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)
Phase: NA
Conditions: Cancer, Pediatrics, Fever, Neutropenia, Fever in Neutropenia
Sponsor: Swiss Pediatric Oncology Group

__________________________________________________________________________________ 
__________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 1 of 37 
 
SPOG 2015 FN Definition 
 
A Swiss Paediatric 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) 
 
 
Study Committee 
Roland A. Ammann, MD 
roland.ammann@insel.ch 
Ped. Oncology, Chair 
Nicole Bodmer, MD 
nicole.bodmer@kispi.uzh.ch 
Ped. Oncology, Vice Chair 
Cécile Adam, MD 
cecile.adam@chuv.ch  
Ped. Oncology 
Philipp Agyeman, MD 
philipp.agyeman@insel.ch 
Ped. Infectiology 
Marc Ansari, MD 
marc.ansari@hcuge.ch  
Ped. Oncology 
Nannette Keller, MSc 
nanette.keller@gmx.ch  
Parent 
Kurt Leibundgut, MD 
kurt.leibundgut@insel.ch 
Ped. Oncology 
David Nadal, MD 
david.nadal@kispi.uzh.ch 
Ped. Infectiology 
Felix Niggli, MD 
felix.niggli@kispi.uzh.ch 
Ped. Oncology 
Martina Peluso, MSc 
Martina.Peluso@spog.ch 
Regulatory Affairs 
Johannes Rischewski, MD 
johannes.rischewski@luks.ch 
Ped. Oncology 
Katrin Scheinemann, MD 
katrin.scheinemann@ukbb.ch 
Ped. Oncology 
Arne Simon, MD 
arne.simon@uks.eu 
 
Ped. Oncology & Infectiology 
Oliver Teuffel, MD MSc 
oteuffel@mail.de 
 
Ped. Oncology 
Nicolas von der Weid, MD 
Nicolas.VonderWeid@ukbb.ch 
Ped. Oncology 
Karin Zimmermann, MSc 
karin.zimmermann@unibas.ch 
Ped. Nurse 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 3 of 37 
 
