Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Improvement in endothelial function and lactate clearance.
研究概览
简要总结
Background: Mortality from severe malaria remains ~15% despite the use of the most rapidly parasiticidal antimalarial therapy, artesunate. Adjunctive treatments may improve outcome. Our overall goal is to determine if adjunctive treatment with L-arginine is safe and improves outcomes in severe malaria. In studies to date, we have shown that L-arginine is safe in moderately severe malaria, increases nitric oxide production and improves endothelial function. We now propose to extend these studies to patients with severe malaria.
Aims: To determine the safety, preliminary efficacy, pharmacokinetics and pharmacodynamics of L-arginine infusion in severe malaria.
Hypothesis: L-arginine will improve endothelial function, lactate clearance time and tissue oxygen delivery compared to saline with no clinically significant adverse effects.
Methods: Based on previous pharmacokinetic modeling and simulations, we propose a phase 2A randomised controlled trial of L-arginine vs saline in severe malaria, each given over 8 hours. If safety is demonstrated this will be followed by a phase 2B open-label study of 24-hour infusion of L-arginine in severe malaria with safety and preliminary efficacy compared with the 8 hour infusions given in phase 2A.
The primary outcomes will be the improvement in endothelial function and lactate clearance in patients given L-arginine infusion compared with those who received saline. Among the secondary outcomes will be safety and the effect of L-arginine vs saline on tissue oxygen delivery (NIRS).
Data from both phase 2A and 2B will be used to generate a pharmacokinetic/ pharmacodynamic model.
详细描述
See brief summary
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
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age 18-60 years
- •informed consent obtained
- •time of commencement of artesunate ≤18 hrs before infusion of L-arginine
- •any level of P. falciparum parasitemia, and one or more of the following criteria: i. acute renal failure (creatinine >265umol/L) ii. hyperbilirubinemia (total bilirubin >50 umol/L) with either renal impairment (creatinine >130umol/L) or parasitemia of >100,000 parasites/uL iii. blackwater fever iv. hyperparasitemia (>10% parasitised red cells) v. cerebral malaria (Glasgow coma score <11) vi. Hypoglycemia vii. Respiratory distress (RR >32)
排除标准
- •pregnancy or lactation
- •serious pre-existing disease (cardiac, hepatic, kidney)
- •systolic blood pressure <90 mmHg after fluid resuscitation
- •initial iSTAT test showing any of the following values: i. K+ > 5.5 meq/L ii. Cl- > 110 meq/L iii. HCO3- < 15 meq/L
- •known allergy to L-arginine
- •evidence of concurrent bacterial infection
- •concurrent therapy with any of the following medications: iv. spironolactone, v. oral nitrates, vi. phosphodiesterase inhibitor (eg sildenafil [Viagra]) vii. alpha-blocking antihypertensive agents (eg prazosin) viii. L-arginine
研究组 & 干预措施
A
L-arginine infusion
干预措施: L-arginine hydrochloride (Drug)
S
Normal saline infusion
干预措施: Normal saline (Other)
结局指标
主要结局
Improvement in endothelial function and lactate clearance.
时间窗: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal
次要结局
- Tissue oxygen consumption and delivery (NIRS)(one and eight hours)
- parasite clearance time(parasite clearance time)
- Paired change in endothelial function(paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen)
- Fever clearance time(Fever clearance time)
- Safety: Clinical and biochemical measures.(During and after infusion. In those receiving L-arginine, biochemical and hemodynamic measures at the completion of infusion will also be compared with measures at the start of infusion.)
- Change in endothelial function in each arginine infusion regimen vs saline placebo combined(1 hour response and end of infusion response)
- Lactate clearance for each infusion regimen(Time for lactate to return to upper limit of normal)
- Lactate:pyruvate ratio(area under curve/time to normal)
- Change in L-arginine concentration(at 1 and 8 hours)
- Improvement in microvascular obstruction (OPS)(at 1 and 8 hours)
- change in exhaled NO(one and eight hours)
- improvement in endothelial activation (decrease in angiopoietin-2 concentrations)(area under curve)
- improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)(8 hours)