Clinical trial NCT00147368: Arginine Malaria Trial: Study of Adjunctive Arginine in Falciparum Malaria
Official title: Pharmacokinetic-Pharmacodynamic Study of Adjunctive Arginine in Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malaria, Falciparum
Keywords: falciparum
malaria
arginine
Lead sponsor: Menzies School of Health Research
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
name: National Health and Medical Research Council, Australia
name: MSHR
name: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
name: Rumah Sakit Mitra Masyarakat Hospital
name: University of Utah
name: University of Sydney
First posted: 2005-09-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Acute falciparum malaria is associated with low plasma arginine and impaired nitric oxide (NO) production. Both are associated with poor outcome. This study will examine the safety and effect of escalating doses of arginine in falciparum malaria. It will determine whether arginine can increase NO production and have an effect on NO-dependent physiological measurements. The hypothesis is that arginine: will be safe in falciparum malaria; will return plasma arginine concentration to normal/supranormal levels; will increase systemic and exhaled NO; reduces oxidant stress; and improves a number of NO-dependent physiological measures of relevance to malaria.


Eligibility criteria: Inclusion Criteria:

1. Ages 18-60 years
2. P. falciparum parasitemia (1,000-100,000 parasites/ul).
3. Clinical syndrome consistent with malaria associated with documented fever (axillary temperature \> 38℃) or self-reported history of fever in the last 48 hours with no other cause present
4. Commenced oral quinine ≤ 18 hours prior to scheduled commencement of arginine
5. An indication for hospital admission (eg relative cannot look after/supervise treatment at home but not having any warning signs or severe malaria criteria in "exclusion criteria" below)
6. Informed consent obtained

Exclusion Criteria:

1. Pregnancy or lactation
2. Mixed infection with P. falciparum and P. vivax
3. Warning signs of altered mental state and inability to sit unaided
4. Features of severe/complicated malaria
5. Diabetes
6. Systolic blood pressure (BP) \< 100 mmHg
7. Serious underlying disease (cardiac, hepatic, kidney)
8. Initial iSTAT test showing any of the following values:

   * glucose \< 4 mmol/L;
   * K+ ≥ 4.2 meq/L;
   * Cl- \> 106 meq/L;
   * HCO3- \< 20 meq/L.
9. Known allergy to L-arginine
10. Concurrent therapy with any of the following medications:

    * spironolactone;
    * oral nitrates;
    * phosphodiesterase inhibitor (eg sildenafil \[Viagra\]);
    * alpha-blocking antihypertensive agents (eg prazosin);
    * L-arginine.

Primary outcomes:
measure: exhaled and systemic nitric oxide production
measure: endothelial function
Secondary outcomes:
measure: safety
measure: pharmacokinetic (PK) parameters
measure: pharmacodynamic (PD) parameters
measure: oxidant stress
measure: gas transfer
measure: endothelial activation
measure: a priori subgroup analysis: endothelial function in those with baseline impairment of function
Other outcomes:
Locations:
city: Timika
country: Indonesia
facility: RSMM Hospital
Study officials:
affiliation: MSHR
name: Nick M Anstey, MBBS
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, Gitawati R, Tjitra E, Kenangalem E, Granger DL, Weinberg JB, Lopansri BK, Price RN, Celermajer DS, Duffull SB, Anstey NM. Safety profile of L-arginine infusion in moderately severe falciparum malaria. PLoS One. 2008 Jun 11;3(6):e2347. doi: 10.1371/journal.pone.0002347.