 
Table of Contents 
STUDY SYNOPSIS............................................................................................................................................... 6 
STUDY SUMMARY IN LOCAL LANGUAGE ................................................................................................ 9 
ABBREVIATIONS ............................................................................................................................................. 10 
1. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................................... 11 
1.1 
Sponsor ....................................................................................................................................................... 11 
1.2 
Study Chair ................................................................................................................................................. 11 
1.3 
Study Committee ........................................................................................................................................ 11 
1.4 
Study Statistician ........................................................................................................................................ 11 
1.5 
Study chair site, study center ...................................................................................................................... 11 
1.6 
Principal Investigators ................................................................................................................................ 11 
2. 
ETHICAL AND REGULATORY ASPECTS .......................................................................................... 12 
2.1 
Study registration ........................................................................................................................................ 12 
2.2 
Categorisation of study ............................................................................................................................... 12 
2.3 
Competent Ethics Committee (CEC) .......................................................................................................... 12 
2.4 
Ethical conduct of the study ........................................................................................................................ 12 
2.5 
Declaration of interest ................................................................................................................................. 12 
2.6 
Patient and parent/legal representative information, and informed consent ............................................... 12 
2.7 
Patient privacy and confidentiality ............................................................................................................. 13 
2.8 
Early termination of the study..................................................................................................................... 13 
2.9 
Protocol amendments .................................................................................................................................. 13 
3. 
BACKGROUND AND RATIONALE ....................................................................................................... 13 
3.1 
Background and rationale ........................................................................................................................... 13 
3.1.1 
Fever in neutropenia in pediatric patients with cancer ....................................................................... 13 
3.1.2 
TLDFs currently used to define FN ................................................................................................... 14 
3.1.3 
ANC limits defining neutropenia for FN ........................................................................................... 15 
3.1.4 
Methods to measure temperature in pediatric oncology .................................................................... 15 
3.1.5 
The impact of different TLDFs in FN: safety versus efficacy ........................................................... 15 
3.2 
Clinical evidence to date ............................................................................................................................. 15 
3.2.1 
Literature search ................................................................................................................................ 15 
3.2.2 
Retrospective study in Bern and Zurich, 2004-2011 ......................................................................... 16 
3.2.3 
Pediatric FN Definition 2012 Bern .................................................................................................... 16 
3.2.4 
Summary ............................................................................................................................................ 17 
3.3 
Explanation for choice of TLDFs to be compared ...................................................................................... 17 
3.4 
Risks and benefits ....................................................................................................................................... 17 
3.5 
Justification of choice of study population ................................................................................................. 18 
4. 
STUDY OBJECTIVES ............................................................................................................................... 18 
4.1 
Overall objective ......................................................................................................................................... 18 
4.2 
Primary objective ........................................................................................................................................ 18 
4.3 
Secondary objective .................................................................................................................................... 18 
4.4 
Tertiary objective ........................................................................................................................................ 18 
5. 
DEFINITIONS AND STUDY OUTCOMES ............................................................................................ 18 
5.1 
Definitions .................................................................................................................................................. 18 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 4 of 37 
5.1.1 
Temperature measurement method and device, fever, and TLDFs ................................................... 18 
5.1.2 
Severe chemotherapy-induced neutropenia ....................................................................................... 19 
5.1.3 
Types of clinically defined FN episodes ............................................................................................ 19 
5.1.4 
Types of FN episodes comparing high versus low TLDF ................................................................. 19 
5.1.5 
Duration of FN episodes .................................................................................................................... 19 
5.1.6 
Chemotherapy intensity ..................................................................................................................... 20 
5.1.7 
Chemotherapy exposure time ............................................................................................................ 20 
5.1.8 
Safety-relevant event ......................................................................................................................... 20 
5.2 
Primary outcome and its assessment ........................................................................................................... 20 
5.3 
Secondary outcomes and their assessment .................................................................................................. 21 
6. 
STUDY DESIGN ......................................................................................................................................... 21 
6.1 
General study design and justification of design ........................................................................................ 21 
6.2 
Methods of minimizing bias ....................................................................................................................... 21 
6.2.1 
Randomisation ................................................................................................................................... 21 
6.2.2 
