A Multicentre Phase II Prospective Pilot Study of Pharmacokinetic- and TDM-guided Oritavancin Dosing Strategies for the Management of Gram-positive Cardiac Infections (the OSCAR Study)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 20
- 试验地点
- 3
- 主要终点
- Desirability of Outcome Ranking (DOOR) at Day 70
研究概览
简要总结
Cardiac infections, including infective endocarditis and cardiovascular implantable electronic device infections, are associated with substantial morbidity and mortality and are commonly caused by gram-positive bacteria. Standard management typically requires prolonged courses of intravenous antibiotics and extended hospitalisation, which are costly, burdensome, and associated with complications related to long-term vascular access. People who inject drugs are disproportionately affected and often experience stigma, barriers to care, and poorer outcomes. Long-acting lipoglycopeptides such as oritavancin maintain therapeutic serum concentrations for prolonged periods and may offer an alternative to conventional intravenous antibiotic regimens. Oritavancin is not TGA-registered in Australia and is accessed as an unregistered medicine (for example, via SAS or clinical trials). It is approved in other jurisdictions, including the United States and European Union, for acute bacterial skin and skin structure infections. Prospective data in cardiac infections remain limited, and optimal dosing strategies, including the role of therapeutic drug monitoring, are uncertain. This multicentre, open-label pilot study will assess the feasibility, pharmacokinetics, safety, acceptability, and preliminary efficacy of oritavancin for gram-positive cardiac infections using both standard fixed dosing and TDM-guided dosing strategies. Findings will inform PK/PD modelling, the potential role of TDM, and the design of future larger-scale trials and models of care, including alternatives to prolonged inpatient intravenous therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years
- •Hospitalised for management of a cardiac infection (infective endocarditis or cardiovascular implantable electronic device infections)
- •Gram-positive organism identified in blood or tissue culture, that in the opinion of the investigator is the cause of cardiac infection and would be treatable with a finite antibiotic duration (e.g., 4-6 weeks)
- •Afebrile for at least 24 hours at screening
- •Clearance of blood cultures for at least 24 hours at screening
- •Receiving effective antibiotic therapy for at least 24 hours and no more than 14 days at screening
- •Willingness of both treating provider and participant to proceed with oritavancin therapy
- •Able to provide written informed consent
- •Willingness and ability to participate in study procedures, including follow-up visits and drug monitoring
排除标准
- •History of severe allergic reaction or hypersensitivity to oritavancin or any of its components
- •Severe renal impairment (eGFR < 30 mL/min/1.73 m²) or currently receiving dialysis
- •Severe hepatic impairment (Child-Pugh class C)
- •Current infection involving the central nervous system, including septic emboli, ischemic or haemorrhagic stroke, epidural abscess, or meningitis (excluding prior/unrelated central nervous system events).
- •Presence of prosthetic heart valve
- •Culture negative endocarditis
- •Presence of any other active infection requiring concurrent antibiotic treatment that could interfere with study outcomes
- •Infection with Gram positive organism not susceptible to oritavancin or vancomycin (vancomycin MIC > 2 μg/mL).
- •Use of contraindicated medications (see Section 8)
- •Participation in another interventional clinical trial that may confound study outcomes
- •Pregnant or breastfeeding people, or those planning to become pregnant during the study period (people of childbearing potential must have a negative pregnancy test during hospitalization and use effective contraception for trial duration and for 3 months after last infusion of study medication).
- •Immunosuppression (defined as active chemotherapy expected to cause absolute neutrophil count <100 cells/mm3 lasting >7 days during the study period, bone marrow transplantation in the preceding 90 days, solid organ transplantation within prior 3 months or receipt of augmented immunosuppression for rejection within 3 months, chronic granulomatous disease, HIV with a CD4 count <50 cells/mm3 based on last known measure).
- •Any condition (e.g. severe cognitive impairment, psychiatric illness, active withdrawal) that, in the opinion of the investigator, would limit the participant's ability to comply with study procedures or give informed consent
- •Medically unstable in opinion of treating clinician that would preclude participation
- •Cases in which the investigator deem curative or finite antibiotic treatment unlikely (e.g., long term indefinite suppressive antibiotics are likely such as retained hardware).
研究组 & 干预措施
Cohort A1: Oritavancin, guideline-based dosing
Participants will receive oritavancin intravenously using a fixed weekly dosing schedule consistent with contemporary guideline-based practice. Intensive pharmacokinetic sampling will be performed to develop a population pharmacokinetic model
干预措施: Oritavancin (Drug)
Cohort A2: Oritavancin (TDM-guided dosing)
Participants will receive oritavancin intravenously with subsequent dosing intervals and/or additional doses guided by therapeutic drug monitoring and individual pharmacokinetic estimates derived from the population pharmacokinetic model developed in Cohort A1
干预措施: Oritavancin (Drug)
结局指标
主要结局
Desirability of Outcome Ranking (DOOR) at Day 70
时间窗: Day 70 post-enrolment
Composite ordinal outcome adapted for Gram-positive cardiac infections. Participants will be ranked from most to least desirable outcome as follows: 1. = alive with no clinical failure, infectious complication, or serious adverse event/adverse event leading to study drug discontinuation; 2. = alive with 1 of these events; 3. = alive with 2 of these events; 4. = alive with all 3 of these events; 5. = death. Within each rank, ties will be resolved using net change in EQ-5D score from baseline to Day 70, with greater improvement indicating a more desirable outcome.
次要结局
- Total oritavancin plasma concentration at scheduled sampling time points(From post-dose Day 1 through Day 70 post-enrolment)
- Oritavancin dosing interval achieved in the therapeutic drug monitoring-guided cohort(From Day 1 to Day 70 post-enrolment)
- Number of participants with treatment-emergent adverse events in the oritavancin cohorts(From enrolment to Day 180 post-enrolment)
- Number of participants with serious adverse events in the oritavancin cohorts(From enrolment to Day 180 post-enrolment)
- Number of participants with infusion-related reactions in the oritavancin cohorts(From enrolment to Day 180 post-enrolment)
- Change from baseline in EQ-5D score at Day 70(Baseline to Day 70 post-enrolment)
- Proportion of participants completing protocol-specified dosing and monitoring through Day 70(From enrolment to Day 70 post-enrolment)
- Recruitment rate(From study opening to completion of enrolment)
- Retention rate at Day 70(From enrolment to Day 70 post-enrolment)
- Number of participants who complete planned study treatment(By Day 70 post-enrolment)
- Number of participants with clinical or microbiological failure(By Day 70 post-enrolment)
- Number of participants with hospital readmission by Day 70(By Day 70 post-enrolment)
- Number of participants who die by Day 70(By Day 70 post-enrolment)
- Number of participants with hospital readmission by Day 180(By Day 180 post-enrolment)
- Number of participants who die by Day 180(By Day 180 post-enrolment)
- Change from Baseline to Day 70 in EuroQol 5-Dimension 5-Level Index Score(Baseline to Day 70 post-enrolment)