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

Status

Recruiting

Phases

Phase 2

Study type

Interventional

Source

ANZCTR

Registry ID

ACTRN12612000571875

Acronym

ARGISM-2

Enrollment

Registered

2012-05-28

Start date

2012-06-24

Completion date

Unknown

Last updated

2020-01-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

None listed

Brief 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.

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

Study design

Allocation

Randomised controlled trial

Intervention model

Parallel

Primary purpose

Treatment

Eligibility

Sex/Gender

All

Age

16 Years to 60 Years

Healthy volunteers

Inclusion criteria

1. 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 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 (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 criteria

1. pregnancy or lactation 2. diabetes 3. serious pre-existing disease (eg advanced cardiac, hepatic, kidney disease) 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. HCO3- < 12 meq/L iii. Chloride > 117 mmol/L iv. pH <7.1 6. known allergy to L-arginine 7. 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 8. hemoglobin <5 g/dL

Outcome results