A Two-part Phase IIb Randomized, Multicenter, Open-label Comparative Study to Firstly Evaluate the Safety and Efficacy Trial of BV100 in Combination With Low Dose Polymyxin B Plus Ceftazidime/Avibactam, or Plus Cefiderocol Versus Best Available Therapy in Patients With Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia and Bloodstream Infection, Suspected or Confirmed to be Due to Carbapenem-resistant Acinetobacter Baumannii Calcoaceticus Complex (CRABC), and Secondly to Evaluate the Pharmacokinetics of BV100 in Combination With Low Dose Polymyxin B Plus Cefideroc
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- BioVersys AG
- 入组人数
- 120
- 主要终点
- The incidence of treatment-related treatment emergent adverse events (TRTEAEs) in the Safety population, assessed through End of Study (EoS) visit in Part A and Part B.
研究概览
简要总结
This Phase IIb study aims to evaluate the safety and efficacy of BV100 in combination with low dose polymyxin B plus ceftazidime/avibactam or cefiderocol in patients with suspected or confirmed CRABC infections. The study is divided into two parts (Part A and Part B), recruiting in parallel. Approximately 10 subjects will be recruited in Part B, with enrollment ending once Part A enrollment is complete (at least 30 patients randomized to all of the three groups). Eligible patients, who have given informed consent, will be enrolled, and pre-treatment microbiology samples submitted to a local laboratory.
详细描述
Part A will be the randomized, active-controlled portion of the study, evaluating patients with suspected or confirmed CRABC nosocomial pneumonia (VABP and HABP) and BSI of non-urinary tract origin. This is an open-label study, and therefore, no blinding will be done.
In Part A, patients will be randomized 1:1:1, to one of the three treatment groups until the CRABC m-MITT population includes 30 evaluable subjects per group:
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Group 1: 300 mg BV100 in combination with 500,000 IU (50 mg) polymyxin B infused over 2 hours every 12 hours (q12h), plus 2 g/0.5 g ceftazidime/avibactam*,# infused over 2 hours every 8 hours (q8h).
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Group 2: 300 mg BV100 in combination with 500,000 IU (50 mg) polymyxin B infused over 2 hours every 12 hours (q12h), plus 2 g cefiderocol infused over 3 hours every 8 hours (q8h).
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Group 3: Best Available Therapy (BAT), which is determined by the site for each individual patient according to local epidemiology and the patient's antibiotic history.
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In case of non-Acinetobacter metallo-beta-lactamase (MBL)-producing infections confirmed by culture or identified by RDT, including polymicrobial infections,, aztreonam (2 g infused over 2 hours, q8h) should be infused simultaneously with ceftazidime-avibactam via a Y-site administration used per manufacturer's instructions, subject to Medical Monitor approval.
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If rapid diagnostic test (RDT) on positive blood culture broths show Acinetobacter only, concomitant ceftazidime-avibactam can be omitted.
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 82 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provide written informed consent prior to any study-related procedures not part of normal medical care. Surrogate consent/use of a legally authorized representative may be provided if permitted by local country and institution-specific guidelines
- •Male subjects or female subjects ≥ 18 and ≤ 82 years of age at the time of signing informed consent.
- •A known or highly suspected infection caused by CRABC (VABP, HABP, or BSI of non-urinary tract origin) as either a single pathogen or member of a polymicrobial infection
- •Diagnosed with HABP, VABP or BSI
- •Acute Physiology and Chronic Health Evaluation (APACHE II) score ≤ 30, within 24 hours prior to randomization.
- •Part B specific inclusion criteria
- •Confirmed CRABC ventriculitis or meningitis based on evidence from CSF culture collected within 72 hours prior to enrollment (as per standard of care).
- •Functioning EVD that can be used for safe and timely CSF sampling.
- •No contraindications to CSF sampling via EVD in the volumes required by the protocol
排除标准
- •1. Urinary tract infection as source of A. baumannii BSI
- •Known or suspected community acquired bacterial pneumonia or viral (including SARS-CoV-2), pneumonia within the last 7 days
- •Known or suspected viral pneumonia within the last 7 days before screening e.g. positive for SARS-CoV-2 or influenza.
- •4. Known fungal or parasitic pneumonia.
- •Patients classified under futility of care, as determined by the medical team, indicating a lack of potential for benefit from intervention or patients who are permanent residents of long-term care facilities and have been assessed as receiving palliative or comfort-focused care.
- •6. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg (calculate mean arterial pressure = diastolic pressure plus 1/3 (systolic pressure minus diastolic pressure)) with patients requiring escalating vasopressor support to maintain adequate arterial pressure in conjunction with rising lactate.
- •Known or suspected allergies to polymyxins, rifabutin, ceftazidime/avibactam, cefiderocol, or their excipients.
- •8. Inability to insert a central catheter or a peripherally inserted central catheter (PICC).
- •Acute graft versus host disease Grade ≥
- •12. Expected survival < 72 hours or a Do Not Resuscitate Order.
- •Burns > 40% of total body surface area.
- •Presence of neutropenia (absolute neutrophil count < 1500/mm3) obtained from a local laboratory at Screening, or anticipated neutropenia with absolute neutrophil count < 1500 cells/mm
- •15. Severe renal disease defined as an estimated glomerular filtration rate (eGFR) as per Modification of Diet in Renal Disease (MDRD) formula (MDRD eGFR) < 30 mL/min/1.73 m2, or requirement for peritoneal dialysis, hemodialysis, hemofiltration, or a urine output < 20 mL/hour over a 24 hour period.
研究组 & 干预措施
Part A - Group 1
干预措施: BV100 with 50 mg polymyxin B plus ceftazidime/avibactam (Drug)
Part A - Group 2
干预措施: BV100 with 50 mg polymyxin B plus cefiderocol (Drug)
Part A - Group 3
干预措施: Best Available Therapy (BAT) (Drug)
Part B
干预措施: BV100 with 50 mg polymyxin B plus cefiderocol (Drug)
结局指标
主要结局
The incidence of treatment-related treatment emergent adverse events (TRTEAEs) in the Safety population, assessed through End of Study (EoS) visit in Part A and Part B.
时间窗: 30 days
次要结局
- 14-day all cause mortality (ACM) in the CRABC m-MITT Population in Part A.(14 days)
- 28-day all cause mortality (ACM) in the CRABC m-MITT Population in Part A.(28 days)
- Clinical cure at Test of Cure (ToC) in the CRABC m-MITT population in Part A.(21 days)
- Concentration of rifabutin and 25-O-deacetyl-rifabutin in CSF and plasma at steady state in Part B(7 days)