Hand Foot and Mouth Disease Clinical Trial
Official title:
A Prospective Cohort Study Evaluating Prognostic Indicators and Sequelae Following Severe Hand Foot and Mouth Disease
Hand Foot and Mouth Disease (HFMD) is a common infectious disease in childhood. Several
enteroviruses are associated with the disease. However, since 1997, large outbreaks of HFMD
in Taiwan, Malaysia and Vietnam have seen unusual neurological complications such as
brainstem encephalitis with rare fatal outcomes. The pathogen associated with this severe
disease is Enterovirus 71.
In 2011, Vietnam had a large outbreak of Hand Foot and mouth disease resulting in 110,000
cases and 164 deaths. HFMD affects children during their early years of child development,
but there is limited information on what the potential long-term consequences are. Small
studies have suggested language and cognitive difficulties in more severe disease but this
has not been evaluated in a large cohort.
Internationally recognized and standardized assessment tools are not available for early
childhood in Vietnam. This project will translate and adapt the Bayley Scales of Toddler and
Infant Development 3rd edition (Bayley III) and Movement ABC, 2nd edition (MABC) into
Vietnamese as outcome measures.
This study will evaluate whether there are neurodevelopment difficulties following severe
HFMD. The study design is a prospective observational cohort study. Hospitalised children
with a clinical diagnosis of HFMD will be eligible to enroll. Written parental consent will
be required. Participants enrolled will be assessed 3 times over 18 months from discharge
from hospital into the study. Since there is no standardization of Bayley III or MABC for
Vietnam, a healthy cohort, age and sex matched to the least severe HFMD participants will be
recruited. This healthy cohort will follow the same assessment program over 18 months. A
total of 350 HFMD participants and 150 healthy children (matched to the least severe HFMD
participants) will be recruited.
Background:
Hand foot and mouth disease outbreaks associated with enterovirus 71 (EV71) were unusual in
their neurological manifestations. Since 1997, Taiwan, Malaysia and Vietnam have experienced
large outbreaks of EV71-HFMD.
Neurological manifestations include meningitis, brainstem encephalitis, and rare
cardiopulmonary failure, thought to be neurogenic in origin.
In Vietnam, children are admitted to hospital if they show signs of systemic disease. The
Vietnam Ministry of Health has developed a grading system to stratify management and
intervention. Grade 1 have solely the typical rash on palms of hands, soles on feet and
buttock with ulcers in the mouth. Grade 2 have systemic features such has high fever,
irritability and myoclonus. Grade 2 is split into 2a for parental report of symptoms or 2b
if a health professional has observed neurological signs. Grade 2 onwards are admitted to
hospital. Grade 3 develop irregular breathing, persistent tachycardia, hypertension, all
features of autonomic disturbance due to brainstem encephalitis. Grade 4 develop often fatal
cardiopulmonary failure, believed to be a consequence of excessive unopposed sympathetic
activation from brainstem disease.
Different countries use different grading or staging systems for HFMD. A study in 142 EV71
suggested children affected at a younger age of onset of disease might have consequences for
verbal comprehension. In 63 children with EV71 disease, 14% had cognitive or motor deficits.
Hypothesis and Aims:
The study aims to identify the neurological and neurodevelopmental outcomes following severe
(hospitalised) HFMD in Vietnam.
Study Design:
Prospective observational cohort study. There are two cohorts in this study. The HFMD
participants and healthy children. All children hospitalized with HFMD are eligible for
participation. From preliminary review of admissions to the hospital, we identified the
majority of patients were admitted from a local district in Ho Chi Minh City (HCMC)
(District 8). All participants will be asked if they agree for an optional brain magnetic
resonance imaging (MRI).
We will approach kindergartens in that district to enroll healthy children, and also
approach participants in another Oxford University Clinical Research Unit, HCMC study run at
a local obstetric hospital to enroll healthy infants. This healthy cohort will be age and
sex matched to the least severe grade of HFMD participants.
HFMD will have neurological and neurodevelopmental assessments carried out 1 week after
discharge, 6 months later and the last assessment 18 months after the initial assessment.
The Healthy cohort will have a neurodevelopmental assessment at enrollment. 6 months and 18
months after the initial assessment.
Primary Outcomes
1. Comparison of neurodevelopment scores at discharge, at 6 and at 18 months of follow up
between least severe HFMD children and an age and sex matched healthy comparison
cohort.
2. Comparison of neurodevelopment scores at 1 week after discharge, at 6 and at 18 months
after discharge between children stratified by HFMD disease grade.
Other Outcomes
1. Descriptive Brain MRI Changes according to severity of HFMD
Sample size and analysis plan:
We aim to include up to 350 children with HFMD grade 2a, 2b, 3 and 4, and 150 healthy
children (matched for Grade 2a) and follow them up at enrolment, 6 and 18 months of
follow-up.
The Bayley scoring system has a mean score of 100 with a standard deviation (SD) of 15 in
healthy American children. Based on this, we assume an SD of approximately 15 in all 5 study
populations. As little is known about within-child longitudinal changes in Bailey scores
over time, power considerations are based on pair-wise comparisons between groups at each
time point separately. With the sample sizes given, we will have 80% power at the two-sided
5% significance level to detect differences in mean scores of - 7.4 or larger between grade
2a or 2b children compared to grade 3 or 4 children, respectively.
Statistical Methods Standard data summaries such as median (inter-quartile range) for
continuous variables and frequency (%) for categorical variable together with graphical
summaries (histograms, box plots and scatterplots) will be used for descriptive analyses in
all studies.
Longitudinal profiles of development scores over time will be visualized by line plots of
individual subjects' data with overlaid smoothed lines for average development scores over
time within groups. Modeling of longitudinal profiles over time and group comparisons will
be based on standard methods for longitudinal data analysis such as linear mixed effects
models.
Potential Impact:
To public health implications of HFMD require evaluation of long-term. If the burden of
disease continues to have a neurological impact on a significant proportion of children, a
vaccine-based approach is essential and cost-effective.
As intense efforts are underway in vaccine development, research is essential in helping
clinicians on the front line to identify the minority of children who may progress and focus
limited resources appropriately.
;
Observational Model: Case Control, Time Perspective: Prospective
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Not yet recruiting |
NCT02889497 -
Safety, Three Batches Consistency and Immunity Duration of the Post-marketing Inactivated Enterovirus Type 71 (EV71) Vaccine in Children Aged 6-71 Months
|
Phase 4 |