Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 210
- 试验地点
- 1
- 主要终点
- Change in serum Ang-2 levels in the first 96 hours of hospital admission.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Months 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Rosiglitazone
Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days
干预措施: Rosiglitazone (Drug)
Placebo
Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days
干预措施: Placebo (Drug)
结局指标
主要结局
Change in serum Ang-2 levels in the first 96 hours of hospital admission.
时间窗: 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
次要结局
- Time to clinical recovery(up to 96 hours after hospital admission)
- Blood glucose levels(up to 96 hours after hospital admission)
- Time to parasitological recovery(up to 96 hours after hospital admission)
- Mortality(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(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(at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups)
- Cardiac effects(from baseline to 24h, and day 4)
- Biochemical and hematological parameters(up to 96 hours after hospital admission)
- AE/SAE(up to day 14 after hospital admission)
- Neurocognitive outcomes(From baseline to 6 months post discharge, and 18 months post discharge)