please see Table 2; Hydration factor for children (11, 12) Randomization After
assessing suitable for initiating the rehabilitation phase, infants will be randomized
to the test diets in blocks of 6 using a random numbers table (EPI-INFO 6.04, CDC
Atlanta, GA). Allocation will be concealed in sealed envelopes. The codes will be kept
secure and not broken until data analysis is complete. Medical and nursing staff and
the children's carers will be blind as to the formula given. Infant formula, F-100 and
diluted F-100 will be similar as much as possible in appearance and will be prepared by
the dietician. The invitation to participate in the research will be given at admission
before randomization.
Data collection
1. Rate of weight gain (g/kg/day):
Body weight will be measured daily with a digital scale, precision 2g.
Calculation of weight gain (13,14,15):
Weight gain in g/kg.day = (W2 - W1) x 1000/(W1 x number of days from W1 to W2)
Where:
- W1 = lowest weight during the NRW stay in kg (usually the 1st day of NRW-weight in
case of marasmic children, but it may vary in case of oedematous children)
- W2 = weight in kg on the day of calculation
2. Intake (kcal/kg/day):
During the stay at NRU, amounts of the test diets offered and eaten, and water
consumed, will be recorded by the research assistants.
3. Renal solute load (mOsmol/l):
Potential renal solute load: PRSL = N/28 + Na + C1 + K + Pa Where, N= Nitrogen content
of the diet (mg/28=mosm) Na= Sodium content of the diet (mg/23=mosm) Cl= Sodium content
of the diet (mg/35=mosm) K= Potassium content of the diet (mg/39=mosm) Pa= Available
Phosphorous content of the diet (mg/31=mosm)
0.9 mOsm of PRSL are retained per gram of weight gain (4). RSL will, therefore, be
estimated using the equation: RSL est = PRSL - (0.9 x gain) Where: RSL est and PRSL are
expressed as mOsmoles per day and gain is weight gain in grams per day (7).
4. Serum sodium and plasma osmolality:
Two ml blood will be taken from antecubital vein of the child on days 1, 3, and 7 for
measuring serum sodium, potassium, chloride, total carbon dioxide, creatinine and
osmolality. This will allow monitoring of osmolar state of the child i.e.
hypernatremia. Spot urine samples on the above mentioned days will be checked for
specific gravity and osmolality/creatinine ratio. Urine will be collected in paediatric
urine collector bags. Standard methods will be used for measuring electrolytes,
creatinine, osmolality and specific gravity in the Clinical Biochemistry Laboratory of
ICDDR,B.
5. Extra-renal water losses: Loss of body fluids due to diarrhoea and vomiting will be
recorded, as will fever, environmental temperature and humidity.
Outcome measures:
1. Rate of weight gain (g/kg/day)
2. Food Intake (kcal/kg/day)
3. Breast milk intake (if the child is breastfed) (g/kg/d) and (kcal/kg/d)
4. Renal solute load (mOsmol/l):
Sample size estimation:
In NRU of Dhaka Hospital of ICDDR,B, 124 children suffering from SAM who were managed with
infant formula along with other recommended WHO-guidelines had a daily mean ± SD weight gain
of 10.25 ± 6.7 g/kg/day. If, we assume that with F-100 or diluted F-100 the rate of weight
gain will be 15 g/kg/d, then we require 40 children in each group with 80% power and 5%
level of significance. If, the investigators further consider 10% attrition then each group
will require 44 infants. So, the investigators will study 44 infant in each group giving a
total of 132 children in three study groups.
data Analysis: All recording forms will be pre-coded and checked daily for completeness and
consistency. Differences among the groups will be assessed using chi-squared tests for
proportions and analysis of variance (ANOVA) for normally-distributed continuous variables.
Paired t-test for paired comparison before and after the intervention will be performed. The
analysis will be on an intention-to-treat basis. Statistical analysis will be with the
Statistical Package for the Social Sciences, version 11.5 for Windows (SPSS Inc, Chicago,
Ill). Subgroup analyses will be conducted to test if age has a differential effect on renal
solute load among the groups.
