Ignite Creation Date:
2025-12-24 @ 6:41 PM
Ignite Modification Date:
2025-12-29 @ 11:21 PM
Study NCT ID:
NCT03309657
Status:
COMPLETED
Last Update Posted:
2020-09-10
First Post:
2017-07-30
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Pharmacokinetics of Ceftolozane/Tazobactam in Plasma and Cerebrospinal Fluid
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'interventionBrowseModule': {'meshes': [{'id': 'C000594038', 'term': 'ceftolozane, tazobactam drug combination'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'j.roberts2@uq.edu.au', 'phone': '+61 7 334 65032', 'title': 'Prof. Jason Roberts', 'organization': 'University of Queensland Center for Clinical Research'}, 'certainAgreement': {'piSponsorEmployee': True}}, 'adverseEventsModule': {'timeFrame': 'The duration of the study enrolment up to 24 hours.', 'eventGroups': [{'id': 'EG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only', 'otherNumAtRisk': 10, 'deathsNumAtRisk': 10, 'otherNumAffected': 0, 'seriousNumAtRisk': 10, 'deathsNumAffected': 0, 'seriousNumAffected': 0}], 'frequencyThreshold': '0'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Unbound Ceftolozane Exposure in the Plasma', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'classes': [{'categories': [{'measurements': [{'value': '322.6', 'groupId': 'OG000', 'lowerLimit': '182.7', 'upperLimit': '413.9'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Ceftolozane Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).', 'unitOfMeasure': 'mg*h/L', 'dispersionType': 'Inter-Quartile Range', 'reportingStatus': 'POSTED'}, {'type': 'PRIMARY', 'title': 'Unbound Tazobactam Exposure in the Plasma', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'classes': [{'categories': [{'measurements': [{'value': '52.1', 'groupId': 'OG000', 'lowerLimit': '35.7', 'upperLimit': '79.6'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Tazobactam Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).', 'unitOfMeasure': 'mg*h/L', 'dispersionType': 'Inter-Quartile Range', 'reportingStatus': 'POSTED'}, {'type': 'PRIMARY', 'title': 'Unbound Ceftolozane Exposure in the CSF', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'classes': [{'categories': [{'measurements': [{'value': '30.2', 'groupId': 'OG000', 'lowerLimit': '18.8', 'upperLimit': '128.3'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Ceftolozane Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).', 'unitOfMeasure': 'mg*h/L', 'dispersionType': 'Inter-Quartile Range', 'reportingStatus': 'POSTED'}, {'type': 'PRIMARY', 'title': 'Unbound Tazobactam Exposure in the CSF', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'classes': [{'categories': [{'measurements': [{'value': '5.6', 'groupId': 'OG000', 'lowerLimit': '1.6', 'upperLimit': '24.4'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Tazobactam Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).', 'unitOfMeasure': 'mg*h/L', 'dispersionType': 'Inter-Quartile Range', 'reportingStatus': 'POSTED'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'periods': [{'title': 'Overall Study', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '10'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '10'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}]}]}]}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'groups': [{'id': 'BG000', 'title': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.\n\nCeftolozane/tazobactam: IV ceftolozane 2000mg /tazobactam 1000mg once only'}], 'measures': [{'title': 'Age, Continuous', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '60.5', 'groupId': 'BG000', 'lowerLimit': '53.5', 'upperLimit': '64.75'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'years', 'dispersionType': 'INTER_QUARTILE_RANGE'}, {'title': 'Sex: Female, Male', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'title': 'Female', 'measurements': [{'value': '7', 'groupId': 'BG000'}]}, {'title': 'Male', 'measurements': [{'value': '3', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Race and Ethnicity Not Collected', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '0', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants', 'populationDescription': 'Race and Ethnicity were not collected from any participant.'}, {'title': 'Region of Enrollment', 'classes': [{'title': 'Australia', 'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '10', 'groupId': 'BG000'}]}]}], 'paramType': 'NUMBER', 'unitOfMeasure': 'participants'}, {'title': 'Weight', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '75', 'groupId': 'BG000', 'lowerLimit': '65', 'upperLimit': '87'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'kg', 'dispersionType': 'INTER_QUARTILE_RANGE'}, {'title': 'Serum Creatinine', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '48.5', 'groupId': 'BG000', 'lowerLimit': '42.25', 'upperLimit': '57.75'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'micro-mole/litre', 'dispersionType': 'INTER_QUARTILE_RANGE'}, {'title': 'Albumin', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '24', 'groupId': 'BG000', 'lowerLimit': '21.25', 'upperLimit': '25.75'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'g/L', 'dispersionType': 'INTER_QUARTILE_RANGE'}, {'title': 'Acute Physiology and Chronic Health