Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria
- Conditions
- Severe Falciparum Malaria
- Interventions
- Other: Normal saline
- Registration Number
- NCT00616304
- Lead Sponsor
- Menzies School of Health Research
- Brief Summary
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.
- Detailed Description
See brief summary
Recruitment & Eligibility
- Status
- SUSPENDED
- Sex
- All
- Target Recruitment
- 8
- 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)
- pregnancy or lactation
- diabetes
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description S Normal saline Normal saline infusion A L-arginine hydrochloride L-arginine infusion
- Primary Outcome Measures
Name Time Method Improvement in endothelial function and lactate clearance. Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal
- Secondary Outcome Measures
Name Time Method Tissue oxygen consumption and delivery (NIRS) one and eight hours improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67) 8 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
Trial Locations
- Locations (1)
Mitra Masyarakat Hospital
🇮🇩Timika, Papua, Indonesia