Fast-track Absolute Neutrophil Count in Suspected Neutropenic Fever (The FRANCiS-NF Trial): A Single-centre, Pragmatic, Open-label, Randomised, Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 344
- 试验地点
- 1
- 主要终点
- Antibiotic stewardship as assessed by proportion of participants receiving Meropenem
研究概览
简要总结
This is a comparative study for adult participants with cancer who are suspected to have neutropenic fever (or fever with low neutrophil count) in emergency department. Neutrophil is a kind of defensive white blood cell combating against infection, especially by bacteria and fungi. Low neutrophil can be part of the disease progress or secondary to some cancer treatment. These participants are at high risk of developing infection-related complications including death.
Currently a dedicated clinical pathway has been in place in emergency department for suspected neutropenic fever, which offers fast-track medical consultation, blood tests and a very strong antibiotic (meropenem) as the first choice within 1 hour of registration. However, majority of such participants' neutrophil counts are not low. Most of them have no bacterial infection in the body, and have unremarkable short hospital stays. Early administration of meropenem in the majority of cases may be unnecessary and imposes risk of developing antibiotic resistance.
This study attempts to answer the question, "In adult participants with cancer presenting to emergency department with suspected neutropenic fever, when compared with conventional treatment, can a new protocol guided by fast-track neutrophil count reduces prescription of meropenem?" Agreed participants will be randomly assigned to the conventional treatment group, or the new treatment group. For those who are assigned to the new treatment group, blood will be taken and sent to the hospital laboratory for urgent analysis of neutrophil count. Participants with proven low neutrophil counts will still receive meropenem, while those without low neutrophil counts will receive less strong antibiotic according to their clinical diagnoses, such as Augmentin. They will be followed up on the first 7 days, and then on the 14th, 30th, 90th, and 180th days after recruitment. Comparisons will be made to see how much less meropenem will be prescribed, and whether more serious adverse events will happen. The study is expected to take 37 months to complete. Duration of data collection, including the day of last follow up, is estimated to be 33 months.
详细描述
- Background
1.a. Burden of neutropenic fever Neutropenic fever (NF), or febrile neutropenia, is characterised by high body temperature and low absolute neutrophil count (ANC) following myelosuppressive cancer treatment.[1] It occurs in 5 - 10 percent of patients with early-stage solid tumours, 20 - 25 percent with non-leukaemic haematological cancers, 85 - 95 percent with acute leukaemia,[2] and 13 - 21 percent with metastatic solid tumours.[1] It is more common after the first cycle of chemotherapy. 7.83 per 1,000 cancer patients were hospitalised for NF annually in the United States (US).[3] With earlier cancer recognition, and more prescriptions of chemotherapeutic agents and targeted therapies, the figures are expected to rise.
NF is associated with unplanned chemotherapy interruptions and relative dose intensity (RDI) reductions more than 15 percent, which undermine treatment success rates and overall survival.[2] When complicated by neutropenic sepsis, a dysregulated host response against infection, NF becomes an oncological emergency. The mortality rate is 3 - 18 percent following complications e.g. hypotension, respiratory failure, encephalopathy, cardiac failure and arrhythmia, renal failure, haemorrhage, and admission to intensive care unit (ICU).[4] Risk factors of life-threatening infections are severe neutropenia, protracted neutropenia, and splenectomy.[5] Mortality risk increases with advanced age, comorbidities, clinically documented infection, bacteraemia, leukaemia and lung cancer as underlying malignancies.[4,6]
The cost of managing NF remains substantial for healthcare systems worldwide. The mean direct hospitalisation costs in the US, Germany, and Singapore were US$19,110 (1995-2000), €3,950 (2005-2006), and US$4,913 (2009-2012) respectively.[6-8] Higher costs are associated with inpatient treatment, comorbidities, discharge, deaths, male sex, and infection.[9]
1.b. Diagnostic criteria NF is defined by 1) single oral temperature ≥ 38.3 degree Celsius (101ºF), or ≥ 38.0 degree Celsius (100.4ºF) sustained over 1 hour; and 2) ANC < 1.0 x 109/L ("moderate" neutropenia). Neutropenia becomes "severe", "profound" and "protracted" if ANC < 0.5 x 109/L, < 0.1 x 109/L, and lasts for more than one week, respectively.[10] This definition applies to oncological and haematological participants only.
