Severe Falciparum MalariaPhase 2ARGISMNCT00616304
Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria
A Phase 2 study testing L-arginine hydrochloride and Normal saline in people with Severe Falciparum Malaria, run by Menzies School of Health Research at 1 site in Indonesia.
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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Severe Falciparum Malaria
- What is being tested?
- L-arginine hydrochloride and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 8 participants
- Where
- 1 siteIndonesia
- Study dates
- Feb 2008to Mar 2009
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- age 18-60 years
- informed consent obtained
- time of commencement of artesunate ≤18 hrs before infusion of L-arginine
- 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)
Who cannot join
- pregnancy or lactation
- diabetes
- serious pre-existing disease (cardiac, hepatic, kidney)
- systolic blood pressure <90 mmHg after fluid resuscitation
- 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
- known allergy to L-arginine
- evidence of concurrent bacterial infection
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria
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.
Read more
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.
Read the detailed description
See brief summary
- Conditions
- Severe Falciparum Malaria
- Being tested
- L-arginine hydrochloride, Normal saline
- Keywords
- severe falciparum malaria
- Medical subject headings
- Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-arginine hydrochlorideDrug
Also called L-arginine hydrochloride (Pharmalab, Australia)
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
Normal salineOther
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).
| Study group | Role | What they receive |
|---|---|---|
| A | Active comparator | L-arginine infusion Receives: Drug: L-arginine hydrochloride |
| S | Placebo comparator | Normal saline infusion Receives: Other: Normal saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement in endothelial function and lactate clearance.
Measured: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal
Secondary outcomes (13)
Safety: Clinical and biochemical measures.
Measured: 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.
Change in endothelial function in each arginine infusion regimen vs saline placebo combined
Measured: 1 hour response and end of infusion response
Paired change in endothelial function
Measured: paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen
Lactate clearance for each infusion regimen
Measured: Time for lactate to return to upper limit of normal
Lactate:pyruvate ratio
Measured: area under curve/time to normal
Fever clearance time
Measured: Fever clearance time
parasite clearance time
Measured: parasite clearance time
Change in L-arginine concentration
Measured: at 1 and 8 hours
Improvement in microvascular obstruction (OPS)
Measured: at 1 and 8 hours
Tissue oxygen consumption and delivery (NIRS)
Measured: one and eight hours
change in exhaled NO
Measured: one and eight hours
improvement in endothelial activation (decrease in angiopoietin-2 concentrations)
Measured: area under curve
improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)
Measured: 8 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2008 (estimated)
- Study startFeb 2008
- Primary completionMar 2009
Why it stopped: Local circumstances \& difficulties in site access has prevented continuation
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Severe Falciparum MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Menzies School of Health Research
- Sponsor type
- University, hospital or other
- Collaborators
- Wellcome Trust, National Health and Medical Research Council, Australia
- Responsible party
- Sponsor
- Investigators
- Nicholas M Anstey, MBBS, Principal investigator, Menzies School of Health ResearchEmiliana Tjitra, MD, Principal investigator, National Institute of Health Research and Development
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00616304
- Sponsor's protocol ID
- arginineSM1
- Acronym
- ARGISM
- Status last verified
- Mar 2024
- First submitted
- 4 Feb 2008
- Last updated
- 13 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 17954570Yeo TW, Lampah DA, Rooslamiati I, Gitawati R, Tjitra E, Kenangalem E, Price RN, Duffull SB, Anstey NM. A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics. PLoS One. 2013 Jul 29;8(7):e69587. doi: 10.1371/journal.pone.0069587. Print 2013.
PubMed 23922746
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria
- ClinicalTrials.gov ID
- NCT00616304
- Acronym / sponsor ID
- ARGISM / arginineSM1
- Conditions
- Severe Falciparum Malaria
- Keywords
- severe falciparum malaria
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Local circumstances \& difficulties in site access has prevented continuation
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Menzies School of Health ResearchUniversity, hospital or other
- Collaborators
- Wellcome Trust, National Health and Medical Research Council, Australia
- Study start
- Feb 2008
- Primary completion
- Mar 2009 (actual)
- First posted
- 15 Feb 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
See brief summary
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Active comparator | Drug: L-arginine hydrochlorideL-arginine infusion |
| S | Placebo comparator | Other: Normal salineNormal saline infusion |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- age 18-60 years
- informed consent obtained
- time of commencement of artesunate ≤18 hrs before infusion of L-arginine
- 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)
Key exclusion criteria (8 listed)
- pregnancy or lactation
- diabetes
- serious pre-existing disease (cardiac, hepatic, kidney)
- systolic blood pressure <90 mmHg after fluid resuscitation
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-arginine hydrochlorideAlso: L-arginine hydrochloride (Pharmalab, Australia)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 | Drug | A |
| Normal salinePatients 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). | Other | S |
Primary outcome
Improvement in endothelial function and lactate clearance.
Time frame: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal
13 secondary outcomes
Safety: Clinical and biochemical measures.
Time frame: 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.
Change in endothelial function in each arginine infusion regimen vs saline placebo combined
Time frame: 1 hour response and end of infusion response
Paired change in endothelial function
Time frame: paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen
Lactate clearance for each infusion regimen
Time frame: Time for lactate to return to upper limit of normal
Lactate:pyruvate ratio
Time frame: area under curve/time to normal
Fever clearance time
Time frame: Fever clearance time
parasite clearance time
Time frame: parasite clearance time
Change in L-arginine concentration
Time frame: at 1 and 8 hours
Improvement in microvascular obstruction (OPS)
Time frame: at 1 and 8 hours
Tissue oxygen consumption and delivery (NIRS)
Time frame: one and eight hours
change in exhaled NO
Time frame: one and eight hours
improvement in endothelial activation (decrease in angiopoietin-2 concentrations)
Time frame: area under curve
improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)
Time frame: 8 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2024.
- Background: PubMed 17954570Yeo 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.
- Derived from this study: PubMed 23922746Yeo TW, Lampah DA, Rooslamiati I, Gitawati R, Tjitra E, Kenangalem E, Price RN, Duffull SB, Anstey NM. A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics. PLoS One. 2013 Jul 29;8(7):e69587. doi: 10.1371/journal.pone.0069587. Print 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nicholas M Anstey, MBBS principal investigator
Menzies School of Health Research
Emiliana Tjitra, MD principal investigator
National Institute of Health Research and Development
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-arginine hydrochloride and Normal saline in people with Severe Falciparum Malaria, run by Menzies School of Health Research at 1 site in Indonesia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 13 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement in endothelial function and lactate clearance. (time frame: Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00616304, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2024.