Plain English Summary
Background and study aims
Dengue is a virus caused by mosquitos. Symptoms include high fever, heaches, vomiting, muscle pains and skin rashes. Low platelets counts (thrombocytopenia) are very common in dengue. Having a low blood platelet count means that the body cannot form blood clots to stop bleeding. Increasing evidence suggests that low platelet numbers play a role in plasma leakage and the bleeding complications of dengue. Patients with dengue can remove certain acids causing a lower amount of platelets. This can be reversed by the neuraminidase inhibitor called oseltamivir. This medication is an approved drug for treatment of influenza. It is speculated that oseltamivir may fasten platelet recovery in dengue-induced thrombocytopenia and prevent plasma leakage. The aim of this study is to investigate whether oseltamivir reduces the time needed for platelet numbers to recover and/or prevent plasma leakage in patients with acute dengue with moderate to severe thrombocytopenia.
Who can participate?
Adults aged 18 and older who go to the hospital for dengue.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group continue with their standard level of care. Those in the second group receive oseltamiriv phosphate twice a day taken by mouth for a maximum of 5 days or when their platelet number reaches a certain level. Platelet numbers are determined twice a day using an ultrasound (using sound waves to create images) and blood tests. Participants are followed three weeks after the start of the study to assess if there are any complications.
What are the possible benefits and risks of participating?
Participation in this study is associated with possible risks and benefits. Possible benefits for participants are that daily laboratory tests are covered by the study and that daily ultrasonography for plasma leakage will be performed. In case the hypothesis that oseltamivir promotes recovery of dengue-associated thrombocytopenia is true, participants randomized to the oseltamivir may be discharged from hospital earlier. There is extensive clinical experience with oseltamivir and severe side effects are uncommon. Nonetheless, the current study employs oseltamivir for a new, unregistered indication and side effects cannot be excluded.
Where is the study run from?
1. RS Nasional Diponegoro (Indonesia)
2. RSUD K.R.M.T. Wongsonegoro (Indonesia)
3. William Booth Hospital (Indonesia)
When is the study starting and how long is it expected to run for?
September 2017 to December 2018
Who is funding the study?
Who is the main contact?
1. Dr Rahageng Tunjunputri (Public)
2. Dr Quirijn de Mast (Scientific)
Dr Rahajeng Tunjungputri
Dr Kariadi meresmikan Center for Tropical and Infectious Diseases (Centrid)
Jl Dr Sutomo 16
Dr Quirijn de Mast
PO Box 9101
Treatment Of Thrombocytopenia with Oseltamivir in acute dengue virus infection (TOTO-trial): a randomized, placebo controlled, multicenter trial
1. Oseltamivir phosphate given to patients with thrombocytopenia in acute dengue reduces the time to platelet recovery (platelets >100 x 10^12/L)
2. Oseltamivir phosphate given to patients with thrombocytopenia in dengue reduces the incidence of dengue-associated plasma leakage
Ethics Committee of the Faculty of Medicine Diponegoro University and Dr Kariadi Hospital, 27/12/2017, ref: 650/EC/FK-RSDK/XI/2017
Phase 2 multicentre randomized placebo-controlled double-blinded interventional trial
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
The study is designed as a phase 2, multicentre, randomized, placebo-controlled, double-blinded intervention trial.
Participants will be randomized using block randomization in a 1:1 allocation ratio.
The trial is double-blinded, i.e. both researchers/study personnel, physicians and participants are blinded.
The intervention tested is oseltamivir phosphate 75mg BID orally (intervention group) or placebo (control group) until platelet number reaches >100 x 10^9/L or for a maximum of 5 days. Patients are randomised using block randomization with variable block size.
Platelet numbers are determined 2 times/daily in all participants and plasma leakage are assessed daily using ultrasonography and by twice daily haematocrit.
Participants will be followed up daily until discharge from hospital or until their platelet count has reached ≥ 100 x 109/l. A follow-up visit at home will be performed three weeks after randomization to assess for late complications and to obtain convalescence laboratory measurements.
Oseltamivir phosphate 75mg BID
Primary outcome measure
1. Time to platelet recovery (platelet count ≥ 100 x 109/l) is measured using twice daily platelet count measurement from enrollment until discharge or until platelet count ≥ 100 x 109/l
2. Plasma leakage is measured by twice daily haematocrit and daily ultrasonography (looking for gall bladder wall thickness, ascites and pleural fluid) from enrollment until discharge or until platelet count ≥ 100 x 109/l
Secondary outcome measures
1. Safety of oseltamivir use in dengue is measured using daily measurement of creatinine and liver enzymes from enrollment until discharge or until platelet count ≥100 x 109/l for a maximum of five days and at week 3 post-enrollment
2. Rate of change of platelet count is measured twice daily using platelet count measurement at 24, 48 and 5 days
3. Number of participants developing severe thrombocytopenia measured using platelet count measurement at enrollment until discharge or until platelet count ≥ 100 x 109/l.
4. Dengue-related complications, especially clinical bleeding is assessed daily using WHO bleeding scores at enrollment until discharge or until platelet count ≥ 100 x 109/l
5. Flow cytometric platelet studies, including platelet activation and reactivity assays as well as platelet sialic acid expression is measured daily using antibodies against P-selectin and the binding of fibrinogen to platelets in unstimulated samples and after stimulation with platelet agonists. Platelet sialic acid content is measured using the lectins SNA, MAL-II and RCA.
6. Markers of inflammation, coagulation and endothelial perturbation is measured using daily plasma samples
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant inclusion criteria
1. Admission to hospital
2. Aged 18 years and above
3. Positive result of NS1 rapid test (proven dengue) or positive for acute dengue serology with probable dengue criteria as defined in WHO 2009 criteria
4. Fever <=6 days
5. Platelet count <70 x 10^9/L
Target number of participants
Participant exclusion criteria
1. Symptoms or signs of another infectious disease
2. Pregnancy or breastfeeding
3. Persistent or recurrent clinical bleeding such as epistaxis, haematemesis, haematochezia, melena, intermenstrual bleeding
4. Chronic liver or kidney disease or active haematological disease
5. Estimated creatinine clearance at moment of enrolment <70 ml/min
6. ALT value > 3x the upper limit of normal
7. Use of platelet function inhibitors or anticoagulants
8. Platelet transfusion during the current hospitalization
9. In patients with earlier platelet count available in past days: platelet number already recovering
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
RS Nasional Diponegoro
Jl. Professor Haji Soedarto S.H.
Trial participating centre
RSUD K.R.M.T. Wongsonegoro
Jl. Fatmawati No.1, Mangunharjo Tembalang
Trial participating centre
William Booth Hospital
Netherlands Organisation for Health Research and Development
Funding Body Type
private sector organisation
Funding Body Subtype
Results and Publications
Publication and dissemination plan
The results of this phase II trial will be published in one manuscript at the end of 2018/early 2019.
IPD sharing statement:
After publication of the trial results, data will be stored in DANS repository (https://dans.knaw.nl).
The type of data stored are quantitative data, including allocation to treatment arm, demographics of the study participants (age, sex), platelet data (counts, activation and reactivity, sialic acid content), data on plasma leakage and safety data (renal and liver function).
Data will be available on request (restricted access). Data will be stored anonymized. Participants have given consent for anonymized data to be stored in a repository.
Intention to publish date
Participant level data
Stored in repository
Basic results (scientific)