Clinical trial

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

Name

arginineSM1

Description

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.

Trial arms

Trial start

2008-02-01

Estimated PCD

2009-03-01

Phase

Early phase I

Treatment

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

Arms:

Other names:

L-arginine hydrochloride (Pharmalab, Australia)

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).

Arms:

Size

Primary endpoint

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

Eligibility criteria

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

Protocol

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'TRIPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 8, 'type': 'ACTUAL'}}

Updated at

2024-03-13

1 organization

1 product

1 indication

Organization

Menzies School of Health Research

Product

L-arginine

Indication

Severe Falciparum Malaria