Blinding procedures ........................................................................................................................... 21 
6.2.3 
Other methods of minimizing bias ..................................................................................................... 21 
7. 
STUDY POPULATION ............................................................................................................................. 22 
7.1 
Requirements for study sites ....................................................................................................................... 22 
7.2 
Eligibility criteria for patients ..................................................................................................................... 22 
7.3 
Screening and recruitment .......................................................................................................................... 22 
7.4 
Assignment to study groups ........................................................................................................................ 22 
7.5 
Criteria for withdrawal / discontinuation of patients .................................................................................. 22 
8. 
INTERVENTION ....................................................................................................................................... 23 
8.1 
Intervention: temperature limit defining fever ............................................................................................ 23 
8.2 
Compliance with study intervention ........................................................................................................... 23 
8.3 
Data Collection and Follow-up for withdrawn participants ........................................................................ 23 
9. 
STUDY PROCEDURES AND ASSESSMENTS ..................................................................................... 23 
9.1 
Assessment of eligibility ............................................................................................................................. 23 
9.2 
Mandatory clinical procedures throughout the study .................................................................................. 23 
9.2.1 
Mandatory procedures by patients and/or parents throughout the study ............................................ 23 
9.2.2 
Mandatory procedures by the responsible local PHO in case of reported fever ................................ 24 
9.2.3 
Mandatory procedures at diagnosis of FN ......................................................................................... 24 
9.3 
Assessments of outcomes ........................................................................................................................... 24 
10. SAFETY ....................................................................................................................................................... 25 
10.1 
Definition of serious adverse events ........................................................................................................... 25 
10.2 
Reporting of SAE ....................................................................................................................................... 25 
10.3 Annual Safety Report ..................................................................................................................................... 25 
10.3 
Further safety issues.................................................................................................................................... 26 
11. STATISTICAL METHODS ...................................................................................................................... 26 
11.1 
Hypothesis for the primary objective / primary outcome ........................................................................... 26 
11.2 
Determination of sample size and study duration ....................................................................................... 26 
11.3 
Statistical criteria of termination of trial ..................................................................................................... 27 
11.4 
Planned statistical analyses ......................................................................................................................... 27 
11.4.1 General strategy of analysis, and datasets to be analysed .................................................................. 27 
11.4.2 Primary objective safety: Main analysis ............................................................................................ 27 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 5 of 37 
11.4.3 Primary objective safety: Further analyses ........................................................................................ 28 
11.4.4 Secondary objective efficacy: Main analysis ..................................................................................... 28 
11.4.5 Secondary objective efficacy: Further analyses ................................................................................. 28 
11.4.6 Tertiary objective, risk prediction rules ............................................................................................. 28 
11.4.7 Interim analyses for the primary outcome ......................................................................................... 28 
11.4.8 Safety analysis ................................................................................................................................... 29 
11.4.9 Deviations from the original statistical plan ...................................................................................... 29 
11.5 
Handling of missing data and drop-outs ..................................................................................................... 29 
12. QUALITY ASSURANCE AND CONTROL ............................................................................................ 29 
12.1 
Data handling and record keeping / archiving ............................................................................................ 29 
12.1.1 Case Report Forms ............................................................................................................................ 29 
12.1.2 Specification of source documents .................................................................................................... 29 
12.1.3 Record keeping / archiving ................................................................................................................ 29 
12.2 
Data management ....................................................................................................................................... 29 
12.2.1 Data Management System ................................................................................................................. 29 
12.2.2 Data security, access and back-up ..................................................................................................... 30 
12.2.3 Analysis and archiving ....................................................................................................................... 30 
12.2.4 Electronic and central data verification ............................................................................................. 30 
12.3 
Monitoring .................................................................................................................................................. 30 
12.4 
Audits and Inspections ................................................................................................................................ 30 
12.5 
Confidentiality, Data Protection ................................................................................................................. 30 
13. PUBLICATION AND DISSEMINATION POLICY ............................................................................... 30 
14. FUNDING AND SUPPORT ....................................................................................................................... 31 
15. INSURANCE ............................................................................................................................................... 31 
16. REFERENCES ............................................................................................................................................ 32 
17. APPENDICES ............................................................................................................................................. 35 
 
