Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01229579 |
| Other study ID # |
1291-Peds/ERC-09 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 2010 |
| Est. completion date |
January 2011 |
Study information
| Verified date |
February 2021 |
| Source |
Aga Khan University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Pakistan is one of the 4 developing countries where cases of poliomyelitis are still being
identified. Despite the incessant efforts by WHO and UNICEF, this disease is far from
control. There is a need to develop new and innovative strategies to contain the disease and
eradicate it from the countries where new cases continue to be identified.
Zinc is an essential component of scores of enzymes in the human body. Recent reports have
indicated that this trace element along with other micronutrients enhances the protective
functions of immune cells. Moreover, zinc deficiency leads to dysregulation of balanced host
responses to infection resulting into decreased antibody production and suppressed immunity.
Zinc is also an essential cofactor for thymulin which is known to modulate cytokine release
and induce immune cell proliferation. Zinc deficiency is also found to impair an individual's
epithelial barrier function, which may further depress the vaccine entry into the mucosal
cells.
Role of zinc in the prevention of diarrheal diseases and other infections in children is well
documented. However, there are very few reports about its contribution to enhanced immunity
by supporting body's natural defense system.
Zinc insufficiency is widespread in socioeconomically deprived children in South Asia and the
recent most national nutrition survey (2003) . Moreover, diarrhea is also very common in
infants in Pakistan. Such diarrheal episodes can limit entry of attenuated polio virus into
the mucosal cells, thereby, leading to inadequate immune response. Association between recent
diarrheal history and increased vaccine failure in infants has been shown in a study from
Brazil. The recent Lancet Nutrition series has also recommended regular zinc supplementation
to address child undernutrition and stunting and underscored the need to treat diarrheal
episodes with zinc to expedite recovery. Other recent studies of zinc supplementation in low
birth weight infants in South Asia have also shown significant improvement in diarrheal
disease burden and mortality.
On the basis of these lines of evidence, it is possible that some of the cases of vaccine
failure in this region could be a consequence of compromised immunity and, hence, diminished
response to OPV. This could potentially be reversed by addressing such gross undernutrition
and micronutrient deficiencies. It can thus be hypothesized that zinc supplementation at
community scale would enhance the immune response in infants to OPV.
In order to test this research question, the investigators propose to undertake 12-month
randomized controlled trial among a cohort of Pakistani infants of 0-14 days of age. Such a
trial would enable us to understand the synergistic role of zinc (if any) with OPV in
enhancing immune response against polio and sero-conversion rates.
Description:
The investigators propose to carry out a randomized controlled clinical trial in Pakistan to
assess the efficacy of zinc supplementation in the first 18 weeks of life on seroconversion
due to OPV.
Infants of 0-14 days of age will be recruited and randomized into 2 groups; all the groups
would receive the respective OPV doses according to the EPI schedule, and the intervention
group, in addition, would receive 10 mg of elemental zinc on a daily basis, for 18 weeks,
starting at the age of 14 days.
At 18 weeks (after the 4 weeks of last OPV), the investigators provide an additional dose of
bOPV as a challenge and collect stool samples to at 0 and 7 days after delivery at of the
bOPV.
Study settings The rural settlement of Hala (population ~ 200,000), located about 200 km
north-east of Karachi, Pakistan would be the selected study site, as a high proportion of
at-risk under 5 children reside in the area. The large proportion of this population falls in
the lower socioeconomic group, according to a recently conducted census in 2008, making the
site eminently suitable to test out the trial hypotheses.
The Department of Pediatrics & Child Health, AKU has established liaison with the community
members and local government stakeholders, with its research office located in a
district-level tertiary care hospital. The nearby vaccination center would assist in
delivering the OPV doses, according to the EPI schedule, along with other EPI vaccines. The
tertiary health care center (Taluka Hospital, Hala) would provide a place for evaluation and
treatment for any unforeseen adverse reactions / events, free of cost.
Study population The trial would recruit full term healthy infants of either sex at or soon
after birth and randomize them for supplementation as soon as possible after birth (within 72
hours and in tandem with the first OPV dose). Infants beyond this age and preterm infants (<
37 weeks gestation or < 2 kg birth weight) would be excluded.
Sampling strategy Eligible subjects would be identified and randomized to the respective
intervention and comparative groups using computer generated three cell block randomization
permutation tables.
Group A: Standard OPV schedule and oral zinc supplement (as 10 mg zinc sulfate liquid
preparation) daily for 18 weeks.
