SPOG 2015 FN Definition. A Multi-center Non-inferiority Trial on Safety of a High Versus Low Temperature Limit Defining Fever in Pediatric Patients With Cancer at Risk for Fever in Chemotherapy-induced Neutropenia

SPOG 2015 FN Definition. A Swiss Pediatric Oncology Group (SPOG) Initiated Multi-center Open-label Randomized Controlled Multiple Crossover Non-inferiority Trial on Safety of a High Versus Low Temperature Limit Defining Fever in Pediatric Patients With Cancer at Risk for Fever in Chemotherapy-induced Neutropenia (FN)

In a multi-center open-label cluster-randomized controlled parallel-group multiple crossover non-inferiority trial in children and adolescents up to 20 years diagnosed with cancer requiring chemotherapy, primarily the safety, and secondarily the efficacy and other endpoints, of a high (39.0°C) versus low (38.5°C) temperature limit defining fever (TLDF) for the diagnosis of fever in chemotherapy-induced neutropenia (FN) is studied. Safety is assessed by the rate of safety relevant events per chemotherapy exposure time, a composite endpoint including serious medical complications and bacteremia during FN. Patients are repeatedly randomized (cluster: study site) to the high or the low TLDF every month, resulting in possible multiple crossovers in one patient. The high TLDF is declared not to be inferior regarding safety compared to the low TLDF if non-inferiority of the rate ratio of safety relevant events is proven, with a single-sided non-inferiority margin of 1.33, applying mixed Poisson regression.

Study Overview

• Status: Completed
• Conditions: Cancer; Neutropenia; Fever; Pediatrics; Fever in Neutropenia
• Intervention / Treatment: Other: 39.0°C temperature limit defining fever; Other: 38.5°C temperature limit defining fever

• Study Type: Interventional
• Enrollment (Actual): 269
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, CH-4031
    • Basel: Universitätskinderklinik beider Basel
  • Bern, Switzerland, CH-3010
    • Bern: Universitätsklinik für Kinderheilkunde, Inselspital
  • Geneva, Switzerland, CH-1211
    • Geneva: Département de Pédiatrie, Hôpital Cantonal de Genève
  • Lausanne, Switzerland, CH-1011
    • Lausanne: Hémato-Oncologie Pédiatrique, CHUV
  • Lucerne, Switzerland, CH-6000
    • Luzern: Pädiatrische Hämatologie/Onkologie, Kinderspital
  • Zurich, Switzerland, CH-8032
    • Zürich: Pädiatrische Onkologie Kinderspital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chemotherapy treatment because of any malignancy for at least 2 months at time of recruitment for myelosuppressive therapy, or at least 1 cycle of myeloablative chemotherapy followed by autologous hematopoietic stem cell transplantation
• Age ≥12 months and <18 years at time of recruitment
• Written informed consent from patients and/or parents

Exclusion Criteria:

