Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT00548379 |
Other study ID # |
1963 |
Secondary ID |
WT082476MA |
Status |
Active, not recruiting |
Phase |
Phase 3
|
First received |
October 23, 2007 |
Last updated |
May 15, 2008 |
Start date |
November 2007 |
Est. completion date |
July 2009 |
Study information
Verified date |
May 2008 |
Source |
London School of Hygiene and Tropical Medicine |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
Afghanistan: Ministry of Public Health |
Study type |
Interventional
|
Clinical Trial Summary
Background: Pneumonia is the leading cause of childhood mortality, accounting for 19% of the
10.6 million deaths that occur each year1. Case-control studies from Ethiopia2 and India3
suggest that sub-clinical vitamin D deficiency may increase ten times the risk of pneumonia
in children. We postulate that controlling childhood vitamin D deficiency has the potential
to dramatically reduce the incidence of pneumonia and save >700,000 lives each year since
vitamin D deficiency is widespread in developing countries.
Aim: To investigate whether 3-monthly oral supplementation of 100,000iu vitamin D reduces
pneumonia and its consequences among children aged 1-12 months (followed for 18 months),
living in a deprived area of Kabul, Afghanistan, where >70% of young children are vitamin D
deficient (<8ng/dl). The effect of vitamin D on the incidence of other diseases, in
particular diarrhea and rickets will also be investigated.
Methods: Randomised double-blind placebo-controlled trial: 3000 children will be randomised
to receive either 6 doses of vitamin D or placebo. The first dose will be given at the start
of autumn and the second and subsequent doses every 3 months thereafter; children will be
followed for 18 months. Incidence of pneumonia will be ascertained though weekly home visits
(active surveillance) and from attendances and admissions at the trial clinic and wards in
the hospital serving the study area (passive surveillance).
Description:
Vitamin D, an essential micronutrient has a biological function in the formation and
maintenance of strong bones. Vitamin D may help maintain a healthy immune system. In vitro
studies have shown that 1,25-dihydroxyvitamine D3 (1,25(OH)2D3), the active metabolite of
vitamin D is important for promoting and regulating immune responses. 1,25(OH)2D3 is an
immune system modulator and induces expression of the TLR co-receptor CD145. 1,25(OH)2D3
directly induces antimicrobial gene expression an activity points to important therapeutic
uses in treatment of opportunistic and some antibiotic resistant infections. Sub-clinical
vitamin D deficiency has been associated with an increased risk of tuberculosis in adults
through modification of polymorphisms in the vitamin D receptor. Vitamin is acquired
primarily from sunlight; ultraviolet rays trigger synthesis in the skin, which is reduced in
darker skins. The required UV light also reduces with distance from the equator to zero at
latitudes above 500 in winter. Vitamin D deficiency can cause rickets, a common problem in
many developing countries; prevalences of 5 to 45% in under-5 year old children have been
found, even in places with abundant sunlight. Pneumonia is the leading cause of childhood
mortality, accounting for 19% of the 10.6 million deaths that occur each year.
Hospital-based case-control studies from Ethiopia and India suggest that vitamin D
deficiency may substantially increase the risk of severe pneumonia in young children. High
rates of vitamin D deficiency have also been found among children admitted to hospital for
pneumonia, ranging from 43% in Tehran and Kuwait 27 to 50% in Yemen. Afghanistan has a very
high under-5 and infant mortality (257 and 165 deaths/1000 live births respectively), and
pneumonia is a leading cause of death in children. Women and young children have little
exposure to sunlight, and thus are at risk of vitamin D deficiency. Women do not travel out
of the home regularly; wear burkas or clothing that covers all but their hands and face.
Swaddling of infants reduces exposure to sunlight, as does keeping young children in the
mother's vicinity indoors. A survey during the winter of 2005 confirmed very high levels of
vitamin D deficiency among young children in Kabul.