Evaluation (APACHE) II', 'classes': [{'denoms': [{'units': 'Participants', 'counts': [{'value': '10', 'groupId': 'BG000'}]}], 'categories': [{'measurements': [{'value': '17.5', 'groupId': 'BG000', 'lowerLimit': '14', 'upperLimit': '22.5'}]}]}], 'paramType': 'MEDIAN', 'description': 'Acute Physiology and Chronic Health Evaluation II \\[APACHE II\\] score on ICU admission was calculated from 12 routine physiologic measurements using the standard approach. APACHE II score ranges from 1 to 71, with higher scores correlating with an increased risk of mortality. For a detailed description, please refer to Crit Care Med. 1985 Oct;13(10):818-29.', 'unitOfMeasure': 'units on a scale', 'dispersionType': 'INTER_QUARTILE_RANGE'}]}}, 'documentSection': {'largeDocumentModule': {'largeDocs': [{'date': '2017-03-21', 'size': 505810, 'label': 'Study Protocol and Statistical Analysis Plan', 'hasIcf': False, 'hasSap': True, 'filename': 'Prot_SAP_000.pdf', 'typeAbbrev': 'Prot_SAP', 'uploadDate': '2020-08-20T20:27', 'hasProtocol': True}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE1', 'PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NA', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'BASIC_SCIENCE', 'interventionModel': 'SINGLE_GROUP', 'interventionModelDescription': 'Open label pharmacokinetic study where enrolled critically ill patients with infection receive a single dose of ceftolozane-tazobactam (in addition to other active therapy).'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 10}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2018-02-01', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2020-08', 'completionDateStruct': {'date': '2020-06-01', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2020-08-21', 'studyFirstSubmitDate': '2017-07-30', 'resultsFirstSubmitDate': '2020-08-05', 'studyFirstSubmitQcDate': '2017-10-09', 'lastUpdatePostDateStruct': {'date': '2020-09-10', 'type': 'ACTUAL'}, 'resultsFirstSubmitQcDate': '2020-08-21', 'studyFirstPostDateStruct': {'date': '2017-10-13', 'type': 'ACTUAL'}, 'resultsFirstPostDateStruct': {'date': '2020-09-10', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2020-05-01', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Unbound Ceftolozane Exposure in the Plasma', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Ceftolozane Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).'}, {'measure': 'Unbound Tazobactam Exposure in the Plasma', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Tazobactam Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).'}, {'measure': 'Unbound Ceftolozane Exposure in the CSF', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Ceftolozane Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).'}, {'measure': 'Unbound Tazobactam Exposure in the CSF', 'timeFrame': 'Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis', 'description': 'Unbound Tazobactam Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).'}]}, 'oversightModule': {'isUsExport': False, 'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'conditions': ['Pharmacokinetics']}, 'descriptionModule': {'briefSummary': 'Ceftolozane/tazobactam is an emerging newly available antibiotic that has a broad spectrum of activity, and could be potentially useful in the management of central nervous system infections. However, data relating to penetration of ceftolozane/ tazobactam into the central nervous system, where a barrier against drug distribution exists (i.e. blood brain barrier), is currently limited. In critically ill patients this is all the more challenging as achieving adequate antibiotic concentrations even in blood is difficult.\n\nThe aim of this study is to describe the concentrations achieved in the cerebrospinal fluid (i.e. bodily fluid found surrounding and inside of the brain) and blood after a single dose of ceftolozane/tazobactam administered in critically ill patients with an existing external ventricular drain (i.e. a device used in neurosurgery that relieves elevated intracranial pressure in the brain). It is planned that this information gained will help develop dosing strategies that will achieve target concentrations that will successfully treat central nervous system infections in the future.', 'detailedDescription': "Although relatively less frequent, Gram negative nosocomial meningitis and ventriculitis are observed in critical care settings, often associated with brain trauma, brain surgery, spinal fluid shunt after brain surgery, spinal abnormalities or severe urinary tract infections with bacteraemia. Gram negative meningitis is particularly challenging for treatment, when reduced susceptibility of some of the common etiologic bacteria is encountered (e.g. Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter aerogenes). Furthermore, the presence of the blood brain barrier (BBB) has meant that the choice of systemic antibiotics is very restricted due to the limited ability of many antibiotics to achieve adequate concentrations in the cerebrospinal fluid (CSF). The poor CSF penetration may also contribute to an accelerated rate of the emergence of resistant pathogens in some patients/units. A significant proportion of Gram negative bacilli clinical isolates (from patients with meningitis) are resistant to broad spectrum antibiotics such as the third or later generation cephalosporins. With the wide spread use of these antibiotics, the incidence of resistant nosocomial infections has increased. Thus, there is an acute need for novel antibiotics that can achieve adequate concentrations in the CSF, while exhibiting an excellent spectrum of activity.