Ignite Creation Date:
2025-12-24 @ 9:09 PM
Ignite Modification Date:
2026-02-03 @ 7:20 AM
Study NCT ID:
NCT00616304
Status:
SUSPENDED
Last Update Posted:
2024-03-13
First Post:
2008-02-04
Is Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D016778', 'term': 'Malaria, Falciparum'}], 'ancestors': [{'id': 'D008288', 'term': 'Malaria'}, {'id': 'D011528', 'term': 'Protozoan Infections'}, {'id': 'D010272', 'term': 'Parasitic Diseases'}, {'id': 'D007239', 'term': 'Infections'}, {'id': 'D000096724', 'term': 'Mosquito-Borne Diseases'}, {'id': 'D000079426', 'term': 'Vector Borne Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000077330', 'term': 'Saline Solution'}], 'ancestors': [{'id': 'D000077324', 'term': 'Crystalloid Solutions'}, {'id': 'D007552', 'term': 'Isotonic Solutions'}, {'id': 'D012996', 'term': 'Solutions'}, {'id': 'D004364', 'term': 'Pharmaceutical Preparations'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'TRIPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'OUTCOMES_ASSESSOR']}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 8}}, 'statusModule': {'whyStopped': 'Local circumstances \\& difficulties in site access has prevented continuation', 'overallStatus': 'SUSPENDED', 'startDateStruct': {'date': '2008-02'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2024-03', 'lastUpdateSubmitDate': '2024-03-11', 'studyFirstSubmitDate': '2008-02-04', 'studyFirstSubmitQcDate': '2008-02-04', 'lastUpdatePostDateStruct': {'date': '2024-03-13', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2008-02-15', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2009-03', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Improvement in endothelial function and lactate clearance.', 'timeFrame': 'Endothelial function: end of 8 hour infusion. Lactate clearance: area under the curve until lactate returns to the upper limit of normal'}], 'secondaryOutcomes': [{'measure': 'Safety: Clinical and biochemical measures.', 'timeFrame': '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.'}, {'measure': 'Change in endothelial function in each arginine infusion regimen vs saline placebo combined', 'timeFrame': '1 hour response and end of infusion response'}, {'measure': 'Paired change in endothelial function', 'timeFrame': 'paired comparison of post-vs pre-infusion values, overall, and in each arginine infusion regimen'}, {'measure': 'Lactate clearance for each infusion regimen', 'timeFrame': 'Time for lactate to return to upper limit of normal'}, {'measure': 'Lactate:pyruvate ratio', 'timeFrame': 'area under curve/time to normal'}, {'measure': 'Fever clearance time', 'timeFrame': 'Fever clearance time'}, {'measure': 'parasite clearance time', 'timeFrame': 'parasite clearance time'}, {'measure': 'Change in L-arginine concentration', 'timeFrame': 'at 1 and 8 hours'}, {'measure': 'Improvement in microvascular obstruction (OPS)', 'timeFrame': 'at 1 and 8 hours'}, {'measure': 'Tissue oxygen consumption and delivery (NIRS)', 'timeFrame': 'one and eight hours'}, {'measure': 'change in exhaled NO', 'timeFrame': 'one and eight hours'}, {'measure': 'improvement in endothelial activation (decrease in angiopoietin-2 concentrations)', 'timeFrame': 'area under curve'}, {'measure': 'improvement in RHPAT among those with baseline dysfunction (RHPAT<1.67)', 'timeFrame': '8 hours'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['severe falciparum malaria'], 'conditions': ['Severe Falciparum Malaria']}, 'referencesModule': {'references': [{'pmid': '17954570', 'type': 'BACKGROUND', '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.'}, {'pmid': '23922746', 'type': 'DERIVED', 'citation': 'Yeo 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.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nAims: To determine the safety, preliminary efficacy, pharmacokinetics and pharmacodynamics of L-arginine infusion in severe malaria.\n\nHypothesis: L-arginine will improve endothelial function, lactate clearance time and tissue oxygen delivery compared to saline with no clinically significant adverse effects.\n\nMethods: 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.\n\nThe 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).\n\nData from both phase 2A and 2B will be used to generate a pharmacokinetic/ pharmacodynamic model.', 'detailedDescription': 'See brief summary'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT'], 'maximumAge': '60 Years', 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n1. age 18-60 years\n2. informed consent obtained\n3. time of commencement of artesunate ≤18 hrs before infusion of L-arginine\n4. 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)\n\nExclusion Criteria:\n\n1. pregnancy or lactation\n2. diabetes\n3. serious pre-existing disease (cardiac, hepatic, kidney)\n4. systolic blood pressure \\<90 mmHg after fluid resuscitation\n5. 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\n6. known allergy to L-arginine\n7. evidence of concurrent bacterial infection\n8. 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'}, 'identificationModule': {'nctId': 'NCT00616304', 'acronym': 'ARGISM', 'briefTitle': 'Safety and Preliminary Efficacy of L-arginine in Severe Falciparum Malaria', 'organization': {'class': 'OTHER', 'fullName': 'Menzies School of Health Research'}, 'officialTitle': 'Safety and Preliminary Efficacy, Pharmacokinetics, Pharmacodynamics of L-arginine in Severe Falciparum Malaria', 'orgStudyIdInfo': {'id': 'arginineSM1'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'ACTIVE_COMPARATOR', 'label': 'A', 'description': 'L-arginine infusion', 'interventionNames': ['Drug: L-arginine hydrochloride']}, {'type': 'PLACEBO_COMPARATOR', 'label': 'S', 'description': 'Normal saline infusion', 'interventionNames': ['Other: Normal saline']}], 'interventions': [{'name': 'L-arginine hydrochloride', 'type': 'DRUG', 'otherNames': ['L-arginine hydrochloride (Pharmalab, Australia)'], 'description': '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', 'armGroupLabels': ['A']}, {'name': 'Normal saline', 'type': 'OTHER', 'description': '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).', 'armGroupLabels': ['S']}]}, 'contactsLocationsModule': {'locations': [{'city': 'Timika', 'state': 'Special Region of Papua', 'country': 'Indonesia', 'facility': 'Mitra Masyarakat Hospital'}], 'overallOfficials': [{'name': 'Nicholas M Anstey, MBBS', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Menzies School of Health Research'}, {'name': 'Emiliana Tjitra, MD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'National Institute of Health Research and Development'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Menzies School of Health Research', 'class': 'OTHER'}, 'collaborators': [{'name': 'Wellcome Trust', 'class': 'OTHER'}, {'name': 'National Health and Medical Research Council, Australia', 'class': 'OTHER'}], 'responsibleParty': {'type': 'SPONSOR'}}}}