Inhaled Nitric Oxide for the Adjunctive Therapy of Severe Malaria: a Randomized Controlled Trial
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 180
- 试验地点
- 1
- 主要终点
- Change in serum angiopoietin-2 level
研究概览
简要总结
Despite the use of highly effective anti-malarial medications, 10-30% of African children with severe malaria will die, underscoring the need for adjunctive therapies that can be applied in endemic areas. A clinical trial of adjunctive inhaled nitric oxide (iNO) in severe malaria is warranted on the basis of firm proof of concept from animal studies and a human study using the NO donor L-arginine, together with evidence of safety from clinical experience and trials of iNO for other conditions. Our objective is to determine whether supplemental iNO (80 ppm) in addition to Ugandan Standard of Care treatment reduces levels of Angiopoietin-2 (Ang-2), a quantitative biomarker of malaria severity, in children with severe malaria compared to Standard of Care treatment alone. We will conduct a randomized placebo-controlled trial among children 1-10 years of age admitted to Jinja Hospital (Uganda) with severe malaria to test the efficacy of inhaled nitric oxide in severe malaria.
详细描述
Severe malaria remains a major cause of global morbidity and mortality. While the use of artemisinin-based antimalarial therapy has improved outcomes in severe malaria, the mortality rate remains high. Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality. Endothelial activation plays a central role in the pathogenesis of severe malaria, of which the angiogenic factors angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) have recently been shown to function as key regulators. Nitric oxide (NO) is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes. Low-flow inhaled nitric oxide gas (iNO) is a US FDA-approved treatment for hypoxic respiratory failure in neonates. Based on compelling data on the efficacy of iNO in experimental cerebral malaria in animal models, coupled with the documented safety of iNO in clinical practice and trials for other diseases, we propose a randomized clinical trial of iNO for the adjunctive treatment of severe malaria in Ugandan children.
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
- 1 Year 至 10 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 1-10 years
- •Positive malaria rapid diagnostic test in the presence of any of the features of severe malaria
- •Willing and able to complete follow up schedules for the study - 14 day and 6 months after hospital discharge
排除标准
- •Baseline methemoglobinemia
- •Known renal, cardiac, or hepatic disease or other chronic illnesses like diabetes, epilepsy, cerebral palsy, clinical AIDS
- •Severe malnutrition
- •Severe malarial anemia without other signs of severe malaria
研究组 & 干预措施
Inhaled Nitric Oxide
iNO, a gaseous molecule, will be administered by inhalational route over a maximum period of 72 hours.
干预措施: Inhaled Nitric Oxide (Drug)
Room air
Room air will be delivered by air compressor through an indistinguishable mask system.
干预措施: Inhaled Nitric Oxide (Drug)
结局指标
主要结局
Change in serum angiopoietin-2 level
时间窗: Admission through 72 hours
Daily Ang-2 measurements over the first 72 hours of hospital admission will be the primary efficacy outcome. Elevated Ang-2 levels are associated with poor clinical outcome in severe malaria and Ang-2 has been used to follow disease progression and recovery in previous studies of malaria. Thus, Ang-2 is an objective, quantitative surrogate marker of disease severity, validated for longitudinal follow-up of patients with malaria.
次要结局
- Mortality(48 hours and 14 days after admission)
- Time to hospital discharge(From admission to approximately 72 hours)
- Time to parasite clearance.(From admission to approximately 72 hours)
- Biomarkers and genetic determinants of endothelial activation, inflammation and coagulopathy, to be determined.(From admission to approximately 72 hours)