RecruitingPhase 2ACTRN12612000571875

A randomised phase 2a trial of safety, efficacy, pharmacokinetics and pharmacodynamics of L-Arginine in severe falciparum malaria

A randomised phase 2a trial of safety, efficacy (in improving lactate clearance and endothelial function), pharmacokinetics and pharmacodynamics of L-Arginine in adults with severe falciparum malaria

Sponsor

Menzies School of Health Research

Enrollment

57 participants

Start Date

Jun 24, 2012

Study Type

Interventional

Conditions

Severe falciparum malaria

Summary

Mortality from severe malaria remains ~15% despite use of the most effective parasiticidal antimalarial therapy, intravenous artesunate. Adjunctive treatments in combination with anti-parasitic agents have the potential to improve outcome. Our overall goal is to determine if adjunctive treatment with L-arginine is safe and improves outcomes in severe malaria. In early phase studies to date, we have shown that L-arginine is safe in moderately severe malaria, increases nitric oxide (NO) production and improves endothelial function. In a pilot study in severe malaria (ARGISM 1 trial; NCT00616304), L-arginine infusion was safe. We now propose to extend these studies to larger numbers of patients with severe malaria to determine the safety, preliminary efficacy, pharmacokinetics and pharmacodynamics of L-arginine infusion in severe malaria.

Eligibility

Sex: Both males and femalesMin Age: 16 YearssMax Age: 60 Yearss

Inclusion Criteria2

age 16-60 years (inclusive) 2. informed consent obtained 3. <=18 hrs since commencement of parenteral artesunate OR <= 24 hours since commencement of full-dose parenteral quinine
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 (black urine and dipstick positive for blood) iv. hyperparasitemia (>10% parasitised red cells) v. cerebral malaria (Glasgow coma score <11) vi. Hypoglycemia (blood glucose <2.2 mmol/L or <40 mg/dL) vii. Venous bicarbonate 12-15 meq/L; viii. Lactate > 4 mmol/L

Exclusion Criteria17

pregnancy or lactation
diabetes
serious pre-existing disease (eg advanced cardiac, hepatic, kidney disease)
systolic blood pressure <90 mmHg after fluid resuscitation
initial iSTAT test showing any of the following values:
i. K+ > 5.5 meq/L
ii. HCO3- < 12 meq/L
iii. Chloride > 117 mmol/L
iv. pH <7.1
known allergy to L-arginine
concurrent therapy with any of the following medications:
i. spironolactone,
ii. oral nitrates,
iii. phosphodiesterase inhibitor (eg sildenafil)
iv. alpha-blocking antihypertensive agents (eg prazosin)
v. L-arginine
hemoglobin <5 g/dL

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Interventions

intravenous L-arginine in saline commencing within 18 hours of standard therapy: 0.33g/kg (to maximum 20g) over 8 hours. All patients receive standard intravenous artesunate therapy (Artesunate 2.4mg/kg IV then 2.4mg/kg at 12h and 24h then every 24 hours) followed, after minimum of 3 doses, once eating & drinking without vomiting, with oral therapy with artemether/lumefantrine (20/120mg) 4 tabs orally at 0h, 8h then every 12h x 2 more days

Locations(1)

Bangladesh

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ACTRN12612000571875