Dengue Hemorrhagic Fever Clinical Trial
Official title:
Prospective Study for the Evaluation of Dengue Prognostic Biomarkers in Singapore
World Health Organisation (WHO) has identified Dengue as the fastest spreading mosquito-borne disease in the world. This study follows on from the National Medical Research Council STOP Dengue Translational and Clinical Research flagship grant. Differential serum concentrations of alpha2-macroglobulin (A2M), chymase (CMA1) and vascular endothelial growth factor A (VEGFA) were discovered to accurately identify dengue patients who will develop severe disease from those who will not, prior to the development of severe complications. By identifying patients at risk of developing severe disease in advance, these patients can be monitored more closely to provide more timely fluid interventions, and hopefully further reduce fatality rate. At the same time, more patients who are not at risk can be managed as outpatients to further minimize unnecessary hospitalization costs and wastage of healthcare resources. After discovery of the Dengue prognostic biomarkers, a multivariate logistic regression predictive model was built from a small retrospective derivative cohort (50 subjects), followed by validation using a small prospective validation cohort (50 subjects). The model had a receiver operating characteristic (ROC) curve AUC (area under the curve) of 0.944, and a sensitivity and specificity of 90% and 91% during validation, respectively. The premise of this study is to validate our observations in a larger prospective cohort (200 subjects). At the same time, we would like to better understand the characteristics of the Dengue prognostic biomarkers, especially whether there are situations in which the biomarkers cannot predict Dengue Haemorrhagic Fever (DHF)/ Dengue Shock Syndrome (DSS) and/or Severe Dengue (SD) and how the biomarkers can further improve the cost-effectiveness of the clinical management of Dengue patients.
This is a non-interventional, prospective study aim to recruit 200 subjects from National
University Hospital, Tan Tock Seng Hospital and Ng Teng Feng General Hospital over a period
of 2 years to determine whether differential serum A2M, CMA1 and VEGFA concentrations can
predict whether a dengue patient will develop severe disease. Serum A2M, CMA1 and VEGFA
concentrations will be quantitated using enzyme-linked immunosorbent assays. The objectives
of this study as below:
1. Determine the optimum cut-off for the prediction of DHF/DSS (WHO 1997 classification)
and Severe Dengue (SD; WHO 2009 classification).
2. Better understand the characteristics (e.g. daily kinetics) of A2M, CMA1 and VEGFA in
Dengue and how their serum concentrations are affected by other variables e.g. patient
age and gender, day of sample collection, primary/secondary infection (based on patient
memory and/or Standard Diagnostics SD BIOLINE Dengue Duo) and virus serotype.
3. Perform a cost-effectiveness analysis for the adoption of such a Dengue prognostic
technology in hospital.
Eligible participants will be aged 21 and above with a laboratory confirmed dengue patients
(either positive PCR or positive NS1), and meet all inclusion/exclusion criteria. Each
participant will be given an information sheet and informed consent obtained from him/her.
Blood will be drawn for PCR Dengue serotyping and measurements of serum concentrations of
A2M, CMA1 and VEGFA via quantitative enzyme-linked immunosorbent assays (ELISA). Blood
collection will be performed on the day of recruitment.
Participants may be managed as inpatients or outpatients as decided by their treating
physician. For participants who are managed as Dengue outpatients, they will be asked to
return to the outpatient clinic every day. For both Dengue inpatient and outpatient
participants, blood will be drawn every day until they are discharged from care or Day 7 of
the study, whichever earlier. If the participants are discharged from care (discharge from
hospital or dengue clinic) on the day of recruitment, they will be asked to come back for
study visit on Day 2. And 2 ml of blood will be collected for research purpose on Day 2. On
the day of discharge, for both Dengue inpatients and outpatients, participants will each be
given a questionnaire to complete. A separate questionnaire will also be filled up by the
study team for the discharge of each Dengue inpatient participant. Should the participant be
discharged prior to Day 7 of the study, a telephone call will be made to the discharged
participant on Day 7 of the study to establish his/her health status. Upon completion of the
study, each participant will be reimbursed a lump sum of $50.
Data collected will be entered into a paper case report forms and will be transcribed onto
eCRF. All participants identifiers will not be collected. The system will allow for audit
tracking. During the course of the study, auditors from relevant authorities may visit the
study site to review protocol compliance, check electronic case report form (eCRFs) and
ensure that the study is being conducted according to Good Clinical Practice (GCP).
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