Safety and Preliminary Efficacy of L-Arginine in Severe Falciparum Malaria - Full Text View

Sponsors and Collaborators:	Menzies School of Health Research Wellcome Trust National Health and Medical Research Council, Australia
Information provided by:	Menzies School of Health Research
ClinicalTrials.gov Identifier:	NCT00616304

Purpose

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	Intervention	Phase
Severe Falciparum Malaria	Drug: L-arginine hydrochloride Other: Normal saline	Phase II

MedlinePlus related topics: Malaria

Drug Information available for: Artesunate Sodium chloride Arginine Arginine hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Official Title:	Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-Arginine in Severe Falciparum Malaria

Further study details as provided by Menzies School of Health Research:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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. ] [ Designated as safety issue: Yes ]
Change in endothelial function in each arginine infusion regimen vs saline placebo combined [ Time Frame: 1 hour response and end of infusion response ] [ Designated as safety issue: No ]
Paired change in endothelial function [ Time Frame: paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen ] [ Designated as safety issue: No ]
Lactate clearance for each infusion regimen [ Time Frame: Time for lactate to return to upper limit of normal ] [ Designated as safety issue: No ]
Lactate:pyruvate ratio [ Time Frame: area under curve/time to normal ] [ Designated as safety issue: No ]
Fever clearance time [ Time Frame: Fever clearance time ] [ Designated as safety issue: No ]
parasite clearance time [ Time Frame: parasite clearance time ] [ Designated as safety issue: Yes ]
Change in L-arginine concentration [ Time Frame: at 1 and 8 hours ] [ Designated as safety issue: No ]
Improvement in microvascular obstruction (OPS) [ Time Frame: at 1 and 8 hours ] [ Designated as safety issue: No ]
Tissue oxygen consumption and delivery (NIRS) [ Time Frame: one and eight hours ] [ Designated as safety issue: No ]
change in exhaled NO [ Time Frame: one and eight hours ] [ Designated as safety issue: No ]
improvement in endothelial activation (decrease in angiopoietin-2 concentrations) [ Time Frame: area under curve ] [ Designated as safety issue: No ]
improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67) [ Time Frame: 8 hours ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	February 2008
Estimated Study Completion Date:	December 2010
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Active Comparator 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
S: Placebo Comparator 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).

Arms

Assigned Interventions

A: Active Comparator

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

S: Placebo Comparator

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).

Detailed Description:

See brief summary

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00616304

Contacts

Contact: Nicholas M Anstey, MBBS	+61-8-89228932	anstey@menzies.edu.au
Contact: Emiliana Tjitra, MD	+62-21-426 1088 ext 157	emilt@litbang.depkes.go.id

Locations

Indonesia, Papua
Mitra Masyarakat Hospital	Recruiting
Timika, Papua, Indonesia
Principal Investigator: Daniel A Lampah, MD
Principal Investigator: Tsin W Yeo, MD

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

More Information

Publications:

Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, Darcy CJ, Granger DL, Weinberg JB, Lopansri BK, Price RN, Duffull SB, Celermajer DS, Anstey NM. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007 Oct 29;204(11):2693-704. Epub 2007 Oct 22.

Responsible Party:	Menzies School of Health Research ( Nicholas Anstey )
Study ID Numbers:	arginineSM1
Study First Received:	February 4, 2008
Last Updated:	May 30, 2008
ClinicalTrials.gov Identifier:	NCT00616304
Health Authority:	Indonesia: National Agency of Drug and Food Control

Keywords provided by Menzies School of Health Research:

severe falciparum malaria

Study placed in the following topic categories:

Artesunate
Protozoan Infections
Parasitic Diseases
Malaria
Malaria, Falciparum

Additional relevant MeSH terms:

Coccidiosis

ClinicalTrials.gov processed this record on January 14, 2009