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

Study Status: Suspended
Recruit Status: Suspended
Study Type: Interventional

Official Title: Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria

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 Summary: See brief summary
Sponsor: Menzies School of Health Research

Current Primary Outcome: 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 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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 ]


Original Secondary Outcome:

  • 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 ]


Information By: Menzies School of Health Research

Dates:
Date Received: February 4, 2008
Date Started: February 2008
Date Completion:
Last Updated: June 24, 2013
Last Verified: June 2013