Rosiglitazone Adjunctive Therapy for Severe Malaria in Children (ROSI)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02694874|
Recruitment Status : Active, not recruiting
First Posted : March 1, 2016
Last Update Posted : January 27, 2021
|Condition or disease||Intervention/treatment||Phase|
|Malaria||Drug: Rosiglitazone Drug: Placebo||Not Applicable|
Although the use of artemisinin-based therapy has improved outcomes in severe malaria, the mortality rates remain high. Adjunctive therapies that target the underlying immunopathology may further reduce morbidity and mortality in severe and cerebral malaria beyond that possible with anti-malarials alone. Pre-clinical data have established a beneficial role for PPARγ agonists in experimental cerebral malaria. A proof-of-concept randomized clinical trial of uncomplicated malaria in Thailand has extended these findings to an informative patient population, showing that adjunctive treatment with the PPARγ agonist rosiglitazone improves parasite clearance, and reduces biomarkers of inflammation (IL-6 and MCP-1) and endothelial activation (Ang-2 to Ang-1 ratio), and increases neuro-protective pathways (BDNF). The previous clinical trial also established the safety and tolerability of short course rosiglitazone in adults with malaria infection. Importantly, rosiglitazone does not induce insulin release or hypoglycemia in malaria-infected patients. Based on these data, and on studies demonstrating neuro-protective effects on PPARγ agonists in CNS disease and injury, the investigators believe that PPARγ agonists are promising candidates for adjunctive therapy for severe and cerebral malaria.
In this study the efficacy of rosiglitazone vs. placebo control as adjunct to standard of care anti-malarial therapy in children with severe (including cerebral) malaria will be tested.
The underlying hypothesis is that the addition of rosiglitazone to standard antimalarial therapy in severe P. falciparum infection is safe and will result in improved clinical outcomes and lower rates of long-term neurocognitive impairment.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||210 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Rosiglitazone Adjunctive Therapy for Severe Malaria in Children|
|Study Start Date :||February 2016|
|Actual Primary Completion Date :||March 2020|
|Estimated Study Completion Date :||December 2021|
Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days
This is the experimental drug, rosiglitazone, being tested against placebo to assess its efficacy as an adjunctive treatment for severe malaria
Other Name: Avandia
Placebo Comparator: Placebo
Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days
This is the placebo control
Other Name: crushed powder placebo
- Change in serum Ang-2 levels in the first 96 hours of hospital admission. [ Time Frame: first 96 hours of hospital admission. ]We will assess the effect of the intervention (vs. placebo) on Ang-2 levels as a biomarker of severe disease in severe malaria
- Time to clinical recovery [ Time Frame: up to 96 hours after hospital admission ]
Time to recovery including:
- Time to fever resolution for at least 24h. Temperature measurements will be taken at admission and every 4h for the first 4 days, and then every 12h until 2 normal results (<37.5oC) are reported.
- Time to sit unsupported
- Time to hospital discharge
- Time to parasitological recovery [ Time Frame: up to 96 hours after hospital admission ]Time to parasitological recovery: Time (in hours) to clearance of parasitemia from the blood (both 50% and 90% decrease from admission baseline value). Parasitemia will be quantified at admission and every 6h, for 4 days or until 2 negative readings are reported.
- Mortality [ Time Frame: first 48h post-hospital admission and at 14 days post-hospital admission ]Mortality in the first 48h post-hospital admission and at 14 days post-hospital admission
- Blood lactate levels, assessed at admission, every 12h for 24 hours then daily for Blood lactate levels [ Time Frame: Assessed at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups ]Blood lactate levels, assessed at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
- Change in levels of biomarkers of host response [ Time Frame: at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups ]Change in levels of biomarkers of host response at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
- Blood glucose levels [ Time Frame: up to 96 hours after hospital admission ]Blood glucose levels assessed at admission and every 6h for the first 48h, and then every 24h for following 2 days
- Cardiac effects [ Time Frame: from baseline to 24h, and day 4 ]Monitor for cardiac effects by conducting ECG at baseline, at 24h (immediately before third doses of rosiglitazone and artesunate treatment are administered) and at the end of rosiglitazone treatment (day 4). Main outcome of interest will be changes in QTc from baseline to the two different time points.
- Biochemical and hematological parameters [ Time Frame: up to 96 hours after hospital admission ]Biochemical and hematological parameters including: AST, ALT, creatinine, complete blood count (e.g. hemoglobin, WBC and differential, hematocrit, platelet count) will be assessed at admission and every 24h until day 4
- AE/SAE [ Time Frame: up to day 14 after hospital admission ]AE/SAE monitored using the pediatric toxicity tables modified from the US National Institutes of Allergy and Infectious Diseases
- Neurocognitive outcomes [ Time Frame: From baseline to 6 months post discharge, and 18 months post discharge ]Participants with Adverse Events that Are Related and unrelated to Treatment by a variety of standard neurocognitive tests
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02694874
|Centro de Investigação em Saude da Manhiça|
|Manhiça, Maputo, Mozambique, CP1929|
|Study Director:||Eusebio Macete, PhD||Fundaçao Manhiça|