Clinical trial NCT00107081: Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting
Official title: A Prospective Multi-Center Study on Pediatric Patients With Fever in Severe Chemotherapy Induced Neutropenia, Including a Randomized Comparison of Outpatient Management and Oral Antimicrobial Therapy Versus Inpatient Management and Intravenous Antimicrobial Therapy in a Subgroup With Low Risk of Adverse Events (Low-Risk Subgroup Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Fever
Neutropenia
Cancer
Keywords: children
oral antibiotics
outpatient treatment
fever and neutropenia
Lead sponsor: Swiss Pediatric Oncology Group
Sponsor class: OTHER
Collaborators: name: Swiss Cancer League
name: Bayer
name: GlaxoSmithKline
First posted: 2005-04-05
Enrollment: 70
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether, in children with cancer presenting with fever in severe chemotherapy-induced neutropenia at low risk for medical complications, oral antibiotics in an outpatient setting after an initial phase of intravenous antibiotics and in-hospital observation for 8 to 22 hours, is not inferior as to safety and efficacy compared to continued intravenous antibiotics given in-hospital.

Detailed description: Details on antimicrobial therapy

* At presentation with FN (fever and neutropenia) and during an initial inpatient observation period of 8 to 22 hours, empirical intravenous broad-spectrum antibiotics are given. Type and dosage are chosen by the treating physician.
* Patients randomized to continued intravenous antibiotics continue with these antibiotics.
* Patients randomized to oral antibiotics receive a combination of oral ciprofloxacin (25 to 30 mg/kg/day, top dose 1500 mg/day) plus oral amoxicillin (65 to 80 mg/kg/day, top dose 2250 mg/day), both given in two doses per day.
* In both groups, the study gives guidelines (for certain situations) and rules (for other situations) when to change and when to stop antibiotics.

Details on clinical and laboratory controls

* During antibiotic therapy, patients are seen daily, either as inpatients or as outpatients according to randomization. Complete blood counts are performed at least every second day.
* After stopping antibiotic therapy and until resolution of severe neutropenia (if applicable), patients are seen every other day, with a complete blood count.
* Patients randomized to outpatient management have the possibility to contact at any time of the day (and night) a pediatric oncologist in case of problems, in order to discuss necessity for emergency control and/or rehospitalization.

Eligibility criteria: Inclusion Criteria:

* Chemotherapy because of malignancy
* Severe neutropenia (absolute neutrophil count ≤ 0.5x10E9/L)
* Fever (axillary temperature ≥ 38.5°C once or ≥ 38.0°C during ≥ 2 hours)
* Able to swallow oral medication
* Written informed consent from patients and/or parents

Exclusion Criteria:

* Status post myeloablative chemotherapy
* Diagnosis: acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or B-cell Non-Hodgkin lymphoma
* Bone marrow involvement by malignancy ≥ 25%
* Any comorbidity requiring hospitalization: \[1\] mean arterial blood pressure \< 50 mmHg (up to 10 years) / \< 60 mmHg (older than 10 years); \[2\] oxygen saturation \< 94% at room air; \[3\] radiologically defined pneumonia; \[4\] focal bacterial infection; \[5\] blood cultures taken at presentation reported positive at reassessment; \[6\] need for inpatient treatment or observation due to any other reason, as judged by the physician in charge
* Ever shaking chills
* Ever axillary temperature ≥ 39.5°C
* Antibacterial treatment before presentation with fever and neutropenia (except for prevention against Pneumocystis jiroveci \[formerly P. carinii\] pneumonia)
* Modification or de novo institution of a prophylaxis against P. jiroveci pneumonia
* Modification or de novo institution of a therapy with G-CSF or GM-CSF.
* Allergy to ciprofloxacin and/or amoxicillin
* Serum creatinine level above the upper limit of normal range

