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Trial registered on ANZCTR


Registration number
ACTRN12612000571875
Ethics application status
Approved
Date submitted
22/05/2012
Date registered
28/05/2012
Date last updated
18/07/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised phase 2a trial of safety, efficacy, pharmacokinetics and pharmacodynamics of L-Arginine in severe falciparum malaria
Scientific title
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
Secondary ID [1] 280534 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
ARGISM-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe falciparum malaria 286528 0
Condition category
Condition code
Infection 286795 286795 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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
Intervention code [1] 284909 0
Treatment: Drugs
Comparator / control treatment
Comparator: intravenous saline (0g L-arginine, but identical volume of saline)

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 PO at 0h, 8h then every 12h x 2 more days
Control group
Active

Outcomes
Primary outcome [1] 287167 0
Area under the curve for microvascular reactivity (RH-PAT)
Timepoint [1] 287167 0
0-9 hours
Primary outcome [2] 287168 0
Lactate clearance: area under the curve until venous blood lactate returns to the upper limit of normal.
Timepoint [2] 287168 0
Every 4 hours until lactate returns to the upper limit of normal
Secondary outcome [1] 297531 0
Safety: clinical and biochemical measures
Timepoint [1] 297531 0
until hospital discharge
Secondary outcome [2] 297532 0
Improvement in microvascular function. Area under the curve for microvascular reactivity (Near Infrared Spectroscopy)
Timepoint [2] 297532 0
0-9 hrs
Secondary outcome [3] 297535 0
Paired comparison of post-vs pre-infusion endothelial function (NIRS and RH-PAT) relative to saline
Timepoint [3] 297535 0
4 , 8 and 24 hrs
Secondary outcome [4] 297536 0
Venous blood lactate clearance for each infusion regimen
Timepoint [4] 297536 0
Every 4 hours until lactate returns to the upper limit of normal
Secondary outcome [5] 297537 0
Change in plasma L-arginine, Ang-2 and VWFa concentrations
Timepoint [5] 297537 0
8 and 24 hours
Secondary outcome [6] 297538 0
Fever clearance time defined as the time taken for the tympanic temperature (measured by infrared thermometry) to fall below 37.5 deg C and remain there for at least 24 hours. Temperature will be the average of the left and right ears.
Timepoint [6] 297538 0
Every 6 hours until fever cleared
Secondary outcome [7] 297539 0
Parasite clearance time assessed using peripheral blood films, defined as the interval between start of treatment and the first of two consecutive negative blood films
Timepoint [7] 297539 0
Every 6 hours until parasites cleared
Secondary outcome [8] 297540 0
Improvement in microvascular obstruction (Orthogonal Polarising Spectroscopy)
Timepoint [8] 297540 0
8 and 24 hours
Secondary outcome [9] 297541 0
Change in tissue oxygen consumption (measured by NIRS occlusion phase)
Timepoint [9] 297541 0
2, 8, 24 hours
Secondary outcome [10] 297542 0
Change in NO production (exhaled NO and urine nitrate/creatinine ratio)
Timepoint [10] 297542 0
2, 4, 8, 24 hours
Secondary outcome [11] 297543 0
Change in red cell deformability (LORCA)
Timepoint [11] 297543 0
8, 24 hours
Secondary outcome [12] 297544 0
Coma recovery time
Timepoint [12] 297544 0
Every hour for 12 hours then 6 hourly until Glasgow Coma Score 15
Secondary outcome [13] 297545 0
Time to resolution of acidosis (measured by venous blood base excess)
Timepoint [13] 297545 0
Every 4 hours until acidosis normalises
Secondary outcome [14] 297546 0
Change in pulmonary artery pressures (non-invasive using echocardiography)
Timepoint [14] 297546 0
8, 24 hours

Eligibility
Key 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
Minimum age
16 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2012
Actual
24/06/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
57
Accrual to date
Final
Recruitment outside Australia
Country [1] 4327 0
Bangladesh
State/province [1] 4327 0

Funding & Sponsors
Funding source category [1] 285297 0
Government body
Name [1] 285297 0
NHMRC
Country [1] 285297 0
Australia
Primary sponsor type
University
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina
NT 0811
Country
Australia
Secondary sponsor category [1] 284159 0
None
Name [1] 284159 0
Address [1] 284159 0
Country [1] 284159 0

Ethics approval
Ethics application status
Approved

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34211 0
Dr Nicholas Anstey
Address 34211 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Australia
Country 34211 0
Australia
Phone 34211 0
+61-8-8922 8932
Fax 34211 0
Email 34211 0
nicholas.anstey@menzies.edu.au
Contact person for public queries
Name 17458 0
Nicholas Anstey
Address 17458 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country 17458 0
Australia
Phone 17458 0
+61-8-8922 8932
Fax 17458 0
Email 17458 0
anstey@menzies.edu.au
Contact person for scientific queries
Name 8386 0
Nicholas Anstey
Address 8386 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country 8386 0
Australia
Phone 8386 0
+61-8-8922 8932
Fax 8386 0
Email 8386 0
anstey@menzies.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.