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
- •Age criteria: 18 years old or above; AND
- •Body temperature criteria: Tympanic temperature ≥ 38.3 degree Celsius (100.9 degree Fahrenheit) within 24 hours before emergency department registration; AND
- •Chemotherapy timeframe criteria: Last chemotherapy or targeted therapy within 6 weeks for any solid tumor, or in any period following therapies against leukemia, lymphoma, myelodysplastic syndrome, aplastic anemia, multiple myeloma, or recipient of hematopoietic stem cell transplantation; AND
- •Modified Early Warning Score (MEWS) ≤ 4
排除标准
- •Unable to provide informed consent
- •Previous enrolment to this trial within 180 days, or without current resolution of the first episode
- •Enrolment to other interventional trials within 187 days
- •Sepsis or septic shock
- •Suspected central nervous system infection
- •Severe desaturation (SpO2 < 88% in room air for patients with chronic obstructive pulmonary disease, severe chest wall or spinal disease, neuromuscular disease, severe obesity, cystic fibrosis, bronchiectasis; or < 94% in room air without)
- •Currently on prophylactic antibiotic
- •Any antibiotic treatment for > 48 h within 1 week
- •Known human immunodeficiency virus infection
- •Primary humoral immunodeficiency
- •Complement deficiency
- •Vulnerable subjects (illiterate, pregnancy, mentally incapacitated, impoverished, prisoner, subordinate or students of investigators, ethnic minorities)
- •Research staff not available
- •Unable to randomize within 1 hour of emergency department registration
- •Inter-hospital transfer
- •Scheduled "clinical" admissions
- •Body temperature not documented
- •Blood sample not taken in emergency department
研究组 & 干预措施
Fast-tRack Absolute Neutrophil Count (FRANC) Protocol
Patient's blood sample will be expedited for complete blood count with differentials. Intravenous antibiotic is given depending on absolute neutrophil count. If neutropenia is present, broad-spectrum antibiotic (meropenem 1 g or levofloxacin 500 mg) will be given after septic workup within 1 hour of registration in emergency department before transfer to wards. If absent, antibiotic according to "Hospital Authority Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT)" with reference to previous bacterial sensitivity pattern, or amoxiclav 1.2 g if not specified, will be given. Other interventions are given according to clinical needs. The regimen is continued until clinicians recommend an alternative antimicrobial based on clinical grounds, or detection of other pathogens which indicate another antimicrobial.
干预措施: Meropenem Injection (Drug)
Fast-tRack Absolute Neutrophil Count (FRANC) Protocol
Patient's blood sample will be expedited for complete blood count with differentials. Intravenous antibiotic is given depending on absolute neutrophil count. If neutropenia is present, broad-spectrum antibiotic (meropenem 1 g or levofloxacin 500 mg) will be given after septic workup within 1 hour of registration in emergency department before transfer to wards. If absent, antibiotic according to "Hospital Authority Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT)" with reference to previous bacterial sensitivity pattern, or amoxiclav 1.2 g if not specified, will be given. Other interventions are given according to clinical needs. The regimen is continued until clinicians recommend an alternative antimicrobial based on clinical grounds, or detection of other pathogens which indicate another antimicrobial.
干预措施: Levofloxacin (Drug)
Fast-tRack Absolute Neutrophil Count (FRANC) Protocol
Patient's blood sample will be expedited for complete blood count with differentials. Intravenous antibiotic is given depending on absolute neutrophil count. If neutropenia is present, broad-spectrum antibiotic (meropenem 1 g or levofloxacin 500 mg) will be given after septic workup within 1 hour of registration in emergency department before transfer to wards. If absent, antibiotic according to "Hospital Authority Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT)" with reference to previous bacterial sensitivity pattern, or amoxiclav 1.2 g if not specified, will be given. Other interventions are given according to clinical needs. The regimen is continued until clinicians recommend an alternative antimicrobial based on clinical grounds, or detection of other pathogens which indicate another antimicrobial.
