Condition category
Infections and Infestations
Date applied
08/01/2018
Date assigned
12/01/2018
Last edited
12/01/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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?
ZonMw (Netherlands)

Who is the main contact?
1. Dr Rahageng Tunjunputri (Public)
2. Dr Quirijn de Mast (Scientific)
quirijn.demast@radboudumc.nl

Trial website

Contact information

Type

Public

Primary contact

Dr Rahajeng Tunjungputri

ORCID ID

http://orcid.org/0000-0001-6168-4758

Contact details

Dr Kariadi meresmikan Center for Tropical and Infectious Diseases (Centrid)
Jl Dr Sutomo 16
Semarang
50111
Indonesia

Type

Scientific

Additional contact

Dr Quirijn de Mast

ORCID ID

http://orcid.org/0000-0001-6056-157X

Contact details

Radboudumc
PO Box 9101
Nijmegen
6500HB
Netherlands
+316 42095442
quirijn.demast@radboudumc.nl

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

650/EC/FK-RSDK/XI/2017

Study information

Scientific title

Treatment Of Thrombocytopenia with Oseltamivir in acute dengue virus infection (TOTO-trial): a randomized, placebo controlled, multicenter trial

Acronym

TOTO

Study hypothesis

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 approval

Ethics Committee of the Faculty of Medicine Diponegoro University and Dr Kariadi Hospital, 27/12/2017, ref: 650/EC/FK-RSDK/XI/2017

Study design

Phase 2 multicentre randomized placebo-controlled double-blinded interventional trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Dengue

Intervention

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.

Intervention type

Drug

Phase

Phase II

Drug names

Oseltamivir phosphate 75mg BID

Primary outcome measures

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

01/09/2017

Overall trial end date

31/12/2018

Reason abandoned

Eligibility

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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

70

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

13/01/2018

Recruitment end date

31/08/2018

Locations

Countries of recruitment

Indonesia

Trial participating centre

RS Nasional Diponegoro
Jl. Professor Haji Soedarto S.H.
Semarang
50275
Indonesia

Trial participating centre

RSUD K.R.M.T. Wongsonegoro
Jl. Fatmawati No.1, Mangunharjo Tembalang
Semarang
50272
Indonesia

Trial participating centre

William Booth Hospital
1269
Indonesia

Sponsor information

Organisation

Center for Tropical and Infectious Diseases (Centrid)

Sponsor details

Fakultas Kedokteran Universitas Diponegoro-RSUP Dr Kariadi
Jl Dr Sutomo 16
Semarang
50111
Indonesia

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

ZonMw

Alternative name(s)

Netherlands Organisation for Health Research and Development

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

Netherlands

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

01/12/2018

Participant level data

Stored in repository

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes