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

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

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.

Study Overview

• Status: Suspended
• Conditions: Severe Falciparum Malaria
• Intervention / Treatment: Drug: L-arginine hydrochloride; Other: Normal saline

Detailed Description

See brief summary

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • Papua
    • Timika, Papua, Indonesia
      • Mitra Masyarakat Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Collaborators: National Health and Medical Research Council, Australia; Wellcome Trust
• Investigators: Principal Investigator: Nicholas M Anstey, MBBS, Menzies School of Health Research; Principal Investigator: Emiliana Tjitra, MD, National Institute of Health Research and Development

Publications and helpful links

General 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. doi: 10.1084/jem.20070819. Epub 2007 Oct 22.
• Yeo TW, Lampah DA, Rooslamiati I, Gitawati R, Tjitra E, Kenangalem E, Price RN, Duffull SB, Anstey NM. A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics. PLoS One. 2013 Jul 29;8(7):e69587. doi: 10.1371/journal.pone.0069587. Print 2013.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: February 4, 2008
• First Submitted That Met QC Criteria: February 4, 2008
• First Posted (Estimated): February 15, 2008

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: severe falciparum malaria
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Malaria, Falciparum
• Other Study ID Numbers: arginineSM1