SuspendedPhase 2

Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria

Stopped: Local circumstances \& difficulties in site access has prevented continuation

Indonesia8 participantsStarted 2008-02

Plain-language 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.

Who can participate

Age range18 Years – 60 Years

SexALL

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Inclusion criteria

✓. 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)

Exclusion criteria

✕. 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

What they're measuring

Improvement in endothelial function and lactate clearance.

Timeframe: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal

Trial details

NCT IDNCT00616304

SponsorMenzies School of Health Research

Sponsor typeOTHER

Study typeINTERVENTIONAL

Primary completion2009-03

View on ClinicalTrials.gov More Severe Falciparum Malaria trials