Controlling this deficiency has the potential to dramatically reduce the incidence of
pneumonia and by so doing save lives. Three-monthly oral doses of 100,000iu of vitamin D
have been proven to be safe and effective in alleviating vitamin D deficiency in high risk
normal or rackettic children. Thus we propose to conduct a randomized controlled trial (RCT)
in Afghanistan to test this.
Study area:
The trial will be carried out in District 1,2,3,7 and 8 of Kabul (latitude 34.280 N), where
the vitamin D deficiency prevalence study was conducted in 2005. Most of these are old parts
of Kabul with narrow, shaded lanes often with roofed tops between high walled mud houses;
most houses have small courtyards with high walls so that for much of the day sunshine does
not reach the courtyard. The population is socio-economically deprived with large families
(5-10 children).
Recruitment:
Community sensitisation will be conducted through community and religious leaders and
through public meetings. Recruitment will proceed in all streets of the chosen area which is
within the catchment area of the study and continue house to house along each of those
streets until 3000 children are recruited; 40 female Fieldworkers in pairs will recruit an
average of 6 to 10 children per day over a 1-month period.
Informed consent:
At recruitment the Fieldworker will explain to the family the purpose of the study, the
benefits offered and the procedures involved. An information sheet with the details of the
study objectives, procedures, risk and benefits will also be given to the parents. Informed
consent will then be obtained from both the mother and father of the child: finger prints
and signature (literacy rate estimated at <50%) will be obtained in the presence of two
witnesses, one a friend or family member and one the second Fieldworker.
Baseline data:
At recruitment and at regular periods throughout the study, Fieldworkers will collect data
on a range of socio-economic and demographic variables, as well as the known risk factors
for pneumonia or vitamin D deficiency, including exposure to cigarette smoke, type of fuel,
vaccination, supplementation, diet/breastfeeding, and sun exposure.
Dosing/intervention and period:
6 doses of 100,000iu of vitamin D, or placebo, will be given by Fieldworkers during the
first weekly home visit following recruitment and 3, 6, 9, 12 and 15 months later. If a
child has vomiting at the time of supplementation, the Fieldworker will return weekly and
dose after symptoms have subsided.
Randomization and packaging of intervention/placebo:
An independent statistician will produce the randomization list allocating individual study
numbers to vitamin D or placebo within variable blocks of study numbers. This list will be
used by the sourcing Pharmacy Department of AKU Hospital in Karachi to produce individual
single dose sealed 1ml syringes for each child labeled with one study number. There will be
no characteristics that would distinguish vitamin D dissolved in olive oil from the olive
oil placebo in the syringes; there are no known side-effects that will distinguish those
taking vitamin D from placebo.Oil from the syringes will be dropped in the mouth of each
child at dozing. During the dosing weeks, Fieldworkers will receive 10 syringes each day
with consecutive study numbers to be used that day and checks will be conducted in the
evening. Thus Fieldworkers will only ever have 10 single doses in their possession,
minimizing the possibility of mis-dosing.
Home visits (active case finding follow-up):
For 18 months and every 2 weeks, Fieldworkers will collect information on signs and symptoms
of acute respiratory infections and diarrhea in the last 14 days, current breastfeeding
status and vital status of study children. They will also be trained to take the child's
temperature, count the respiratory rate twice using a UNICEF respiratory rate stop watch,
examine for lower chest wall indrawing, look for dehydration and refer to the study clinic
as appropriate. The causes of death occurring at home will be ascertained using a verbal
autopsy.
Outpatient clinic and hospital admissions of pneumonias:
The first port of call will be a trial outpatient clinic set up within the Maywand Teaching
Hospital located in the study area and within easy reach for all recruited families. This
will be run by 4 paediatricians, who will receive refresher training in the diagnosis of
pneumonia; they will work a shift system covering 24 hours, 7 days a week. They will be
supervised by 1 senior paediatrician and he/she also will examine randomly a sample of other
children seen at the clinic. The paediatricians will fill out a detailed clinical assessment
form for each child, conduct pulse oximetry, request X-rays and treat (according to standard
IMCI) 35 and/or refer for admission if there is severe pneumonia. The trial will cover costs
of all IMCI recommended or hospital inpatient related ALRI medications.