Group B: Will receive standard OPV schedule and standard care. An identical placebo
preparation, similar in taste, color and consistency will also be administered daily for 18
weeks.
The groups would receive standard OPV doses at birth, at 6 weeks, at 10 weeks and at 14 weeks
of age, as recommended by the expanded program of immunization (EPI). As practiced by WHO and
UNICEF, OPV doses would also be administered in the cohort, through the polio mass
vaccination campaign, scheduled twice in every 3 months. The zinc and placebo preparation
will be administered in equal volumes (2.5 ml daily), prepared by Atco Laboratories Limited,
one of the leading pharmaceutical industries in Pakistan. . They would hold the allocation
codes, replenish supplies at fortnightly intervals and maintain consumption records. The
research and monitoring staff will be fully blinded to these preparations.
Given the need to follow individual level response, the investigators have chosen an
individual randomized trial as opposed to a cluster randomized trial. The investigators shall
employ a computerized block randomization strategy with groups matched in blocks of 20, with
the codes maintained by Atco Laboratories Limited and the Chair of the AKU ERC.
Trained field workers will visit the households, 2 times a week to assess compliance to the
assigned intervention at their respective time schedules, motivate families and evaluate the
child as per a standard format. For the recruits in the research study, incentives would be
provided in the form of soaps and cloths to be provided when the field teams visit the
household for collection of blood samples from the study subjects. These have been selected
in view of the immediate need of these to the recruited child residing in the area of Hala
and through years of formative research for comparable projects in rural Sindh. These
incentives have deliberately been kept modest so as not to pose undue incentives for
participation. The health workers would replenish zinc or placebo supplies every 12 days (in
30 ml bottles).
Enrollment of participants Sample size estimates There is scarcity of research indicating the
seroconversion rates to OPV among infants residing in a rural population of Pakistan. The
investigators assumed that a conservative estimate of seroconversion to OPV among infants
till 14 weeks of age for a rural population of Pakistan would be about 50%. These
seroconversion rates are consistent with the lower limits of OPV seroconversion rates
observed among breastfed young infants in one solitary study on the subject in Pakistan. To
detect a 20% improvement in seroconversion rates upon zinc administration, the investigators
would require a minimum of 242 subjects (121 subjects occupying each group) at 5% level of
significance and 90% power. Estimating a 30% maximum dropout or refusal rate in comparable
studies involving serological testing, the investigators would require a total of 320
subjects, with 160 subjects occupying each group.
Identification and informed consent A cohort of pregnant women (in their third trimester)
would be identified through the baseline census and subsequent updates during the
surveillance period. The investigators will then identify births within 24 hours of birth
through an information system employing the assistance of Lady Health Workers (LHWs) of the
area and the traditional birth attendants (TBAs). Families will be visited prior to birth to
sensitize them about the study and provide an information sheet. Following notification of
births, the families will be visited again and informed consent sought prior to initial
randomization. The recruited infants and families will be visited, 3 times per week to assess
morbidity and growth (height, weight, mid-arm circumference and head circumference). Close
liaison would be maintained with the local vaccination centers, where the OPV doses would be
administered to the infants according to the EPI schedule of Immunization. Efforts would be
made by the research staff to maintain a record of all vaccinations of the recruited cohort,
along with dates for subsequent vaccinations.
Surveillance and data collection A research team would be assembled, constituting of research
supervisors, field supervisors, research medical officers, phlebotomists and community health
workers.
For the census update, a data collector is capable of visiting at least 30 households per
day; thus the census update could be covered in a months' time.
Recruitment of subjects in the trial could get covered in less than 2 months. For the trial
activity, at least 8 teams would be delegated, with each covering at least 40 households per
day. Each household (bearing one potential subject) would be visited 2 times in a week.