 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 6 of 37 
STUDY SYNOPSIS  
Sponsor 
Swiss Paediatric Oncology Group (SPOG) 
Study Title: 
A Swiss Paediatric 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) 
Short Title / Study ID: 
SPOG 2015 FN Definition 
Protocol Version and 
Date: 
Version 1.1, November 23, 2016   
Trial registration: 
www.clinicaltrials.gov: NCT02324231, registered Dec 23, 2014 
www.kofam.ch: SNCTP000001776, registered Dec 18, 2014 
Study category and 
Rationale 
Clinical trial (randomly assigned intervention) without investigational 
medicinal product (IMP), without medical device (MD), risk category B 
(more than minimal risk) according to ClinO art. 61. 
Clinical Phase: 
Not applicable (no IMP, no MD) 
Background and 
Rationale: 
Fever in neutropenia (FN), if due to infection, is the most frequent 
potentially lethal complication of chemotherapy for cancer in children and 
adolescents. Emergency hospitalization and empirical treatment with i.v. 
broad-spectrum antibiotics have reduced lethality from >50% in certain 
high risk situations to <1%, at the price of high morbidity and use of 
resources.  
Despite the high economic and personal impact of FN diagnosis, there is a 
vast heterogeneity regarding the temperature limit defining fever (TLDF), 
used for FN. This reflects the scarce evidence for rationally choosing a 
TLDF. In a Swiss single-center study, a high versus low TLDF (39.0°C 
versus 38.5°C measured in the ear) had relevantly reduced the rate of FN 
diagnoses, and thus hospitalizations and intravenous antimicrobial 
therapies, by 21%. The study was too small to reliably assess safety. 
This study primarily aims to assess the safety of a high versus low TLDF.  
Objective(s): 
Primary objective: to determine if a high TLDF (39.0°C) is non-inferior to 
a low TLDF (38.5°C) regarding safety. 
Secondary objective: to determine if a high TLDF is superior to a low 
TLDF regarding efficacy. 
Tertiary objective: to use the data for development of risk prediction rules, 
and for external validation of published risk prediction rules. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 7 of 37 
Outcome(s): 
Primary outcome: Poisson rate of clinically defined FN (FNClin) with ≥1 
safety relevant event (SRE; composite outcome: bacteremia and/or serious 
medical complication) per chemotherapy exposure time (CET).  
Secondary safety-related outcomes: 
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  
B. Adverse events: clinically / microbiologically documented infection,  
     unexplained fever, sepsis / severe sepsis / septic shock, relapse of  
     primary infection  
C. Only for currently active high TLDF: delay time between crossing low  
     and high TLDF; delayed FN diagnosis by high vs. low TLDF 
Secondary efficacy-related outcomes: 
D. Poisson rate of FNClin per CET 
E. Poisson rate of FNTLDF and FNBelow per CET (see 5.1.3) 
F. Duration (days) of hospitalization, intensive care unit (ICU) treatment,  
    i.v. antibiotics, p.o. antibiotics, any antibiotics, delay of chemotherapy  
    for FN  
G. Only for currently active high TLDF: simultaneous and avoided FN 
     diagnosis (see 5.1.4) by applying high vs. low TLDF  
Primary analysis 
Mixed Poisson regression of the rate ratio of the primary outcome of high 
versus low TLDF, with chemotherapy exposure time as rate multiplier, and 
random intercepts per patient nested within study site, in the per protocol 
set. If the upper (one-sided) 95% confidence border of this rate ratio is 
below the non-inferiority margin, i.e., <1.33, non-inferiority of the high 
versus low TLDF regarding safety will be claimed. 
Study design: 
Open-label cluster-randomized controlled parallel-group multiple-
crossover non-inferiority trial, with study sites as units of randomization, 
and patients as units of analysis. 
Inclusion / Exclusion 
criteria: 
Inclusion criteria 
- Chemotherapy treatment because of any malignancy expected to last ≥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 <12 months (reason: difference in temperature measurement 
    method) 
- Past allogeneic hematopoietic stem cell transplantation 
- Denied written informed consent from patients and/or parents 
Reason for inclusion of children/adolescents (vulnerable participants): 
important differences in core FN characteristics between 
children/adolescents and adults 
Measurements and 
procedures: 
Outcomes are determined using clinically available information (patient 
charts, results of laboratory tests performed for clinical reasons). 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 8 of 37 
Intervention:  
Randomization, repeated every month (implying potentially repeated cross-
over) assigns patients, via study sites, for periods of 1 month each, to  
- high (39.0°C) TLDF arm, for definition of FN 
- low (38.5°C) TLDF arm, for definition of FN 
Temperatures are measured in the ear by infrared tympanic thermometry 
throughout the study. If clinically indicated, the responsible pediatric 
hemato-oncologist of the study site (local PHO) is allowed to make the 
diagnosis of FN at lower temperatures in both arms.  
Diagnosis of FN implies emergency hospitalization, essential laboratory 
tests and start of empirical intravenous broad-spectrum antimicrobial 
therapy. The responsible local PHO decides on the antimicrobial substance 
used (which is thus not an IMP here), and on all further diagnostic and 
therapeutic measures.  
Number of Participants 
with Rationale: 
Around 400 patients, the majority will be assigned at least once to each of 
both arms (multiple crossover).  
