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

This study has suspended participant recruitment.
(Local circumstances & difficulties in site access has prevented continuation)
Sponsor:
Collaborators:
Wellcome Trust
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Menzies School of Health Research
ClinicalTrials.gov Identifier:
NCT00616304
First received: February 4, 2008
Last updated: June 24, 2013
Last verified: June 2013
  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 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria

Resource links provided by NLM:


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 ]

Enrollment: 8
Study Start Date: February 2008
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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).

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:

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

Locations
Indonesia
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
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Menzies School of Health Research
ClinicalTrials.gov Identifier: NCT00616304     History of Changes
Other Study ID Numbers: arginineSM1
Study First Received: February 4, 2008
Last Updated: June 24, 2013
Health Authority: Indonesia: National Agency of Drug and Food Control

Keywords provided by Menzies School of Health Research:
severe falciparum malaria

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases

ClinicalTrials.gov processed this record on August 27, 2014