Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Children With Febrile Neutropenia

Study Overview
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Brief Summary
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Febrile neutropenia (FN) continues to be the infectious complication that most commonly requires hospitalization in pediatric cancer patients undergoing chemotherapy. In recent years, data have been published on the effectiveness of treatment of FN events with oral antibiotics, mainly in developed countries, but data from developing countries continue to be scarce. Our hypothesis was that early change from initial in-patient intravenous antibiotic treatment to oral outpatient antibiotic treatment in children with cancer and FN is as safe and effective as in-patient intravenous antibiotic management. The purpose of this clinical study was to determine whether early outpatient oral antibiotic treatment is not inferior in safety and efficacy to in-hospital intravenous antibiotic treatment in pediatric patients with cancer and low-risk FN events. A multicenter, non-inferiority randomized clinical trial was conducted in three public hospitals in Mexico City. Low-risk FN events were identified in children aged 1 to 18 years. After 48 to 72 hours of receiving intravenous in-hospital antibiotics, children were randomly allocated to receive outpatient oral treatment (cefixime) or to continue in-hospital intravenous treatment (cefepime). Daily monitoring was performed until the resolution of neutropenia. Our outcome of interest was the presence of any unfavorable clinical outcome.

Detailed Description
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Introduction: Febrile neutropenia (FN) continues to be the infectious complication that most commonly requires hospitalization in pediatric cancer patients undergoing chemotherapy. Classically these patients have been managed as inpatient. In recent years, data have been published on the effectiveness of treatment of FN events with oral antibiotics, mainly in developed countries, but data from developing countries continue to be scarce. Hypothesis: Our hypothesis was that early change from initial in-patient intravenous antibiotic treatment to oral outpatient antibiotic treatment in children with cancer and FN is as safe and effective as in-patient intravenous antibiotic management. Objectives: The purpose of this clinical study was to determine whether early outpatient oral antibiotic treatment is not inferior in safety and efficacy to in-hospital intravenous antibiotic treatment in pediatric patients with cancer and low-risk FN events. Methodology: A multicenter, non-inferiority randomized clinical trial was conducted in three public hospitals in Mexico City. Low-risk FN events were identified in children aged 1 to 18 years. A complete medical history, physical examination and review of laboratory tests and cultures were performed on all subjects with FN events who were considered low risk. According to local guidelines for the treatment of FN, all subjects began receiving cefepime at a dose of 150 mg/kg/day. Subjects were followed-up daily, and those who met the inclusion/exclusion criteria after 48 to 72 hours of in-hospital intravenous treatment with cefepime were randomly assigned to receive outpatient treatment with oral cefixime at a dose of 8 mg/kg/day or to continue in-hospital intravenous treatment. The treatment was administered by the researchers. Participants in both treatment groups were evaluated daily by a complete physical examination. Subjects in the outpatient group were evaluated at the outpatient clinic of the hospital. All patients underwent a blood count every 48 to 72 hours. FN event resolution was defined as when the patient remained afebrile and the absolute neutrophil count (ANC) increased to above 500 per microliter. If fever resumed, the antibiotic regimen was modified. If the subjects were in the outpatient group, they were re-admitted to the hospital to receive intravenous antibiotics. Resolution of the FN event was defined as the end of participation of the subjects in the study, and they were followed up for an additional 72 hours. The occurrence of any of the following conditions was considered an unfavorable clinical outcome: 1) therapeutic failure, defined as the resumption of fever in a patient with persistent neutropenia. For all patients with resumption of fever, the antibiotic regimen was switched, and if the patients were in the outpatient treatment group, they were re-admitted to the hospital; 2) new focus of infection, documented both by the clinical condition and by laboratory and other diagnostic tests; 3) hemodynamic instability, defined as a decrease in blood pressure below the 5th percentile for the patient age that did not revert with the administration of crystalloid solutions; and 4) death. Sample size: The sample size was calculated to reject a null hypothesis of inferiority, with a non-inferiority margin of presentation of unfavorable clinical outcomes of 15%. A formula including a statistical power of 80% and a one-tailed alpha value of 0.025 was used to calculate the sample size of 2 independent proportions. Based on previous reports of 10% of unfavorable clinical outcomes during the management of FN events, the calculation yielded a total of 63 FN events per group for a total of 126 events. Randomization: A random sequence balanced by blocks of 4 FN events was generated using a computer program. A physician who did not participate in the subject selection assigned subjects to receive either outpatient oral treatment at home or to continue in-hospital intravenous treatment. If the subjects lived more than 1 hour away from the hospital, they were assigned to a care home to ensure that they could return to the hospital in case of any event. Because the study intervention involved outpatient treatment, the study was open. All patients were provided with the antibiotic free of charge. Statistical analysis: The focus of analysis was intention-to-treat. For each comparison group, measures of central tendency and dispersion were estimated for continuous variables, and absolute and relative frequencies were determined for discrete and nominal variables. The statistical test performed to test the hypothesis of non-inferiority is very similar to the traditional test for comparison of proportions; the only difference is that the non-inferiority margin is added to the formula, and a p-value < 0.05 confirms non-inferiority. The statistical program STATA version 14.2 was used for the analysis.