Sample size calculations and thus decisions when to perform interim and 
final analyses refer to FNClin episodes with SRE. Based on 1000-fold 
random simulation studies, 132 FNClin with SRE are needed to reach 80% 
power to detect non-inferiority of the rate ratio of FNClin with SRE of high 
versus low TLDF, assuming a rate ratio of 1.05, at alpha = 0.05 and with a 
non-inferiority limit of 1.33, after accounting for up to 3 interim analyses. 
These 132 FNClin with SRE correspond to 550 FN, to 372 years of 
cumulative chemotherapy exposure time, and to around 400 patients. 
Study Duration: 
3.7 years  
Study Schedule: 
First patient in (planned): March 2016 
Last patient out (planned): October 2019 
Investigator(s): 
Chair of Study Committee, and Principal Investigator: 
Prof. Dr. med. Roland Ammann, Pediatric Hematology/Oncology, 
Department of Pediatrics, University of Bern, Inselspital, CH-3010 Bern, 
Switzerland.  
phone +41 31 632 21 11; fax +41 31 632 95 07; roland.ammann@insel.ch 
Vice-Chair of Study Committee: 
Dr. med. Nicole Bodmer, Pediatric Oncology, University Children’s 
Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland.  
phone +41 44 266 71 11; fax +41 44 266 79 14; 
nicole.bodmer@kispi.uzh.ch 
See Appendix A for the list of Local Principal Investigators.  
Study Sites: 
Multi-center, all SPOG member institutions 
Statistical 
Considerations: 
Up to 3 interim plus 1 final analysis (Power family of one-sided group 
sequential tests, delta=0), adjustments for past analyses to maintain an 
overall alpha of 0.05. 
Legal Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki and all national legal and regulatory 
requirements.  
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 9 of 37 
STUDY SUMMARY IN LOCAL LANGUAGE  
SPOG 2015 FN Definition  
Eine Studie der Schweizerischen Pädiatrischen Onkologie Gruppe (SPOG) über die Sicherheit einer 
hohen versus tiefen Fiebergrenze bei Kindern und Jugendlichen mit einer Krebserkrankung mit dem 
Risiko von Fieber während eines durch Chemotherapie verursachten Mangels an weissen Abwehr-
Blutkörperchen (Neutropenie). 
Die häufigste potentiell tödliche Nebenwirkung der Chemotherapie bei Krebserkrankungen ist Fieber 
in Neutropenie (FN), d.h. Fieber während eines vorübergehenden Mangels an weissen Abwehr-
Blutkörperchen. Die Mehrheit der Kinder und Jugendlichen mit einer Krebserkrankung hat während 
der Chemotherapie mindestens einmal FN. Dank der Standardbehandlung mit Notfallhospitalisation 
und sofortigem Start von intravenösen Breitbandantibiotika sterben heute <1% der Kinder mit FN. 
Jedoch werden bakterielle Infektionen nur bei circa ¼ der FN nachgewiesen. Entsprechend werden 
circa ¾ aller FN übertherapiert, mit an sich unnötigen Hospitalisationen, Antibiotikatherapien, und 
hohen Kosten. Ein Ansatz zur Reduktion dieser Übertherapie ist, bei niedrigem Komplikationsrisiko 
die Diagnose FN gar nicht erst zu stellen, beispielsweise durch Erhöhung der Fiebergrenze zur 
Definition von FN. Diese Grenze wird aktuell in der Kinderonkologie sehr uneinheitlich gehandhabt 
und variiert zwischen 37.5°C und 39.0°C. 
Es ist bekannt, dass eine höhere Fiebergrenze die Anzahl der FN Diagnosen reduziert. Es ist jedoch 
nicht bekannt, ob diese Grenze auch sicher ist, d.h., ob kein höheres Komplikationsrisiko wegen 
verspätetem Therapiebeginn besteht. 
In dieser Studie wird deshalb untersucht, ob eine höhere Fiebergrenze (Ohrtemperatur 39.0°C) 
bezüglich Sicherheit nicht schlechter ist als eine tiefere Grenze (38.5°C). Die Studie ist eine 
sogenannte randomisierte kontrollierte Studie, bei der die für die Patienten gültige Fiebergrenze 
monatlich zufällig (randomisiert) gewechselt wird, um den Vergleich möglichst aussagekräftig zu 
machen. Die Studie wird an mehreren Zentren durchgeführt, die alle Mitglieder der Schweizerischen 
Pädiatrischen Onkologie Gruppe sind. Die vorgesehene Studiendauer beträgt rund 4 Jahre, und es 
werden circa 400 Kinder und Jugendliche mit Krebserkrankung an der Studie teilnehmen. 
Falls die Sicherheit der höheren Fiebergrenze nachgewiesen wird, können Zentren mit aktuell tieferer 
Fiebergrenze auf diese höhere Fiebergrenze wechseln, was zu einer Reduktion der Übertherapie von 
FN führen wird. Falls die Sicherheit nicht nachgewiesen werden kann, sollten Zentren mit aktuell 
höherer Fiebergrenze auf die tiefere Fiebergrenze wechseln, was die Behandlungssicherheit erhöhen 
wird. 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 10 of 37 
ABBREVIATIONS 
AE 
Adverse Event  
AE 
Absolute Neutrophil Count 
AML 
Acute Myeloid Leukemia 
CBC 
Complete Blood Count 
CEC 
Competent Ethics Committee 
CET 
Chemotherapy Exposure Time 
CI 
Confidence Interval 
CRF 
Case Report Form  
CVAD 
Central Venous Access Device 
FN 
Fever in Neutropenia 
FNBelow 
FNClin diagnosed below the currently active TLDF 
FNClin 
Clinically defined FN episode 
FNTLDF 
FNClin diagnosed at/above the currently active TLDF 
ICU 
Intensive Care Unit 
IMP 
Investigational Medicinal Product 
ITT 
Intention To Treat 
MD 
Medical Device 
MDI 
Microbiologically Documented Infection 
PHO 
Pediatric Hemato-Oncologist  
PI 
Principal Investigator 
PP 
Per Protocol  
SAE 
Serious Adverse Event 
SMC 
Serious Medical Complication 
SOP 
Standard Operating Procedure 
SPOG 
Swiss Pediatric Oncology Group 
SRE 
Safety Relevant Event 
TLDF 
Temperature Limit Defining Fever 
UCB 
Upper Confidence Bound 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 11 of 37 
1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 
Sponsor 
The Sponsor of this study is the Swiss Paediatric Oncology Group. 
The central office of the Sponsor is located at: 
 
