Oseltamivir for treatment of thrombocytopenia and plasma leakage in dengue

ISRCTN	ISRCTN35227717
DOI	https://doi.org/10.1186/ISRCTN35227717
Protocol serial number	650/EC/FK-RSDK/XI/2017
Sponsor	Center for Tropical and Infectious Diseases (Centrid)
Funder	ZonMw

Submission date: 08/01/2018
Registration date: 12/01/2018
Last edited: 10/01/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

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 16 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)
4. RSUD Kartini (Indonesia)
5. RSAU Salamun (Indonesia)
6. RSUP Dr. Hasan Sadikin (Indonesia)
7. RSUD Al-Ihsan (Indonesia)

When is the study starting and how long is it expected to run for?
September 2017 to December 2019

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

Contact information

Dr Rahajeng Tunjungputri
Public

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

ORCID ID	0000-0001-6168-4758

Dr Quirijn de Mast
Scientific

Radboudumc
PO Box 9101
Nijmegen
6500HB
Netherlands

ORCID ID	0000-0001-6056-157X
Phone	+316 42095442
Email	quirijn.demast@radboudumc.nl

Study information

Primary study design	Interventional
Study design	Phase 2 multicentre randomized placebo-controlled double-blinded interventional trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Treatment Of Thrombocytopenia with Oseltamivir in acute dengue virus infection (TOTO-trial): a randomized, placebo controlled, multicenter trial
Study acronym	TOTO
Study objectives	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(s)	Ethics Committee of the Faculty of Medicine Diponegoro University and Dr Kariadi Hospital, 27/12/2017, ref: 650/EC/FK-RSDK/XI/2017
Health condition(s) or problem(s) studied	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 75 mg 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 / device / biological / vaccine name(s)	Oseltamivir phosphate
Primary outcome measure(s)	Current primary outcome measures as of 25/02/2019: 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, daily ultrasonography (looking for gall bladder wall thickness, ascites and pleural fluid) and plasma markers (e.g. Syndecan-1) from enrollment until discharge or until platelet count ≥ 100 x 109/l Previous 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
Key secondary outcome measure(s)	Current secondary outcome measures as of 25/02/2019: 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. Markers of inflammation, coagulation and endothelial perturbation is measured using daily plasma samples Previous 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
Completion date	31/12/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	70
Total final enrolment	70
Key inclusion criteria	1. Admission to hospital 2. Aged 18 years and above; Updated 01/11/2018: Aged 16 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
Key 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
Date of first enrolment	13/01/2018
Date of final enrolment	31/07/2019

Locations

Countries of recruitment

Indonesia

Study participating centres

RS Nasional Diponegoro

Jl. Professor Haji Soedarto S.H.
Semarang
50275
Indonesia

RSUD K.R.M.T. Wongsonegoro

Jl. Fatmawati No.1, Mangunharjo
Tembalang
Semarang
50272
Indonesia

William Booth Hospital

1269
Indonesia

RSUD Kartini

Jepara
59413
Indonesia

RSAU Salamun

Jl. Ciumbuleuit No.203
Bandung
40142
Indonesia

RSUP Dr. Hasan Sadikin

Jl. Pasteur No.38
Bandung
40161
Indonesia

RSUD Al-Ihsan

Jl. Kiastramanggala
Bandung
40381
Indonesia

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in repository
IPD sharing plan	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.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		07/01/2022	10/01/2022	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

10/01/2022: Publication reference added.
16/08/2019: The total final enrolment was added.
25/02/2019: The primary and secondary outcome measures were updated.
01/11/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2018 to 31/07/2019.
2. The overall trial end date was changed from 31/12/2018 to 31/12/2019.
3. The intention to publish date was changed from 01/12/2018 to 31/12/2020.
4. The inclusion criteria were updated.
5. RSUD Kartini, RSAU Salamun, RSUP Dr. Hasan Sadikin and RSUD Al-Ihsan were added as trial participating centres.