Outcomes:
The primary outcome of the study is radiologically confirmed first or the only episode of
pneumonia according to the WHO standard classification, i.e. [presence of dense or fluffy
opacity that occupies a portion or whole of a lobe or the entire lung] or [presence of fluid
in the lateral pleural space, between the lung and chest wall or both] 36. X-rays will be
read by independent expert radiologists, blind to the child's allocation and clinical
condition, and using a WHO Proforma Standardised Interpretation 36,37 of chest radiographs
for the diagnosis of pneumonia in children.
The secondary outcome will be:
(1) Moderate or severe ALRI (using IMCI criteria) (2) Moderate or severe diarrhea (history
of loose stools >3 times per day and history of oral rehydration or intravenous fluid
therapy) (3) Incidence of hospital admissions for any illness; (4) Anthropometric indices at
0, 6, 12, 18 months (weight for height, weight for age, and height for age, head
circumference) (5) All cause mortality and pneumonia specific mortality; (6) Biochemical
markers of vitamin D deficiency [proportion of children with 25-OHD3 (cholicalciferol)
<8ng/ml]38 at week 6 post vitamin D doses three (mid-spring) and four (mid-summer) in a
random sample of 50 children each from the intervention and placebo group [We assume that
the proportion of children with vitamin D deficiency will be 60% in the placebo group and it
will be reduced to 30% in the intervention group at post vitamin D doses 3 and 4.]; (7)
Pharmacodynamics of vitamin D supplementation will be determined by measuring serum 25-OHD3
(cholicalciferol) at day 2, week 6 and week 12 post vitamin D dose one in a random sample of
50 children each from the intervention and placebo groups] (8) The Thacher Radiological
Score of Rickets 1 through wrist radiography of 10% random sample of children at the end of
the 18 month follow up period.
Additional informed consent will be obtained for collecting blood samples. The sub-samples
of children for measuring vitamin D level will be selected by the independent statistician.
Venous blood samples will be taken at home by an experienced paediatric phlebotomist, and
transported to the trial laboratory at the end of each morning and afternoon in clotted
sampling bottles inside vaccine cool-boxes containing ice-packs. They will be centrifuged by
experienced and retrained technicians and the extracted plasma frozen and stored at <20◦◦C
At the end of the trial all frozen samples will be transported to the AKU Micronutrient
Research Laboratory in Karachi for high 4 pressure liquid chromatography (HPLC) to establish
vitamin D status.
Sample size:
We estimate that the incidence of acute lower respiratory infections (ALRI) in the placebo
group will be 0.065/child /year 39 and 12% of the ALRI will be pneumonia 1. We assume that
25% of pneumonias will be repeat episodes during the 18 month follow up period. Thus the
incidence of the first or the only episode of pneumonia in the placebo group will be
0.0585/child/year (0.65*0.12*0.75). We expect a 35% reduction in the incidence of pneumonia
in the vitamin D group given that 73% of children have vitamin D deficiency in the study
area and that the incidence of pneumonia is 10 times higher in vitamin D deficient children
than in normal children 18, 26. A study with 80% power and 95% significance to detect a 35%
reduction in the incidence of pneumonia compared to the placebo group will require 22079
child months per group37. Since each child will be followed for 18 months the study will
require 1227 child per group. Assuming a 20% loss to follow up the study requires 1472 child
per group. In order to facilitate randomization and allocation of staff we have rounded this
figure to 1500 child per group.
Sample size for blood test as process measure:
50 children per group will give 80% power to detect a 50% reduction in the proportion of
children with 1,25(OH)2D <8ng/ml (50% being conservative compared to the published
literature29-32), assuming that this deficiency is about 60% in the placebo group (a
conservative estimate).