Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria (ARGISM)
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.
|Severe Falciparum Malaria||Drug: L-arginine hydrochloride Other: Normal saline||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria|
- Improvement in endothelial function and lactate clearance. [ Time Frame: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal ]
- Safety: Clinical and biochemical measures. [ Time Frame: 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 [ Time Frame: 1 hour response and end of infusion response ]
- Paired change in endothelial function [ Time Frame: paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen ]
- Lactate clearance for each infusion regimen [ Time Frame: Time for lactate to return to upper limit of normal ]
- Lactate:pyruvate ratio [ Time Frame: area under curve/time to normal ]
- Fever clearance time [ Time Frame: Fever clearance time ]
- parasite clearance time [ Time Frame: parasite clearance time ]
- Change in L-arginine concentration [ Time Frame: at 1 and 8 hours ]
- Improvement in microvascular obstruction (OPS) [ Time Frame: at 1 and 8 hours ]
- Tissue oxygen consumption and delivery (NIRS) [ Time Frame: one and eight hours ]
- change in exhaled NO [ Time Frame: one and eight hours ]
- improvement in endothelial activation (decrease in angiopoietin-2 concentrations) [ Time Frame: area under curve ]
- improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67) [ Time Frame: 8 hours ]
|Study Start Date:||February 2008|
|Primary Completion Date:||March 2009 (Final data collection date for primary outcome measure)|
Active Comparator: A
Drug: L-arginine hydrochloride
Patients will be randomized in two blocks of 18. The first block of 18 patients will receive either 12 g L-arginine or saline placebo. If safety is demonstrated in the first block, a further 18 patients will be enrolled in the second block and randomized to receive either 24g arginine or saline placebo Block 1: Standard RSMM artesunate regimen for severe falciparum malaria plus 12g of L-arginine diluted to a 10% solution and given over 8 hours (n=12); Block 2: Standard RSMM artesunate regimen for severe falciparum malaria plus a 24g dose of L-arginine diluted to a 10% solution given over 8 hours (n=12) Phase 2b: To evaluate any additional benefits of a longer infusion, a further 24 patients will receive L-arginine infusion 1.5g/hour for 24 hours
Other Name: L-arginine hydrochloride (Pharmalab, Australia)
Placebo Comparator: S
Normal saline infusion
Other: Normal saline
Patients with severe malaria will be randomized in two blocks of 18. The first block of 18 patients will receive either 12 g L-arginine or saline placebo. If safety is demonstrated in the first block, a further 18 patients will be enrolled in the second block and randomized to receive either 24g arginine or saline placebo. Blocks 1 and 2: Standard RSMM antimalarial artesunate regimen for severe falciparum malaria plus saline placebo, 240 ml given over 8 hours (n=12).
Please refer to this study by its ClinicalTrials.gov identifier: NCT00616304
|Mitra Masyarakat Hospital|
|Timika, Papua, Indonesia|
|Principal Investigator:||Nicholas M Anstey, MBBS||Menzies School of Health Research|
|Principal Investigator:||Emiliana Tjitra, MD||National Institute of Health Research and Development|