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

Severe Falciparum Malaria Clinical Trial

— ARGISM  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT00616304
• Other study ID #: arginineSM1
• Status: Suspended
• Phase: Phase 2
• Start date: February 2008

Study information

• Verified date: March 2024
• Source: Menzies School of Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

See brief summary

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 8
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Severe Falciparum Malaria

Intervention

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:
• 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).

Locations

Country	Name	City	State
Indonesia	Mitra Masyarakat Hospital	Timika	Papua

Sponsors (3)

Lead Sponsor	Collaborator
Menzies School of Health Research	National Health and Medical Research Council, Australia, Wellcome Trust

Country where clinical trial is conducted

Indonesia, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	Change in endothelial function in each arginine infusion regimen vs saline placebo combined		1 hour response and end of infusion response
Secondary	Paired change in endothelial function		paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen
Secondary	Lactate clearance for each infusion regimen		Time for lactate to return to upper limit of normal
Secondary	Lactate:pyruvate ratio		area under curve/time to normal
Secondary	Fever clearance time		Fever clearance time
Secondary	parasite clearance time		parasite clearance time
Secondary	Change in L-arginine concentration		at 1 and 8 hours
Secondary	Improvement in microvascular obstruction (OPS)		at 1 and 8 hours
Secondary	Tissue oxygen consumption and delivery (NIRS)		one and eight hours
Secondary	change in exhaled NO		one and eight hours
Secondary	improvement in endothelial activation (decrease in angiopoietin-2 concentrations)		area under curve
Secondary	improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)		8 hours