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

Sponsor

Menzies School of Health Research (Other)

Overall Status

Suspended

CT.gov ID

NCT00616304

Collaborator

Wellcome Trust (Other), National Health and Medical Research Council, Australia (Other)

Enrollment

Location

Arms

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Severe Falciparum Malaria	Drug: L-arginine hydrochloride Other: Normal saline	Phase 2

Detailed Description

See brief summary

Study Design

Study Type:

Interventional

Actual Enrollment :

8 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2008

Actual Primary Completion Date :

Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A L-arginine infusion	Drug: 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 Other Names: L-arginine hydrochloride (Pharmalab, Australia)
Placebo Comparator: S Normal saline infusion	Other: 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).

Arm

Intervention/Treatment

Active Comparator: A

L-arginine infusion

Drug: 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

Other Names:

L-arginine hydrochloride (Pharmalab, Australia)

Placebo Comparator: S

Normal saline infusion

Other: 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).

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mitra Masyarakat Hospital	Timika	Papua	Indonesia

Sponsors and Collaborators

Menzies School of Health Research
Wellcome Trust
National Health and Medical Research Council, Australia

Investigators

Principal Investigator: Nicholas M Anstey, MBBS, Menzies School of Health Research
Principal Investigator: Emiliana Tjitra, MD, National Institute of Health Research and Development