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

Chemotherapy-Induced Febrile Neutropenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04000711
• Other study ID #: HIM-2014-026
• Secondary ID: 233555
• Status: Completed
• Phase: N/A
• Start date: July 1, 2015
• Est. completion date: October 8, 2017

Study information

• Verified date: June 2019
• Source: Hospital Infantil de Mexico Federico Gomez
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 117
• Est. completion date: October 8, 2017
• Est. primary completion date: September 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chemotherapy-Induced Febrile Neutropenia
• Febrile Neutropenia
• Fever
• Neutropenia

Intervention

Other:
• Outpatient oral treatment.
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).
• Inpatient intravenous treatment.
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).

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Hospital Infantil de Mexico Federico Gomez	Hospital Juarez de Mexico, Instituto Nacional de Pediatria

References & Publications (8)

Avilés-Robles M, Ojha RP, González M, Ojeda-Diezbarroso K, Dorantes-Acosta E, Jackson BE, Johnson KM, Caniza MA. Bloodstream infections and inpatient length of stay among pediatric cancer patients with febrile neutropenia in Mexico City. Am J Infect Control. 2014 Nov;42(11):1235-7. doi: 10.1016/j.ajic.2014.07.021. Epub 2014 Sep 16. — View Citation

Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073. — View Citation

Hakim H, Flynn PM, Srivastava DK, Knapp KM, Li C, Okuma J, Gaur AH. Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr Infect Dis J. 2010 Jan;29(1):53-9. doi: 10.1097/INF.0b013e3181c3f6f0. — View Citation

Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, Hakim H, Santolaya M, Castagnola E, Davis BL, Dupuis LL, Gibson F, Groll AH, Gaur A, Gupta A, Kebudi R, Petrilli S, Steinbach WJ, Villarroel M, Zaoutis T, Sung L; International Pediatric Fever and Neutropenia Guideline Panel. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012 Dec 10;30(35):4427-38. doi: 10.1200/JCO.2012.42.7161. Epub 2012 Sep 17. — View Citation

Santolaya ME, Alvarez AM, Avilés CL, Becker A, Cofré J, Enríquez N, O'Ryan M, Payá E, Salgado C, Silva P, Tordecilla J, Varas M, Villarroel M, Viviani T, Zubieta M. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis. 2002 Sep 15;35(6):678-83. Epub 2002 Aug 23. — View Citation

Santolaya ME, Rabagliati R, Bidart T, Payá E, Guzmán AM, Morales R, Braun S, Bronfman L, Ferrés M, Flores C, García P, Letelier LM, Puga B, Salgado C, Thompson L, Tordecilla J, Zubieta M; Sociedad Chilena de Infectología; Sociedad Chilena de Hematología. [Consensus: Rational approach towards the patient with cancer, fever and neutropenia]. Rev Chilena Infectol. 2005;22 Suppl 2:S79-113. Epub 2005 Nov 4. Review. Spanish. — View Citation

Vidal L, Ben Dor I, Paul M, Eliakim-Raz N, Pokroy E, Soares-Weiser K, Leibovici L. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst Rev. 2013 Oct 9;(10):CD003992. doi: 10.1002/14651858.CD003992.pub3. Review. — View Citation

Zapata-Tarrés Marta, Klünder-Klünder Miguel, Cicero-Oneto Carlo, Rivera-Luna Roberto, Ortega-Ríos Velasco Fernando, Cortés Gallo Gabriel et al . Análisis de la atención de las complicaciones durante el tratamiento de niños con leucemia linfoblástica aguda. Bol. Med. Hosp. Infant. Mex.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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	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.