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Fast-track Blood Test for Suspected Fever by Deficiency of a Kind of White Blood Cells As Main Defense Against Infection (FRANCiS-NF)

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ClinicalTrials.gov Identifier: NCT05393505
Recruitment Status : Recruiting
First Posted : May 26, 2022
Last Update Posted : December 6, 2022
Sponsor:
Collaborator:
Queen Mary Hospital, Hong Kong
Information provided by (Responsible Party):
The University of Hong Kong

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neutropenic Fever Drug: Meropenem Injection Drug: Levofloxacin Drug: Amoxicillin Clavulanate Drug: Antibiotic Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 344 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a single-center, pragmatic, open-labelled, randomized, controlled trial with 1:1 parallel-group assignment, which aims to establish superiority in antibiotic stewardship.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fast-track Absolute Neutrophil Count in Suspected Neutropenic Fever (The FRANCiS-NF Trial): A Single-centre, Pragmatic, Open-label, Randomised, Controlled Trial
Actual Study Start Date : October 24, 2022
Estimated Primary Completion Date : March 14, 2025
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics Fever

Arm Intervention/treatment
Experimental: 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.
Drug: Meropenem Injection
Given if patient has no known allergies at 1 g IV bolus within 1 hour of ED registration, then every 8 hours

Drug: Levofloxacin
Given if patient is allergic to beta lactam at 500 g IV in 100 mL 0.9% sodium chloride solution, infused over 1 hour started within 1 hour of ED registration, then every 24 hours. If the patient can tolerate oral drugs, 500 mg daily after the first IV dose.

Drug: Amoxicillin Clavulanate
Given if patient has no known allergies at 1.2 g IV bolus within 1 hour of ED registration, then every 8 hours. If the patient can tolerate oral drugs, 1 g twice daily after the first IV bolus.
Other Name: Augmentin

Drug: Antibiotic
Any antibiotic for empirical therapy of common infections as recommended by the fifth version of "Hospital Authority Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT)" guideline, with reference to previous bacterial sensitivity pattern
Other Name: IMPACT guideline

Active Comparator: 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.

Drug: Meropenem Injection
Given if patient has no known allergies at 1 g IV bolus within 1 hour of ED registration, then every 8 hours

Drug: Levofloxacin
Given if patient is allergic to beta lactam at 500 g IV in 100 mL 0.9% sodium chloride solution, infused over 1 hour started within 1 hour of ED registration, then every 24 hours. If the patient can tolerate oral drugs, 500 mg daily after the first IV dose.




Primary Outcome Measures :
  1. Antibiotic stewardship as assessed by proportion of participants receiving Meropenem [ Time Frame: Up to 7 days post-randomisation ]
    Proportion of participants in each group receiving Meropenem


Secondary Outcome Measures :
  1. Clinically and/or microbiologically documented infections [ Time Frame: Up to 15 days post-randomisation ]
    Rate and type of documented infective focus

  2. Time to clinical improvement [ Time Frame: Up to 15 days post-randomisation ]
    • Days to defervescence (body temperature less than 38 degree Celsius)
    • Days to resolution of symptoms and signs of infection

  3. Incidence of adverse events requiring emergency interventions [ Time Frame: Up to 15 days post-randomisation ]
    • Hypotension (systolic blood pressure < 90 mmHg)
    • Respiratory failure (partial pressure of oxygen in arterial blood < 60 mmHg, or 8 kilopascal, adjusted for hyperventilation)
    • Altered mental state (Glasgow Coma Scale < 15)
    • Congestive heart failure documented radiologically
    • Acute kidney injury (serum creatinine > 2x baseline, or estimated glomerular filtration rate (eGFR) > 50 percent increase from baseline, or urine output < 0.5 mL/kg/h x 12 h)
    • Acute liver failure (International Normalised Ratio (INR) > 1.5 in non-warfarin user, hepatic encephalopathy, total bilirubin > 85.5 µmol/L or 5 mg/dL)
    • Rate of therapeutic failure (recurrence of fever after defervescence)

  4. Rate of life-saving interventions [ Time Frame: Up to 15 days post-randomisation ]
    • Rate of inotrope/ vasopressor use
    • Rate of assisted / mechanical ventilation
    • Rate of renal replacement therapy
    • Rate of 3 or more units of blood transfusion for haemorrhage
    • Rate of additional antimicrobial treatment
    • Rate of Intensive Care Unit (ICU) admission

  5. Length of hospital stay [ Time Frame: Up to 180 days post-randomisation ]
    Total in-hospital days from the time of index ED admission

  6. Proportion of participants with changes in chemotherapy schedule [ Time Frame: Up to 180 days post-randomisation ]
    Changes in chemotherapy schedule following index admission (postponement, dose reductions, participant defaults)