Official Title
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Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Pediatric Patients With Cancer and Febrile Neutropenia: a Non-inferiority Multicenter Randomized Clinical Trial

Conditions
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Chemotherapy-Induced Febrile Neutropenia

Intervention / Treatment
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* Other: Outpatient oral treatment.
* Other: Inpatient intravenous treatment.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children from 1 to 18 years of age. Underlying cancer diagnosis that presented with fever and neutropenia secondary to chemotherapy and after 48-72 hours of inpatient intravenous treatment with Cefepime, were hemodynamically stable, remained afebrile for at least 24 hours, and did not have a documented source of infection. Participants whose caretaker knew how to read and write and accepted to be part of the clinical trial. Exclusion Criteria: Participants with positive cultures. Absolute neutrophil count (ANC) < 100/mm3. Thrombocytopenia < 30,000/mm3. Less than 7 days have passed from the start of the last chemotherapy session. Leukemia on remission induction therapy. Relapsed leukemia. Mucositis grade III or IV. Participants with allergy to cefixime. Need to receive any other medication intravenously. Need of oxygen support, parenteral nutrition or intravenous fluids. Oral intolerance.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multicenter, noninferiority randomized clinical trial was conducted in three public hospitals in Mexico City. A complete medical history, physical examination and review of laboratory tests and cultures were performed on all subjects with FN events who were considered low risk. All subjects began receiving intravenous inpatient treatment with cefepime. Subjects were followed-up daily, and those who met the inclusion/exclusion criteria after 48 to 72 hours of in-hospital intravenous treatment were randomly assigned to receive outpatient treatment with oral cefixime or to continue in-hospital intravenous treatment. The treatment was administered by the researchers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Outpatient oral antibiotic treatment group.<br>After randomization, participants assigned to receive outpatient treatment with oral cefixime at a dose of 8 mg/kg/day were discharged. Treatment was provided by the researchers. Subjects were evaluated daily at the outpatient clinic of the hospital. All patients underwent a blood count every 48 to 72 hours. FN event resolution was defined as when the patient remained afebrile and the ANC increased to above 500 per microliter. If fever resumed in the outpatient group, they were re-admitted to the hospital to receive intravenous antibiotics. Resolution of the FN event was defined as the end of participation of the subjects in the study, and they were followed up for an additional 72 hours. | Other: Outpatient oral treatment.<br>* Participants allocated in oral outpatient group were discharged home with oral antibiotic to continue management. Participants were given Cefixime oral suspension (100 mg/5 mL). Antibiotic was given to the caretakers with written instructions about dosage and time of administration. Dosage indicated was 8 mg/kg/day to be given orally as a single dose (max dose 400 mg/day). Oral antibiotic treatment was given until documented ANC > 500, failure to treatment (restart of fever) or when 14 days of antibiotic were completed (whichever occurred first).<br>|
| Active Comparator: Inpatient intravenous antibiotic treatment group.<br>After randomization, participants continued intravenous inpatient antibiotic with cefepime 150 mg/kg/day according to local standard of care guidelines. Subjects were evaluated daily. All patients underwent a blood count every 48 to 72 hours. FN event resolution was defined as when the patient remained afebrile and the ANC increased to above 500 per microliter. If fever resumed, treatment was changed according to clinical guidelines. Resolution of the FN event was defined as the end of participation of the subjects in the study, and they were followed up for an additional 72 hours. | Other: Inpatient intravenous treatment.<br>* Participants allocated in the intravenous inpatient group continued receiving Cefepime 150 mg/kg/day every 8 hours (max dose 2 grams per dose or 6 grams per day) according to local standard of care guidelines. Intravenous antibiotic treatment was given until documented ANC > 500, failure to treatment (restart of fever) or when 14 days of antibiotic were completed (whichever occurred first).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic failure as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic. | Occurrence of therapeutic failure, defined as the resumption of fever in a patient with persistent neutropenia. For all patients with resumption of fever, the antibiotic regimen was switched, and if the patients were in the outpatient treatment group, they were re-admitted to the hospital. | 17 days after randomization. | 
| New focus of infection as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic. | Presence of a new focus of infection, documented both by the clinical condition and by laboratory and other diagnostic tests. | 17 days after randomization. | 
| Hemodynamic instability as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic. | Presence of hemodynamic instability, defined as a decrease in blood pressure below the 5th percentile for the patient age that did not revert with the administration of crystalloid solutions. | 17 days after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presentation of any adverse reaction to any given antibiotic (oral or intravenous) of children with fever and neutropenia treated with oral outpatient vs intravenous inpatient management. | Moderate and severe adverse reaction to antibiotics given, described as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. | Started on the day of enrollment and concluded 17 days after. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fever and neutropenia, Febrile neutropenia, Cancer, Outpatient treatment, Children