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

Study Overview
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Brief Summary
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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
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See brief summary

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

Conditions
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Severe Falciparum Malaria

Intervention / Treatment
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* Drug: L-arginine hydrochloride
* Other: Normal saline


Participation Criteria
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Eligibility Criteria
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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 known allergy to L-arginine evidence of concurrent bacterial infection 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>L-arginine infusion | Drug: L-arginine hydrochloride<br>* 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<br>* Other names: L-arginine hydrochloride (Pharmalab, Australia);|
| Placebo Comparator: S<br>Normal saline infusion | Other: Normal saline<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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 | 
| Change in L-arginine concentration |  | at 1 and 8 hours | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe falciparum malaria