  7. Unplanned readmission rate [ Time Frame: Up to 30 days post-randomisation ]
    Rates of any readmission except for planned chemotherapy

  8. Overall survival [ Time Frame: Up to 180 days post-randomisation ]
    Time from the day of randomisation to the date of death, all-cause or infection-related

  9. Antibiotics administered [ Time Frame: Up to 180 days post-randomisation ]
    Type and route of antibiotics administered, from the time of randomisation to hospital discharge, or from the time of randomisation to the expected date of completion of prescribed antibiotic courses after discharge, whichever the later

  10. Mean total dose of antibiotics used [ Time Frame: Up to 180 days post-randomisation ]
    Mean total dose of antibiotics used, in milligrams, from the time of randomisation to hospital discharge, or from the time of randomisation to the expected date of completion of prescribed antibiotic courses after discharge, whichever the later

  11. Hospital antibiotics use as total days of antibiotic therapy (DOT) [ Time Frame: Up to 180 days post-randomisation ]
    Total days of therapy (DOT) per admission - the unit measure is defined as one day in which a patient is given a drug, regardless of dose per admission.

  12. Hospital antibiotics use as defined daily dose (DDD) per admission [ Time Frame: Up to 180 days post-randomisation ]
    Defined daily dose (DDD) per admission is the assumed average maintenance dose, in milligrams, per day for a drug used for its main indication.

  13. Microbiological safety as assessed by development of antibiotic resistance [ Time Frame: Up to 180 days post-randomisation ]
    Development of resistance, defined as clinical isolates resistant to antibiotics previously used in the febrile episode. Surveillance sampling will not be conducted.

  14. Health related quality of life as assessed by Functional Assessment of Cancer Therapy - General (FACT-G) [ Time Frame: Up to 180 days post-randomisation ]
    Physical, social, emotional and function well being of participants will be evaluated using the standardised 27-item questionnaire, "Functional Assessment of Cancer Therapy - General" (FACT-G).

  15. Health related quality of life as assessed by Functional Assessment of Cancer Therapy - Neutropenia (FACT-N) [ Time Frame: Up to 180 days post-randomisation ]
    Physical, social, emotional and function well being of participants will be evaluated using the Functional Assessment of Cancer Therapy - Neutropenia (FACT-N). It is a modified version of the Functional Assessment of Cancer Therapy - General (FACT-G) with the Neutropenia subscale, which is targeted for adult cancer patients with neutropenia.

  16. Financial Toxicity related to cancer and its treatment as assessed by Functional Assessment of Chronic Illness Therapy - COprehensive Score for financial Toxicity (FACIT-COST) [ Time Frame: Up to 180 days post-randomisation ]
    Financial toxicity is evaluated using the Functional Assessment of Chronic Illness Therapy - COprehensive Score for financial Toxicity (FACIT-COST). The COST is a patient-reported outcome measure that describes the financial distress experienced by cancer patients. The FACIT System screens for financial toxicity and to provide a global summary item for financial toxicity.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Asplenia
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05393505


Contacts
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Contact: Timothy Hudson Rainer, MBBCh; MRCP +852-93133096 thrainer@hku.hk

Locations
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Hong Kong
Queen Mary Hospital Recruiting
Hong Kong, Hong Kong
Contact: Timothy Hudson Rainer, MBBCh, MRCP    +852-93133096    thrainer@hku.hk   
Sponsors and Collaborators
The University of Hong Kong
Queen Mary Hospital, Hong Kong
Investigators
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Principal Investigator: Timothy Hudson Rainer, MBBCh; MRCP Department of Emergency Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Additional Information:
Publications:
Castagnola E, Mikulska M, Viscoli C. Prophylaxis and Empirical Therapy of Infection in Cancer Patients. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2015:3395-3413.e2. doi: 10.1016/B978-1-4557-4801-3.00310-6. Epub 2014 Oct 31. PMCID: PMC7173426.

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Responsible Party: The University of Hong Kong
ClinicalTrials.gov Identifier: NCT05393505    
Other Study ID Numbers: CTC2178HKU1
First Posted: May 26, 2022    Key Record Dates
Last Update Posted: December 6, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by The University of Hong Kong:
febrile neutropenia
emergency department
cancer
adult
sepsis
randomized controlled trial
antibiotic stewardship
clinical laboratory services
chemotherapy
hematopoietic stem cell transplantation
Additional relevant MeSH terms:
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Febrile Neutropenia
Fever
Body Temperature Changes
Neutropenia
Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Anti-Bacterial Agents
Amoxicillin
Levofloxacin
Ofloxacin
Meropenem
Clavulanic Acid
Clavulanic Acids
Amoxicillin-Potassium Clavulanate Combination
Anti-Infective Agents
Anti-Infective Agents, Urinary
Renal Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
beta-Lactamase Inhibitors