SPOG Office, Effingerstrasse 33, CH-3008 Bern, Switzerland 
 
E-mail: info@spog.ch 
 
Phone: +41 31 389 91 89 
 
Fax: +41 31 508 41 42 
The SPOG Office is responsible for regulatory affairs and monitoring of the study for all participating 
study sites.  
1.2 
Study Chair 
The Sponsor delegates certain responsibilities to the Study Chair who will perform the delegated 
Sponsor’s tasks and responsibilities according to the Swiss Human Research Act of 30 September 
2011 (HRA) in connection with the Swiss Ordinance about Clinical Trials in Human Research of 20 
September 2013 (ClinO).  
The Study Chair constitutes the study committee and is responsible for all its activities including 
development of the study protocol, CRF design, writing patient information and informed consent 
documents, interim analysis and interpretation of data and writing of the final study report. The 
members of the study committee will sign a confidentiality agreement regarding patient data (see 2.7) 
and other confidential aspects of the study.  
1.3 
Study Committee  
See page 1 for the list of Study Committee members. 
The Study Committee can be contacted via: 
Study Chair: Prof Dr med Roland A Ammann; Pediatric Hematology/Oncology; Department of 
Pediatrics; University of Bern; Inselspital; CH-3010 Bern; Switzerland;  
phone +41 31 632 21 11; fax +41 31 632 95 07; roland.ammann@insel.ch 
Study Vice Chair: Dr med Nicole Bodmer; Pediatric Oncology, University Children’s Hospital, 
Steinwiesstrasse 75; CH-8032 Zürich; Switzerland;  
phone +41 44 266 71 11; fax +41 44 266 79 14; nicole.bodmer@kispi.uzh.ch 
1.4 
Study Statistician 
The Study Chair, Prof Dr med R. Ammann, who holds a Diploma of Advanced Studies in Applied 
Statistics, performs as well the duties of the Study Statistician (see 1.2). 
1.5 
Study chair site, study center 
The Study Chair site, in the following called the study center is responsible for the central data 
collection and management of all study data collected from all participating sites (see 12.1 and 12.2). 
The study center can be contacted via: 
Study Chair: Prof Dr med Roland A Ammann; Pediatric Hematology/Oncology; Department of 
Pediatrics; University of Bern; Inselspital; CH-3010 Bern; Switzerland;  
phone +41 31 632 21 11; fax +41 31 632 95 07; roland.ammann@insel.ch 
1.6 
Principal Investigators  
See Appendix A.  

