Early Oral Step-down Antibiotic Therapy Versus Continuing Intravenous Therapy for Uncomplicated Gram-negative Bacteraemia (the INVEST Trial)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 720
- 试验地点
- 27
- 主要终点
- 30-day mortality
研究概览
简要总结
Current management of uncomplicated Gram-negative bacteraemia entails prolong intravenous (IV) antibiotic therapy with limited evidence to guide oral conversion. This trial aim to evaluate the clinical efficacy and economic impact of early switch to oral antibiotics (within 72 hours from index blood culture collection) versus continuing standard of care IV therapy (for at least another 24 hours post-randomisation) for clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia.
详细描述
This is an international, multicentre, randomised controlled, open-label, phase IV, non-inferiority trial with a non-inferiority margin of 6%. Eligible participants must be clinically stable / non-critically ill inpatients over the age of 18 years old (in Singapore, 21 years and above) with uncomplicated Gram-negative bacteraemia. Randomisation into the intervention or standard arms will be performed with 1:1 allocation ratio according to a randomisation list prepared in advance using a secure online randomisation system. Randomisation will be stratified by country and random sequence will be generated using random permuted blocks of unequal length. Participants randomised to the intervention arm (within 72 hours from index blood culture collection) will be immediately converted to oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole. In the event of microbiological or clinical failure of the oral antibiotic treatment, escalation to IV antibiotics may be initiated at any time point post-randomisation. Participants randomised to the standard arm will continue to receive an active IV therapy for at least another 24 hours post-randomisation. All the study drugs (and dosage) would be routinely used in clinical practice and will be ordered/dispensed from the hospital pharmacy as per site institutional practice. The recommended treatment duration by the study team is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Participants may be discharged home or to outpatient parenteral antimicrobial therapy (OPAT) at any time post-randomisation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •One or more set(s) of blood cultures positive for Gram-negative bacteria (GNB) associated with evidence of infection
- •Able to be randomised within 72 hours of index blood culture collection
- •Age ≥18 years (≥21 in Singapore)
- •Latest Pitt bacteraemia score <4
- •Patient or legal representative is able to provide informed consent
排除标准
- •Established uncontrolled focus of infection, including but not limited to:
- •Undrained abdominal abscess, deep seated intra-abdominal infection and other unresolved abdominal sources requiring surgical intervention
- •Central nervous system abscess (patients with focal neurology should have cranial CT prior to enrolment)
- •Undrained moderate-to-severe hydronephrosis
- •Complicated infections, including but not limited to:
- •Necrotising fasciitis
- •Central nervous system infections and meningitis
- •Endocarditis / endovascular infections
- •Septic shock as defined by systolic blood pressure <90 or mean arterial pressure <70 mmHg despite adequate fluid resuscitation or need for inotropic/vasopressor support
- •Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as either growth of 2 or more different microorganism species in the same blood culture, or growth of different species in 2 or more separate blood cultures within the same episode [<48 hours] and with clinical or microbiological evidence of the same source)
- •Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular graft) that cannot be removed
- •Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella spp.
- •Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole
- •Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, urticaria, angioedema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration
- •Unable to consume or absorb oral medications for any reason or unsuitable for ongoing IV therapy (e.g. no intravenous access)
- •Severely immunocompromised in the opinion of the treating doctor, including but not limited to, medical conditions such as:
- •Active leukaemia or lymphoma
- •Aplastic anaemia
- •Bone marrow transplant within two years of transplantation or transplants of longer duration still on immunosuppressive drugs or with graft-versus-host disease
- •Congenital immunodeficiency
- •HIV/AIDS with CD4 lymphocyte count <200
- •Neutropenia or expected post-chemotherapy neutropenia within 14 days from the time of screening, defined as absolute neutrophil count < 500 cells/μL
- •Women who are known to be pregnant or breast-feeding
- •Treatment is not with intent to cure the infection (i.e. palliative care)
- •Unable to collect patient's follow-up data for at least 30 days post-randomisation for any reason
- •Treating doctor deems enrolment into the trial is not in the best interest of the patient
- •Previous enrolment in this trial
研究组 & 干预措施
Continuing intravenous antibiotic therapy
The intravenous antibiotics to be administered will be determined by the treating doctor according to what would be considered standard of care in the hospital site. Commonly used intravenous antibiotics (and doses) for treatment of Gram-negative bacteraemia include ceftriaxone 2 g daily or cefazolin 2 g three times daily. The recommended treatment duration by the study team is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days due to regimen extension or requirement for prolonged regimen as clinically indicated.
干预措施: Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin) (Drug)
Early switch to oral antibiotic therapy
The oral antibiotic options are fluoroquinolones (most commonly, ciprofloxacin) or trimethoprim-sulfamethoxazole. The recommended doses for patients with normal renal function would be ciprofloxacin 750 mg twice daily (if body weight ≥70 kg) or ciprofloxacin 500 mg twice daily (if body weight <70 kg) or trimethoprim-sulfamethoxazole 5 mg/kg (for trimethoprim component) every 12 hourly or trimethoprim-sulfamethoxazole (160 mg / 800 mg; double strength) two tablets twice daily. Doses may be adjusted in the setting of renal dysfunction. The recommended treatment duration by the study team is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days due to regimen extension or requirement for prolonged regimen as clinically indicated.
干预措施: Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole (Drug)
结局指标
主要结局
30-day mortality
时间窗: 30 days
All-cause mortality at day 30 post-randomisation
All-cause mortality at day 30 post-randomisation
时间窗: 30 days
Percentage of all-cause mortality at day 30 from the time of randomisation
次要结局
- Readmission or extended hospitalisation by day 90.(90 days)
- Number of days alive and not in hospital by day 90(90 days)
- 14-day and 90-day mortality(90 days)
- Duration of survival by day 90(90 days)
- Number of days on IV antibiotic therapy in the total index hospitalisation(90 days)
- Adverse events from the time of randomisation until day 90(90 days)
- Health economic evaluation(90 days)
- Assessment of patient's quality of life(90 days)
- Number of days alive and free of antibiotics by day 90(90 days)
- Change in treatment strategy between the time of randomisation and day 30(30 days)
- Time to being discharged alive from the total index hospitalisation between the time of randomisation and day 90(90 days)
- All-cause mortality at day 14 and day 90 post-randomisation(14 days and 90 days, respectively)
- Duration of survival (in days) up to day 90 post-randomisation(90 days)
- Number of days on IV antibiotic therapy in the total index hospitalisation until (i) hospital discharge and (ii) day 90(Up to 90 days)
- Number of days alive and free of antibiotics (i. for all antibiotics, and ii. for IV antibiotics) between the time of randomisation and day 90(90 days)
- Treatment-emergent adverse events from the time of randomisation until day 90(90 days)
- Change in treatment strategy, either due to an adverse event or presumed lack of efficacy of treatment regimen, between the time of randomisation and day 30(30 days)
- Time (in days) to being discharged alive from the total index hospitalisation between the time of randomisation and day 90(90 days)
- Number of days alive and not in hospital (including OPAT) up to day 90 post-randomisation(90 days)
- Readmission or extended index hospitalisation between the time of randomisation and day 90(90 days)
- Health-related quality of life on the day of screening (baseline), on the day of end of treatment, and on day 90 post-randomisation(90 days)
- Health economic evaluation up to day 90 post-randomisation(90 days)
- Health-related quality of life (EQ-5D descriptive system) on the day of screening (baseline), on the day of end of treatment, and on day 90 post-randomisation(90 days)
- Health-related quality of life (EQ visual analogue scale) on the day of screening (baseline), on the day of end of treatment, and on day 90 post-randomisation(90 days)