Primary outcomes:
measure: Safety: No serious medical complication due to infection (death, treatment in ICU [Intensive Care Unit], potentially life-threatening complication) (non-inferiority-design, limit 3.5%)
measure: Efficacy: Response without rehospitalization or changing randomized antibiotics (non-inferiority design, limit 10%)
Secondary outcomes:
measure: Improved prediction of low-risk episodes of fever and neutropenia
measure: Description of characteristics of low-risk episodes of fever and neutropenia
measure: Description of characteristics of high-risk episodes of fever and neutropenia (observational study part)
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Duesseldorf
country: Germany
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Freiburg
country: Germany
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Munich
country: Germany
facility: Pediatric Hematology/Oncology, University Children's Hospital von Hauner
city: Regensburg
country: Germany
facility: Pediatric Hematology/Oncology, University Hospital St. Hedwig
city: Groningen
country: Netherlands
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Basel
country: Switzerland
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Bern
country: Switzerland
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Geneva
country: Switzerland
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Lausanne
country: Switzerland
facility: Pediatric Hematology/Oncology, University Children's Hospital
city: Lucerne
country: Switzerland
facility: Pediatric Hematology/Oncology, Children's Hospital
city: Zurich
country: Switzerland
facility: Pediatric Hematology/Oncology, University Children's Hospital
Study officials:
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland
name: Roland A Ammann, MD
role: STUDY_CHAIR
affiliation: University Children's Hospital, Bern, Switzerland
name: Christoph Aebi, MD
role: STUDY_DIRECTOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Lausanne, Switzerland
name: Maja Beck-Popovic, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Groningen, The Netherlands
name: Eveline SJM de Bont, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Basel, Switzerland
name: Thomas Kuehne, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Children's Hospital, Zurich
name: David Nadal, MD
role: STUDY_DIRECTOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Zurich, Switzerland
name: Felix Niggli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Bonn, Germany
name: Arne Simon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Zurich, Switzerland
name: Nicole Bodmer, MD
role: STUDY_DIRECTOR
affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Geneva, Switzerland
name: Hulya Ozsahin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ammann RA. SPOG 2003 FN: Risikobeurteilung und risikoadaptierte Behandlung bei Kindern und Jugendlichen mit Fieber in Neutropenie. Paediatrica 16(1): 28-31, 2005.
citation: Ammann RA, Simon A, de Bont ES. Low risk episodes of fever and neutropenia in pediatric oncology: Is outpatient oral antibiotic therapy the new gold standard of care? Pediatr Blood Cancer. 2005 Sep;45(3):244-7. doi: 10.1002/pbc.20287. No abstract available.
citation: Ammann RA, Bodmer N, Hirt A, Niggli FK, Nadal D, Simon A, Ozsahin H, Kontny U, Kuhne T, Popovic MB, Luthy AR, Aebi C. Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin Oncol. 2010 Apr 20;28(12):2008-14. doi: 10.1200/JCO.2009.25.8988. Epub 2010 Mar 15.
citation: Brack E, Bodmer N, Simon A, Leibundgut K, Kuhne T, Niggli FK, Ammann RA. First-day step-down to oral outpatient treatment versus continued standard treatment in children with cancer and low-risk fever in neutropenia. A randomized controlled trial within the multicenter SPOG 2003 FN study. Pediatr Blood Cancer. 2012 Sep;59(3):423-30. doi: 10.1002/pbc.24076. Epub 2012 Jan 23.
citation: Luthi F, Leibundgut K, Niggli FK, Nadal D, Aebi C, Bodmer N, Ammann RA. Serious medical complications in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study. Pediatr Blood Cancer. 2012 Jul 15;59(1):90-5. doi: 10.1002/pbc.23277. Epub 2011 Aug 11.
citation: Agyeman P, Aebi C, Hirt A, Niggli FK, Nadal D, Simon A, Ozsahin H, Kontny U, Kuhne T, Beck Popovic M, Leibundgut K, Bodmer N, Ammann RA. Predicting bacteremia in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study. Pediatr Infect Dis J. 2011 Jul;30(7):e114-9. doi: 10.1097/INF.0b013e318215a290.
citation: Ammann RA, Niggli FK, Leibundgut K, Teuffel O, Bodmer N. Exploring the association of hemoglobin level and adverse events in children with cancer presenting with fever in neutropenia. PLoS One. 2014 Jul 14;9(7):e101696. doi: 10.1371/journal.pone.0101696. eCollection 2014.
citation: Agyeman P, Kontny U, Nadal D, Leibundgut K, Niggli F, Simon A, Kronenberg A, Frei R, Escobar H, Kuhne T, Beck-Popovic M, Bodmer N, Ammann RA. A prospective multicenter study of microbiologically defined infections in pediatric cancer patients with fever and neutropenia: Swiss Pediatric Oncology Group 2003 fever and neutropenia study. Pediatr Infect Dis J. 2014 Sep;33(9):e219-25. doi: 10.1097/INF.0000000000000326.
citation: Ammann RA, Bodmer N, Simon A, Agyeman P, Leibundgut K, Schlapbach LJ, Niggli FK. Serum Concentrations of Mannan-Binding Lectin (MBL) and MBL-Associated Serine Protease-2 and the Risk of Adverse Events in Pediatric Patients With Cancer and Fever in Neutropenia. J Pediatric Infect Dis Soc. 2013 Jun;2(2):155-61. doi: 10.1093/jpids/pit005. Epub 2013 Feb 13.