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 12 of 37 
2. ETHICAL AND REGULATORY ASPECTS  
2.1 
Study registration  
The study is registered in www.clinicaltrials.gov (NCT02324231) and in the Swiss National Clinical 
Trial Portal (SNCTP, www.kofam.ch, SNCTP000001776). 
2.2 
Categorisation of study  
Clinical trial (randomly assigned intervention) without investigational medicinal product (IMP), 
without medical device (MD)), risk category B (more than minimal risk) according to ClinO art. 61 
[1,2].  
2.3 
Competent Ethics Committee (CEC)  
The study protocol will be submitted to the lead CEC and all involved local CECs according to the 
swissethics concept for multicenter studies. The responsible investigator at each site ensures that 
approval from the CEC is available before starting with the enrollment of patients. No changes are 
made to the protocol without prior approval by Sponsor and CEC, except where necessary to eliminate 
apparent immediate hazards to study participants. 
Premature study end or interruption of the whole study is reported within 15 days. The regular end of 
the study is reported to the CEC within 90 days, the final study report shall be submitted within one 
year after study end. Amendments are reported according to chapter 2.9. 
2.4 
Ethical conduct of the study  
The study will be carried out in accordance to the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki [3] and the Swiss Law [1,2]. The CEC will receive 
annual safety reports and will be informed about study stop/end in agreement with legal requirements.  
2.5 
Declaration of interest  
There is no conflict of interest for the Sponsor and for all members of the Study Committee. 
2.6 
Patient and parent/legal representative information, and informed consent 
The investigators will explain to each patient and/or the parents/legal representative the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and 
any discomfort it may entail. Each patient and/or the parents/legal representative will be informed that 
the participation in the study is voluntary and that he/she may withdraw from the study at any time and 
that withdrawal of consent will not affect the subsequent medical assistance and treatment. The patient 
and/or parents/legal representative are informed that the medical records may be examined by 
authorised individuals other than their treating physician. All patients and/or the parents/legal 
representative will be provided a patient information sheet and/or a parent information sheet and a 
consent form describing the study and providing sufficient information for the patient and/or the 
parents to make an informed decision about study participation. A sufficient time frame of at least two 
days will be given to make this decision.  
The patient information sheet, the parent information sheet and the consent form will be submitted to 
the CEC to be reviewed and approved. The formal consent of a patient and/or parents/legal 
representative, using the approved consent form, must be obtained before the patient is submitted to 
any study procedure.   
If a minor and/or patient under tutelage is capable of judgment, his/her assent is collected (required 
from the age of 14 years) in addition to the consent of the parents/legal representative on the informed 
consent form. If a patient incapable of judgment displays signs and symptoms showing that he/she is 
unwilling to participate in the study, he/she is excluded from participation. 
The patient and/or the parents/legal representative should read and consider the statement before 
signing and dating the informed consent form, and should be given a copy of the signed document. 
The consent form must also be signed and dated by the investigator (or his designee) and it will be 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 13 of 37 
retained as part of the study records. 
2.7 
Patient privacy and confidentiality  
The investigator affirms and upholds the principle of the patients’ right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the patients shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilizing 
subject identification code numbers to correspond to treatment data in the computer files. 
For quality assurance or quality control purposes, authorised representatives of the sponsor, or the 
CEC may require direct access to study documentation and medical records relevant to the study, 
including patients’ medical history. 
2.8 
Early termination of the study  
Upon recommendation of the study committee the Sponsor may terminate the study prematurely in 
case of certain circumstances, e.g., ethical concerns, insufficient participant recruitment, when the 
safety of the participants is doubtful or at risk, respectively, alterations in accepted clinical practice 
that make the continuation of the study unwise, or early evidence of benefit or harm (see 11.3, 11.4.4).  
2.9 
Protocol amendments 
The Study Committee may amend the protocol. Substantial amendments are only implemented after 
approval by the Sponsor and the CEC. All non-substantial amendments are communicated to the CEC 
within the Annual Safety Report.  
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the Sponsor and the CEC. Such 
deviations shall be documented and reported to the Sponsor and the CEC as soon as possible. 
