Dengue Hemorrhagic FeverNCT04048837
Prospective Study for the Evaluation of Dengue Prognostic Biomarkers in Singapore
An observational study of Dengue Hemorrhagic Fever and Dengue Shock Syndrome, run by National University Hospital, Singapore at 3 sites in Singapore.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 21 to 100 years
- Conditions the study is for
- Dengue Hemorrhagic Fever, Dengue Shock Syndrome, Severe Dengue
- How many people
- 200 participants
- Where
- 3 sitesSingapore
- Study dates
- 30 Jul 2018to 1 Jul 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Participants will be recruited from patients presenting themselves to the emergency departments, outpatient clinic or inpatient wards of the participating sites, and who are diagnosed by laboratory tests to be infected with Dengue. Delegated research staff will screen laboratory-confirmed dengue patients with inclusion/exclusion criteria. Each participant will be given an information sheet and informed consent will obtained from him/her before any study procedures.
Who may be able to join
- Confirmed Dengue i.e. laboratory confirmation of acute Dengue for this current disease episode by either (i) Positive polymerase chain reaction (PCR) for viral ribonucleic acid (RNA), or (ii) Positive NS1 antigen test with a compatible clinical syndrome
- At least 21 years of age based on his/her birthday, and
- Willing and able to give informed consent.
Who cannot join
- Already classified as having Dengue Haemorrhagic Fever or Dengue Shock Syndrome (WHO 1997 classification) or severe Dengue (WHO 2009 classification) when they first present themselves to the hospital.
- Assessed by Investigators to be unlikely to comply with trial procedures.
- Have known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the past 6 months or long term corticosteroid therapy.
- Have received blood or blood-derived products in the past three months that might interfere with the assessment of the biomarker responses.
- Have participated in another clinical trial investigating a vaccine or drug in the four weeks preceding the study.
- Have received any vaccine in the four weeks preceding the study.
- Are deprived of freedom by an administrative or court order or in an emergency setting or hospitalized without his/her consent.
Trial locations and contacts
3 sites in 1 country.
Singapore3 sites
Tan Tock Seng Hospital
Singapore, 308433
Ng Teng Fong General Hospital
Singapore, 609606
National University Hospital
Singapore
About this study
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.
Read the detailed description
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:
- Determine the optimum cut-off for the prediction of DHF/DSS (WHO 1997 classification) and Severe Dengue (SD; WHO 2009 classification).
- 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.
- 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).
- Keywords
- Dengue
- Medical subject headings
- Severe Dengue, Dengue
What is being measured
The primary outcome is the main question the study is designed to answer.
Concentration of serum A2M, CMA1 and VEGFA will be use to predict whether a dengue patient will develop severe disease as defined by WHO 1997 and WHO 2009 classifications.
Blood will be drawn for measurements of serum concentrations of biomarkers via quantitative enzyme-linked immunosorbent assays (ELISA).
Measured: 7 days
Secondary outcomes (4)
Number of participants develop Dengue Haemorrhagic fever (DHF) within study periods
Patient symptoms will be accessed using WHO 1997 classification for DHF.
Measured: 7 days
Number of participants develop Dengue Shock Syndrome (DSS) within study periods
Patient symptoms will be accessed using WHO 1997 classification for DSS
Measured: 7 days
Number of participants develop Severe Dengue within study periods
Patient symptoms will be accessed using WHO 2009 classification for severe dengue)
Measured: 7 days
Cost of dengue treatments for adoption of such a dengue prognostic technology in hospital
Hospital bills from and outpatient care will be collected to calculate the cost of dengue treatment.
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2019
- Study start30 Jul 2018
- Primary completion1 Jul 2019
- Study completion1 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Dengue Hemorrhagic FeverStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 200 participants (actual)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Tan Tock Seng Hospital, Ng Teng Fong General Hospital
- Responsible party
- Sponsor
- Investigators
- Sophia Archuleta, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04048837
- Sponsor's protocol ID
- PrognosDen
- Status last verified
- Sep 2019
- First submitted
- 19 Oct 2018
- Last updated
- 13 Sep 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Lee LK, Earnest A, Carrasco LR, Thein TL, Gan VC, Lee VJ, Lye DC, Leo YS. Safety and cost savings of reducing adult dengue hospitalization in a tertiary care hospital in Singapore. Trans R Soc Trop Med Hyg. 2013 Jan;107(1):37-42. doi: 10.1093/trstmh/trs009.
PubMed 23296696Ingram PR, Mahadevan M, Fisher DA. Dengue management: practical and safe hospital-based outpatient care. Trans R Soc Trop Med Hyg. 2009 Feb;103(2):203-5. doi: 10.1016/j.trstmh.2008.07.007. Epub 2008 Aug 29.
PubMed 18760815Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060. Epub 2013 Apr 7.
