Severe Falciparum Malaria
Conditions
Keywords
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 description
See brief summary
Interventions
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
OTHERNormal 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).
Sponsors
Wellcome Trust
National Health and Medical Research Council, Australia
Menzies School of Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. age 18-60 years 2. informed consent obtained 3. time of commencement of artesunate ≤18 hrs before infusion of L-arginine 4. 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
1. pregnancy or lactation 2. diabetes 3. serious pre-existing disease (cardiac, hepatic, kidney) 4. systolic blood pressure \<90 mmHg after fluid resuscitation 5. 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 6. known allergy to L-arginine 7. evidence of concurrent bacterial infection 8. concurrent therapy with any of the following medications: iv. spironolactone, v. oral nitrates, vi. phosphodiesterase inhibitor (eg sildenafil \[Viagra\]) vii. alpha-blocking antihypertensive agents (eg prazosin) viii. L-arginine
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Improvement in endothelial function and lactate clearance. | Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal |
Secondary
| Measure | Time frame |
|---|---|
| Change in endothelial function in each arginine infusion regimen vs saline placebo combined | 1 hour response and end of infusion response |
| Paired change in endothelial function | paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen |
| Lactate clearance for each infusion regimen | Time for lactate to return to upper limit of normal |
| Lactate:pyruvate ratio | area under curve/time to normal |
| Fever clearance time | Fever clearance time |
| parasite clearance time | parasite clearance time |
| Safety: Clinical and biochemical measures. | 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. |
| Improvement in microvascular obstruction (OPS) | at 1 and 8 hours |
| Tissue oxygen consumption and delivery (NIRS) | one and eight hours |
| change in exhaled NO | one and eight hours |
| improvement in endothelial activation (decrease in angiopoietin-2 concentrations) | area under curve |
| improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67) | 8 hours |
| Change in L-arginine concentration | at 1 and 8 hours |
Countries
Indonesia
Outcome results
None listed