Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria (ARGISM)
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|ClinicalTrials.gov Identifier: NCT00616304|
Recruitment Status : Suspended (Local circumstances & difficulties in site access has prevented continuation)
First Posted : February 15, 2008
Last Update Posted : June 26, 2013
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.
|Condition or disease||Intervention/treatment||Phase|
|Severe Falciparum Malaria||Drug: L-arginine hydrochloride Other: Normal saline||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||8 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Outcomes Assessor)|
|Official Title:||Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria|
|Study Start Date :||February 2008|
|Actual Primary Completion Date :||March 2009|
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).
- 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 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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|