Clinical Trial: Rosiglitazone Adjunctive Therapy for Severe Malaria in Children

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Rosiglitazone Adjunctive Therapy for Severe Malaria in Children

Brief Summary: 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 Summary:

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.

Sponsor: Centro de Investigacao em Saude de Manhica

Current Primary Outcome: Change in serum Ang-2 levels in the first 96 hours of hospital admission. [ Time Frame: first 96 hours of hospital admission. ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Time to clinical recovery [ Time Frame: up to 96 hours after hospital admission ]

  Time to recovery including:

  1. 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.
  2. Time to sit unsupported
  3. 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

Original Secondary Outcome: Same as current

Information By: Centro de Investigacao em Saude de Manhica

Dates:
Date Received: December 9, 2015
Date Started: February 2016
Date Completion: August 2018
Last Updated: July 7, 2016
Last Verified: July 2016