A 3-day training program would be imparted to familiarize them of the research protocol, the
field operations for the activities of the census/survey and the research trial and measures
for completing the forms. A series of data collection forms would be drafted (initially in
English; then translated to Urdu and Sindhi languages) to collect information during the
entire research period. A case recruitment form (CRF) would be drafted, which would be filled
by research medical officers and would bear questions/items on birth history, immunization
status, medical history, anthropometry and physical examination. The subjects would be
followed up on a regular basis (2 times a week) by the research appointed community health
workers with a minimum qualification of matriculation (grade 10 education), using a
pre-defined follow up form. The CHWs will record data on immunization status, medical history
and management of any ailment (especially diarrhea), anthropometric assessment and medical
examination, and laboratory test results (blood serology and ELISA). Immunization status of
each recruit would be maintained for every OPV dose provided to the recruited infants. The
data would be collected by the CHWs during their regular follow ups in the area through
assessment of vaccination records and finger marking during or after campaigns. A
supplementation form would be maintained regularly to ensure compliance in all groups and
replenished. This would be recorded by the community health workers undertaking household
surveillance. All the forms would bear the general information of the child and the
intervention codes allotted by Atco laboratories. Research medical officers, in addition to
leading the field teams, would also be entrusted to oversee any untoward events/reactions,
among the study subjects. These would be brought to their notice by the circulating CHWs. If
encountered, the adverse events would be documented followed by its clinically appropriate
treatment. If a child, outside the recruited cohort is identified as in need of health care,
the CHWs may refer the child to the Taluka Hospital, Hala.
Laboratory Analysis Blood samples (approximately 3 ml from the cubital fossa of either arm)
would be collected at birth, at 6 weeks and at 18 weeks of age of the recruited infant, by
phlebotomists with relevant experience of drawing blood among infants. The blood samples
would be analyzed for polio seroconversion rates. Neutralizing antibodies would be determined
using the methods recommended by WHO [9]. The investigators will evaluate antibody responses
to OPV by serotype in close collaboration with CDC (Atlanta). A subset of the samples will
also be locally tested by ELISA to determine the sensitivity and specificity of ELISA as
compared to the gold standard neutralization assays in detecting polio antibodies.
In order to investigate the impact of zinc on immune response to OPV, the investigators would
determine the status of zinc (serum levels) in infants in all the groups. These would be
determined from blood samples collected at birth, at 6 weeks and at 18 weeks of age and
analyzed using atomic absorption spectrophotometry using established micromethods. Other
micronutrient indicators influencing systemic and mucosal immunity (hemoglobin, ferritin and
vitamin A) would also be analyzed from the collected blood specimens of the recruited
subjects.
The blood samples would be collected from the field and transported to the Nutrition Research
Laboratory, Department of Pediatrics & Child Health, AKU. A transport mechanism is well
established which brings the blood and other biological samples from Hala/Matiari field site
to the main laboratory at AKU on a daily basis. To save costs the same mechanism would also
be employed for transportation of blood samples to the Research Laboratory at AKU.
Study duration The study is expected to last in total for 12 months; initial 3 months for
census activities and field preparation and training activities, 6 months for the actual
research trial, inclusive of recruitment, intervention, follow up and laboratory tests and
the last 3 months for finalization of data analyses and preparation of the final report.
In addition, the investigators will collect stool samples to at 0 and 7 days after delivery
at of the bOPV. The stool samples would be collected from the field and transported to the
National Institute of Health (NIH), Pakistan and processed according to the standard protocol
used in the global polio laboratory network, including poliovirus isolation, ITD and
sequencing. Non-polio enterovirus (NPEV) will be isolated but not characterized. A transport
mechanism is well established which brings the stool and other biological samples from
Hala/Matiari field site to the Aga Khan University on a daily basis, where the samples will
be stored until shipment to the NIH (a WHO Regional Polio Network Laboratory) in Islamabad.
Study variables
- Outcome variables: Seroconversion rates of polio virus (type 1 and type 3), from blood
samples collected at the time of recruitment, at 6 weeks and 18 weeks, and prevalence of
excretion of poliovirus serotypes 1, 3 at 0 and 7 days after the administration of bOPV
- Other variables: Data would be collected on birth history, immunization status, medical
history and management, number and rates of diarrheal episodes, breast feeding
practices, laboratory nutritional indices, anthropometric measurements (weight for age,
weight for height and height for age), physical examination and vital signs, and other
laboratory parameters, like serum zinc, C-reactive protein, polio virus seroconversion
rates, etc.
Statistical analyses The collected data would be dual entered in a data base developed using
Foxpro, and for further analysis using Statistical Package for Social Sciences (SPSS) version
18 (SPSS Inc., Chicago, IL).
Frequencies for continuous variables would be expressed as means ± standard deviations.
Proportions would be calculated for categorical outcomes. Means would be compared using
paired t-test. Chi square tests of independence would be employed for determining differences
in associations. Differences in seroconversion rates and prevalence of excretion, if any,
would be evaluated using ANOVA and non-parametric tests. Multiple logistic regression
analysis will be undertaken to determine the nature of relationship between serum zinc status
and optimal vaccine seroconversion.
