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Sponsors and Collaborators: |
Menzies School of Health Research Wellcome Trust National Health and Medical Research Council, Australia |
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Information provided by: | Menzies School of Health Research |
ClinicalTrials.gov Identifier: | NCT00616304 |
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 | Intervention | Phase |
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Severe Falciparum Malaria |
Drug: L-arginine hydrochloride Other: Normal saline |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study |
Official Title: | Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-Arginine in Severe Falciparum Malaria |
Estimated Enrollment: | 60 |
Study Start Date: | February 2008 |
Estimated Study Completion Date: | December 2010 |
Estimated Primary Completion Date: | December 2009 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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A: Active Comparator
L-arginine infusion
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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
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S: Placebo Comparator
Normal saline infusion
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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). |
See brief summary
Ages Eligible for Study: | 18 Years to 60 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Nicholas M Anstey, MBBS | +61-8-89228932 | anstey@menzies.edu.au |
Contact: Emiliana Tjitra, MD | +62-21-426 1088 ext 157 | emilt@litbang.depkes.go.id |
Indonesia, Papua | |
Mitra Masyarakat Hospital | Recruiting |
Timika, Papua, Indonesia | |
Principal Investigator: Daniel A Lampah, MD | |
Principal Investigator: Tsin W Yeo, MD |
Principal Investigator: | Nicholas M Anstey, MBBS | Menzies School of Health Research |
Principal Investigator: | Emiliana Tjitra, MD | National Institute of Health Research and Development |
Responsible Party: | Menzies School of Health Research ( Nicholas Anstey ) |
Study ID Numbers: | arginineSM1 |
Study First Received: | February 4, 2008 |
Last Updated: | May 30, 2008 |
ClinicalTrials.gov Identifier: | NCT00616304 History of Changes |
Health Authority: | Indonesia: National Agency of Drug and Food Control |
severe falciparum malaria |
Artesunate Antimalarials Protozoan Infections Arginine |
Parasitic Diseases Malaria Malaria, Falciparum |
Protozoan Infections Coccidiosis Parasitic Diseases Malaria Malaria, Falciparum |