\n\nCeftolozane/tazobactam is an emerging newly available antibiotic that has a broad spectrum of activity, and could be potentially useful in the management of Gram negative meningitis. As compared to other commonly used beta lactam antibiotics, it exhibits superior antibacterial activity against difficult to treat Gram negative organisms, such as Pseudomonas aeruginosa and Enterobacteriaceae spp. It is relatively stable against various resistance mechanisms encountered by other beta lactams, and may be useful in the treatment of multi-drug resistant (MDR) infections. However, data relating to CSF penetration is limited. In the critically ill, achieving adequate antibiotic exposure, especially against the high MIC of some Gram negatives (e.g. Pseudomonas), is difficult even in plasma, let alone in CSF for which a distribution barrier (i.e. BBB) exists. Thus, it is prudent to investigate the CSF pharmacokinetics of this new drug before it is used 'off label' by clinicians without supportive data.\n\nThis study will describe the plasma and CSF pharmacokinetics of a 3.0 g dose of ceftolozane/tazobactam in critically ill patients with an indwelling external ventricular drain (EVD). We will use a population pharmacokinetics approach to determine if altered dosing or alternative modes of administration, such as prolonged infusion, should be considered to improve plasma exposure. Given that direct administration into the CSF (e.g. intraventricular route) is not only invasive but also may risk neurotoxicity, pharmacokinetic studies should explore the extent of drug distribution into CSF with systemic administration. There is no clinical data on the CSF penetration of ceftolozane/tazobactam in critically ill patients at the moment, and as such, this is a highly valuable study.\n\nAim of the study is to describe the pharmacokinetics of a single dose of ceftolozane/tazobactam in the plasma and CSF of critically ill patients with an indwelling EVD.\n\nThe study investigators hypothesise:\n\nThe plasma PK of cefolozane/tazobactam may be altered in critically ill patients with an indwelling EVD.\n\nThe distribution of ceftolozane/tazobactam into the CSF may be impaired by the blood brain barrier."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\nPatients with any infection requiring treatment with ceftolozane/tazobactam and who have met the following criteria:\n\n* Age \\>18 years\n* The presence of an indwelling external ventricular drain (EVD) or requiring EVD insertion due to obstructive hydrocephalus/subarachnoid haemorrhage\n\nExclusion Criteria:\n\n* Known or suspected allergy to penicillins and cephalosporins\n* Pregnancy\n* Receiving renal replacement therapy\n* Glomerular filtration rate less than 10 mL/min\n* Receiving piperacillin/tazobactam or having received piperacillin/tazobactam in the past 7 days before enrolment'}, 'identificationModule': {'nctId': 'NCT03309657', 'briefTitle': 'Pharmacokinetics of Ceftolozane/Tazobactam in Plasma and Cerebrospinal Fluid', 'organization': {'class': 'OTHER_GOV', 'fullName': "Royal Brisbane and Women's Hospital"}, 'officialTitle': 'A Prospective Pharmacokinetic Evaluation of the Plasma and Cerebrospinal Fluid Concentrations of a Single Dose Ceftolozane/Tazobactam in Infected Critically Ill Patients With an Indwelling External Ventricular Drain', 'orgStudyIdInfo': {'id': 'HREC/17/QRBW/117'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Ceftolozane Tazobactam', 'description': 'Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.', 'interventionNames': ['Drug: Ceftolozane/tazobactam']}], 'interventions': [{'name': 'Ceftolozane/tazobactam', 'type': 'DRUG', 'otherNames': ['ZERBAXA'], 'description': 'This is an observational pharmacokinetic study whereby patients received a single dose of ceftolozane/tazobactam and plasma and cerebrospinal fluid samples were subsequently collected and analyzed to described the pharmacokinetics.', 'armGroupLabels': ['Ceftolozane Tazobactam']}]}, 'contactsLocationsModule': {'locations': [{'zip': '4029', 'city': 'Brisbane', 'state': 'Queensland', 'country': 'Australia', 'facility': "Royal Brisbane and Women's Hospital", 'geoPoint': {'lat': -27.46794, 'lon': 153.02809}}], 'overallOfficials': [{'name': 'Jason A Roberts, PhD BPharm', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Royal Brisbane and Womens Hospital'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO', 'description': 'There is no plan to make individual participant data available to other researchers'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': "Royal Brisbane and Women's Hospital", 'class': 'OTHER_GOV'}, 'collaborators': [{'name': 'The University of Queensland', 'class': 'OTHER'}], 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Professor', 'investigatorFullName': 'Jason Roberts', 'investigatorAffiliation': "Royal Brisbane and Women's Hospital"}}}}