PubMed 23563266Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, Moyes CL, Farlow AW, Scott TW, Hay SI. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012;6(8):e1760. doi: 10.1371/journal.pntd.0001760. Epub 2012 Aug 7.
PubMed 22880140Chawla S, Sahoo SS, Singh I, Verma M, Gupta V, Kumari S. Dengue vaccine: come let's fight the menace. Hum Vaccin Immunother. 2015;11(2):474-6. doi: 10.4161/21645515.2014.981077.
PubMed 25695523
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Study for the Evaluation of Dengue Prognostic Biomarkers in Singapore
- ClinicalTrials.gov ID
- NCT04048837
- Acronym / sponsor ID
- PrognosDen
- Keywords
- Dengue
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 200 participants (actual)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- Tan Tock Seng Hospital, Ng Teng Fong General Hospital
- Study start
- 30 Jul 2018 (actual)
- Primary completion
- 1 Jul 2019 (actual)
- Study completion
- 1 Jul 2019 (actual)
- First posted
- 7 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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:
- Determine the optimum cut-off for the prediction of DHF/DSS (WHO 1997 classification) and Severe Dengue (SD; WHO 2009 classification).
- 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.
- 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).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 21 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Participants will be recruited from patients presenting themselves to the emergency departments, outpatient clinic or inpatient wards of the participating sites, and who are diagnosed by laboratory tests to be infected with Dengue. Delegated research staff will screen laboratory-confirmed dengue patients with inclusion/exclusion criteria. Each participant will be given an information sheet and informed consent will obtained from him/her before any study procedures.
Key inclusion criteria (3 listed)
- Confirmed Dengue i.e. laboratory confirmation of acute Dengue for this current disease episode by either (i) Positive polymerase chain reaction (PCR) for viral ribonucleic acid (RNA), or (ii) Positive NS1 antigen test with a compatible clinical syndrome
- At least 21 years of age based on his/her birthday, and
- Willing and able to give informed consent.
Key exclusion criteria (7 listed)
- Already classified as having Dengue Haemorrhagic Fever or Dengue Shock Syndrome (WHO 1997 classification) or severe Dengue (WHO 2009 classification) when they first present themselves to the hospital.
- Assessed by Investigators to be unlikely to comply with trial procedures.
- Have known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the past 6 months or long term corticosteroid therapy.
- Have received blood or blood-derived products in the past three months that might interfere with the assessment of the biomarker responses.
- Have participated in another clinical trial investigating a vaccine or drug in the four weeks preceding the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Concentration of serum A2M, CMA1 and VEGFA will be use to predict whether a dengue patient will develop severe disease as defined by WHO 1997 and WHO 2009 classifications.
Time frame: 7 days
Blood will be drawn for measurements of serum concentrations of biomarkers via quantitative enzyme-linked immunosorbent assays (ELISA).
4 secondary outcomes
Number of participants develop Dengue Haemorrhagic fever (DHF) within study periods
Time frame: 7 days
Number of participants develop Dengue Shock Syndrome (DSS) within study periods
Time frame: 7 days
Number of participants develop Severe Dengue within study periods
Time frame: 7 days
Cost of dengue treatments for adoption of such a dengue prognostic technology in hospital
Time frame: 7 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2019.
- Background: PubMed 23296696Lee LK, Earnest A, Carrasco LR, Thein TL, Gan VC, Lee VJ, Lye DC, Leo YS. Safety and cost savings of reducing adult dengue hospitalization in a tertiary care hospital in Singapore. Trans R Soc Trop Med Hyg. 2013 Jan;107(1):37-42. doi: 10.1093/trstmh/trs009.
- Background: PubMed 18760815Ingram PR, Mahadevan M, Fisher DA. Dengue management: practical and safe hospital-based outpatient care. Trans R Soc Trop Med Hyg. 2009 Feb;103(2):203-5. doi: 10.1016/j.trstmh.2008.07.007. Epub 2008 Aug 29.
- Background: PubMed 23563266Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060. Epub 2013 Apr 7.
- Background: PubMed 22880140Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, Moyes CL, Farlow AW, Scott TW, Hay SI. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012;6(8):e1760. doi: 10.1371/journal.pntd.0001760. Epub 2012 Aug 7.
- Background: PubMed 25695523Chawla S, Sahoo SS, Singh I, Verma M, Gupta V, Kumari S. Dengue vaccine: come let's fight the menace. Hum Vaccin Immunother. 2015;11(2):474-6. doi: 10.4161/21645515.2014.981077.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sophia Archuleta principal investigator
National University Hospital, Singapore
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Dengue Hemorrhagic Fever and Dengue Shock Syndrome, run by National University Hospital, Singapore at 3 sites in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Concentration of serum A2M, CMA1 and VEGFA will be use to predict whether a dengue patient will develop severe disease as defined by WHO 1997 and WHO 2009 classifications. (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04048837, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2019.