Rosiglitazone Adjunctive Therapy for Severe Malaria in Children

Study Overview
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Brief Summary
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Even with optimal anti-malaria therapy and supportive care, severe and cerebral malaria are associated with a 10-30% mortality rate and neurocognitive deficits in up to 33% of survivors. Adjunctive therapies that modify host immune-pathological processes may further improve outcome over that possible with anti-malarials alone. Investigators aim to evaluate a PPARγ agonist ( rosiglitazone) as adjunctive therapy for severe malaria.

Detailed Description
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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.

Official Title
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Rosiglitazone Adjunctive Therapy for Severe Malaria in Children

Conditions
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Malaria

Intervention / Treatment
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* Drug: Rosiglitazone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 1-12 years Positive 3-band (HRPII plus pLDH) P. falciparum rapid diagnostic test (RDT) and microscopy confirmed malaria infection with parasitemia >2500 parasites/microlitre if microscopy is available in a timely manner at the time of randomization. One or more features of severe malaria: repeated seizures (two or more generalized seizures in 24 h); prostration (in children 1 year and older, the child is unable to sit unsupported or stand although was able to before the illness); impaired consciousness (Blantyre Coma Score <5 in children 1 to 4 years, GCS <14 for children ≥ 5 years); respiratory distress: age related tachypnea with sustained nasal flaring, deep breathing or subcostal retractions Requiring hospitalization and parenteral artesunate for their malaria infection based on admitting physician assessment Exclusion Criteria: P. falciparum RDT negative OR infection not confirmed by light microscopy or not reaching the predefined inclusion criterion parasitemia threshold according to age Uncomplicated malaria infection not requiring hospitalization Presenting with severe malaria anemia (SMA) alone (Hb < 50g/L) Known underlying illness: neurological or neurodegenerative disorders, cardiac, renal, or hepatic disease, diabetes, epilepsy, cerebral palsy, children known to be HIV-1 positive and receiving antiretroviral treatment* Previous treatment with a TZD Unable to remain in research site region for the follow up period

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rosiglitazone<br>Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days | Drug: Rosiglitazone<br>* This is the experimental drug, rosiglitazone, being tested against placebo to assess its efficacy as an adjunctive treatment for severe malaria<br>* Other names: Avandia;|
| Placebo Comparator: Placebo<br>Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days | Drug: Placebo<br>* This is the placebo control<br>* Other names: crushed powder placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum Ang-2 levels in the 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 | first 96 hours of hospital admission. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical recovery | 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 | up to 96 hours after hospital admission | 
| Time to parasitological recovery | 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. | up to 96 hours after hospital admission | 
| Mortality | Mortality in the first 48h post-hospital admission and at 14 days post-hospital admission | 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 | 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 | 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 | 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 | 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 | Blood glucose levels assessed at admission and every 6h for the first 48h, and then every 24h for following 2 days | up to 96 hours after hospital admission | 
| Cardiac effects | 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. | from baseline to 24h, and day 4 | 
| Biochemical and hematological parameters | 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 | up to 96 hours after hospital admission | 
| AE/SAE | AE/SAE monitored using the pediatric toxicity tables modified from the US National Institutes of Allergy and Infectious Diseases | up to day 14 after hospital admission | 
| Neurocognitive outcomes | Participants with Adverse Events that Are Related and unrelated to Treatment by a variety of standard neurocognitive tests | From baseline to 6 months post discharge, and 18 months post discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjunctive treatment, Severe malaria