Clinical trial NCT00616304: Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria
Official title: Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Severe Falciparum Malaria
Keywords: severe falciparum malaria
Lead sponsor: Menzies School of Health Research
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
name: National Health and Medical Research Council, Australia
First posted: 2008-02-15
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: See brief summary

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

Primary outcomes:
measure: Improvement in endothelial function and lactate clearance.
timeFrame: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal
Secondary outcomes:
measure: Safety: Clinical and biochemical measures.
timeFrame: 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.
measure: Change in endothelial function in each arginine infusion regimen vs saline placebo combined
timeFrame: 1 hour response and end of infusion response
measure: Paired change in endothelial function
timeFrame: paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen
measure: Lactate clearance for each infusion regimen
timeFrame: Time for lactate to return to upper limit of normal
measure: Lactate:pyruvate ratio
timeFrame: area under curve/time to normal
measure: Fever clearance time
timeFrame: Fever clearance time
measure: parasite clearance time
timeFrame: parasite clearance time
measure: Change in L-arginine concentration
timeFrame: at 1 and 8 hours
measure: Improvement in microvascular obstruction (OPS)
timeFrame: at 1 and 8 hours
measure: Tissue oxygen consumption and delivery (NIRS)
timeFrame: one and eight hours
measure: change in exhaled NO
timeFrame: one and eight hours
measure: improvement in endothelial activation (decrease in angiopoietin-2 concentrations)
timeFrame: area under curve
measure: improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)
timeFrame: 8 hours
Other outcomes:
Locations:
city: Timika
country: Indonesia
facility: Mitra Masyarakat Hospital
state: Papua
Study officials:
affiliation: Menzies School of Health Research
name: Nicholas M Anstey, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Health Research and Development
name: Emiliana Tjitra, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.