• Infants <1 years old (reason: differences in temperature measurement method)
• Past allogeneic hematopoietic stem cell transplantation
• Denied written informed consent from patients and/or parents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 39.0°C temperature limit defining fever; Temperature limit defining fever, for definition of fever in neutropenia (FN), is single temperature >=39.0°C measured in the ear by infrared tympanic thermometry. If clinically indicated, the treating physician is allowed to make the diagnosis of FN at lower temperatures.	Other: 39.0°C temperature limit defining fever; Diagnosis of FN, correspondingly hospitalization and start of empirical intravenous broad-spectrum antimicrobial therapy. Further treatment according to treating physician.
Other: 38.5°C temperature limit defining fever; Temperature limit defining fever, for definition of fever in neutropenia (FN), is single temperature >=38.5°C measured in the ear by infrared tympanic thermometry. If clinically indicated, the treating physician is allowed to make the diagnosis of FN at lower temperatures.	Other: 38.5°C temperature limit defining fever; Diagnosis of FN, correspondingly hospitalization and start of empirical intravenous broad-spectrum antimicrobial therapy. Further treatment according to treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of clinically defined FN with at least one safety relevant event	Poisson rate: number of clinically defined FN with at least one SRE divided by the entire chemotherapy exposure time for each patient, estimated to be 1 year on average (Unit: FN per year of chemotherapy exposure time) SRE: Composite endpoint (serious medical complication AND/OR bacteremia), reached until the end of each individual FN episode (Unit: binary)	1 year (estimated average)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Times and delays of diagnosis and therapy (A)	Times (hh:mm) of measurement of fever - telephone to study site - arrival at emergency department - prescription of antibiotics - start and end of first dose of i.v. antibiotics (assessed per FN episode by the responsible local PHO and in patient chart, reported per FN episode; unit: hours:minutes)	1 year (estimated average)
Adverse events (B)	AE: clinically / microbiologically documented infection, unexplained fever, sepsis / severe sepsis / septic shock, relapse of primary infection (assessed in patient charts, reported per FN; unit:binary)	1 year (estimated average)
Delay from crossing low to high TLDF (C)	Only for currently active high TLDF: delay time between crossing low and high TLDF; delayed FN diagnosis (see 5.1.4) by high vs. low TLDF (assessed from patients charts, reported per FN; unit: hours:minutes)	1 year (estimated average)
Rate of clinically defined FN (D)	Poisson rate: number of clinically defined FN divided by the entire chemotherapy exposure time for each patient, estimated to be 1 year on average (Unit: FN per year of chemotherapy exposure time)	1 year (estimated average)
Rate of FN diagnosed at/above TLDF (E)	Poisson rate: number of FN diagnosed at/above TLDF divided by the entire chemotherapy exposure time for each patient, estimated to be 1 year on average (Unit: FN per year of chemotherapy exposure time)	1 year (estimated average)
Rate of FN diagnosed below TLDF (E)	Poisson rate: number of FN diagnosed below TLDF divided by the entire chemotherapy exposure time for each patient, estimated to be 1 year on average (Unit: FN per year of chemotherapy exposure time)	1 year (estimated average)
Duration of treatment (F)	. Duration of hospitalization, ICU treatment, i.v. antibiotics, p.o. antibiotics, any antibiotics, delay of chemotherapy for FN (unit: days)	1 year (estimated average)
Simultaneous and avoided FN diagnoses (G)	Only for currently active high TLDF: Simultaneous and avoided FN diagnoses by high vs. low TLDF (assessed from patients charts, reported per FN; unit: binary)	1 year (estimated average)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of rules predicting risk of FN during chemotherapy	Risk prediction rules for clinically defined FN, clinically defined FN with bacteremia, with serious medical complication, and with safety relevant event during chemotherapy, all based on multivariate mixed Poisson regression (stepwise forward variable selection procedure; unit: predictor)	1 year (estimated average)
Development of rules predicting risk of adverse events during FN	Risk prediction rules for bacteremia, for serious medical complication, and for safety relevant event during FN, all based on multivariate mixed logistic regression (stepwise forward variable selection procedure; unit: predictor)	1 year (estimated average)
External validation of rules predicting risk of FN during chemotherapy	Validation of published risk prediction rules for clinically defined FN, clinically defined FN with bacteremia, with serious medical complication, and with safety relevant event during chemotherapy (units: sensitivity, specificity, positive and negative predictive value, area under receiver operating characteristic curve)	1 year (estimated average)
External validation of rules predicting risk of adverse events during FN	Validation of published risk prediction rules for bacteremia, for serious medical complication, and for safety relevant event during FN (units: sensitivity, specificity, positive and negative predictive value, area under receiver operating characteristic curve)	1 year (estimated average)

Collaborators and Investigators

• Sponsor: Swiss Pediatric Oncology Group
• Investigators: Study Chair: Roland A Ammann, MD, Universitätsklinik für Kinderheilkunde, Inselspital, Bern

Publications and helpful links

General Publications

• Ammann RA. A sequence of Swiss studies on the temperature Limit defining fever in pediatric oncology. Schweizer Krebsbulletin 35(1): 69-71, 2015.
• Lavieri L, Koenig C, Bodmer N, Agyeman PKA, Scheinemann K, Ansari M, Roessler J, Ammann RA. Predicting fever in neutropenia with safety-relevant events in children undergoing chemotherapy for cancer: The prospective multicenter SPOG 2015 FN Definition Study. Pediatr Blood Cancer. 2021 Dec;68(12):e29253. doi: 10.1002/pbc.29253. Epub 2021 Jul 26.
• Koenig C, Bodmer N, Agyeman PKA, Niggli F, Adam C, Ansari M, Eisenreich B, Keller N, Leibundgut K, Nadal D, Roessler J, Scheinemann K, Simon A, Teuffel O, von der Weid NX, Zeller M, Zimmermann K, Ammann RA. 39.0 degrees C versus 38.5 degrees C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial. Lancet Child Adolesc Health. 2020 Jul;4(7):495-502. doi: 10.1016/S2352-4642(20)30092-4. Epub 2020 Jun 1.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): September 15, 2018
• Study Completion (Actual): September 15, 2018

Study Registration Dates

• First Submitted: December 18, 2014
• First Submitted That Met QC Criteria: December 23, 2014
• First Posted (Estimate): December 24, 2014

Study Record Updates

• Last Update Posted (Actual): February 21, 2019
• Last Update Submitted That Met QC Criteria: February 19, 2019
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Neutropenia; Hyperthermia; Fever
• Other Study ID Numbers: SPOG 2015 FN Definition

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No