干预措施: Amoxicillin Clavulanate (Drug)
Fast-tRack Absolute Neutrophil Count (FRANC) Protocol
Patient's blood sample will be expedited for complete blood count with differentials. Intravenous antibiotic is given depending on absolute neutrophil count. If neutropenia is present, broad-spectrum antibiotic (meropenem 1 g or levofloxacin 500 mg) will be given after septic workup within 1 hour of registration in emergency department before transfer to wards. If absent, antibiotic according to "Hospital Authority Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT)" with reference to previous bacterial sensitivity pattern, or amoxiclav 1.2 g if not specified, will be given. Other interventions are given according to clinical needs. The regimen is continued until clinicians recommend an alternative antimicrobial based on clinical grounds, or detection of other pathogens which indicate another antimicrobial.
干预措施: Antibiotic (Drug)
Standard of Care
The control group refers to the existing clinical pathway which guides management of adult patients with suspected NF in ED. Without information of absolute neutrophil count, Meropenem 1 g IV bolus (or Levofloxacin 500 mg IV infusion over 1 hour if Penicillin-allergic) will be given within 1 hour of ED registration after septic workup. Other interventions are given according to clinical needs.
Subsequent treatment in wards will be determined by doctor's clinical judgement, on a personalised basis. Each patient will be assessed by a parent team member. There is no standardised antibiotic de-escalation protocol in place, but it is a usual practice to continue Meropenem or Levofloxacin injections until clinical improvement, rising ANC, and negative culture results. After that it will be replaced with an antibiotic with a narrower spectrum, such as oral Amoxiclav, before discharge.
干预措施: Meropenem Injection (Drug)
Standard of Care
The control group refers to the existing clinical pathway which guides management of adult patients with suspected NF in ED. Without information of absolute neutrophil count, Meropenem 1 g IV bolus (or Levofloxacin 500 mg IV infusion over 1 hour if Penicillin-allergic) will be given within 1 hour of ED registration after septic workup. Other interventions are given according to clinical needs.
Subsequent treatment in wards will be determined by doctor's clinical judgement, on a personalised basis. Each patient will be assessed by a parent team member. There is no standardised antibiotic de-escalation protocol in place, but it is a usual practice to continue Meropenem or Levofloxacin injections until clinical improvement, rising ANC, and negative culture results. After that it will be replaced with an antibiotic with a narrower spectrum, such as oral Amoxiclav, before discharge.
干预措施: Levofloxacin (Drug)
结局指标
主要结局
Antibiotic stewardship as assessed by proportion of participants receiving Meropenem
时间窗: Up to 7 days post-randomisation
Proportion of participants in each group receiving Meropenem
次要结局
- Overall survival(Up to 180 days post-randomisation)
- Antibiotics administered(Up to 180 days post-randomisation)
- Mean total dose of antibiotics used(Up to 180 days post-randomisation)
- Hospital antibiotics use as total days of antibiotic therapy (DOT)(Up to 180 days post-randomisation)
- Health related quality of life as assessed by Functional Assessment of Cancer Therapy - General (FACT-G)(Up to 180 days post-randomisation)
- Health related quality of life as assessed by Functional Assessment of Cancer Therapy - Neutropenia (FACT-N)(Up to 180 days post-randomisation)
- Time to clinical improvement(Up to 15 days post-randomisation)
- Hospital antibiotics use as defined daily dose (DDD) per admission(Up to 180 days post-randomisation)
- Incidence of adverse events requiring emergency interventions(Up to 15 days post-randomisation)
- Rate of life-saving interventions(Up to 15 days post-randomisation)
- Clinically and/or microbiologically documented infections(Up to 15 days post-randomisation)
- Length of hospital stay(Up to 180 days post-randomisation)
- Proportion of participants with changes in chemotherapy schedule(Up to 180 days post-randomisation)
- Unplanned readmission rate(Up to 30 days post-randomisation)
- Microbiological safety as assessed by development of antibiotic resistance(Up to 180 days post-randomisation)
- Financial Toxicity related to cancer and its treatment as assessed by Functional Assessment of Chronic Illness Therapy - COprehensive Score for financial Toxicity (FACIT-COST)(Up to 180 days post-randomisation)