3. BACKGROUND AND RATIONALE  
3.1 
Background and rationale  
3.1.1 
Fever in neutropenia in pediatric patients with cancer 
Fever in neutropenia (FN), if due to infection, is the most frequent potentially lethal complication of 
chemotherapy in pediatric and adult patients with cancer. The specific rate of FN in pediatric 
oncology strongly depends on the myelosuppressive intensity of chemotherapy. This rate varies from 
<0.1 to 0.8 FN episodes per month of chemotherapy in Switzerland. At least one episode of FN is 
diagnosed in more than half of pediatric patients with chemotherapy [4]. Standard treatment of FN 
includes emergency hospitalization and the empirical (before detection of a bacterial infection) start 
of broad-spectrum i.v. antibiotics [5-7]. This has decreased lethality to below 1% in pediatric FN [8,9].  
It is known, however, that a microbiologically documented infection (MDI), including bacteremia, is 
detected in only about a quarter of FN episodes, and any adverse event (AE) occurs in less than half 
of them [6]. The proportion of FN with MDI is increased to more than 50% if polymerase chain 
reaction-based methods for the detection of viral, bacterial and fungal infections are added to 
conventional diagnostics. The clinical implications of such results are not yet known, and these 
methods are not used routinely [7,10,11].  
The majority of patients with FN is thus most likely overtreated, implying hospitalization and further 
inconveniences for the patient, plus costs and the risk that resistances against antibiotics develop [12]. 
Risk stratification and risk-adapted treatment in order to minimize such overtreatment are established 
in adult oncology [13,14]. In pediatric oncology, the feasibility, cost-effectiveness, efficacy, and 
recently as well safety of stepping down from inpatient intravenous antibiotics to outpatient oral 
antibiotics in low-risk FN have been proven [7,15-18]. A range of different clinical decision rules 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 14 of 37 
defining low-risk FN are used in pediatric oncology [19,20]. Their clinical application, supported by 
recent guidelines is increasing, though still not standard in the majority of pediatric oncology 
institutions [7,21]. Complete withholding of antibiotics in low-risk FN has been studied in a small 
proof-of-principle trial [22]. 
Restricting the definition and the diagnosis of FN by using higher temperature limits defining fever 
(TLDF), or lower limits of the absolute neutrophil count (ANC) defining neutropenia, inherently has 
an ever larger potential to reduce overtreatment than the risk-adapted approach mentioned: If the 
diagnosis of FN is not made, e.g., by spontaneous temperature decrease before the TLDF is reached, 
the patient is not hospitalized for FN and not treated with empirical antibiotics at all [23,24]. On the 
other hand, high and very high temperatures are associated with AE in pediatric FN [7,19]. Increasing 
the TLDF may thus be associated with a relative but as well an absolute increase of AE, essentially by 
delaying FN diagnosis, and thus start of empirical antibiotics [25].  
Conversely, lowering the TLDF or increasing the ANC limit defining neutropenia  may lead to 
additional diagnoses of FN on the one side, and to earlier diagnosis on the other side, with the 
potential to reduce AE. 
3.1.2 
TLDFs currently used to define FN 
Despite the important implications on the diagnosis of FN, the TLDF, and thus the definition of FN, 
vary relevantly between different pediatric oncology institutions, even within the same country. In 21 
institutions in the United Kingdom (UK), definitions of fever ranged from a persisting temperature of 
≥37.5°C as determined by multiple measurements to a single measurement of ≥39°C in 2007 (see 
Figure 3.1) [12]. The identical range of temperature limits was observed when combining information 
from 28 original reports on prospective and retrospective studies in pediatric FN, published from 2010 
to 2012 and recently reviewed [26] (unpublished data). The 9 pediatric oncology institutions that are 
members of the Swiss Pediatric Oncology Group (SPOG) were surveyed in January 2012, and they 
reported a range from a single measurement of ≥38.0°C to a single measurement of ≥39.0°C 
(unpublished data).  
Figure 3.1. TLDFs used clinically and in research  
(x-axis, number of centers; from ref. [23], modified) 
 
In all three surveys the majority of fever definitions consisted of either a single measurement of 
≥38.5°C or repeated measurements of ≥38.0°C (“38.0 / 38.5” in Fig. 3.1). This combined definition 
exactly matches the definition in the current European guidelines for adult FN (38.0/38.5°C), and is 
very similar to the definition in the corresponding U.S. guidelines (38.0/38.3°C) [27,28]. Recent 
evidence-based pediatric FN guidelines did not cover the question of the TLDF [7]. And in a recent 
consensus paper on FN research, no consensus for the TLDF in FN could be reached among an 
0
10
20
30
40
37.5 / 38.0
----- / 38.0
38.0 / 38.3
38.0 / 38.5
----- / 38.5
38.0 / 39.0
38.5 / 39.0
----- / 39.0
UK 2007
Review 2012
SPOG 2012

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 15 of 37 
international expert panel of 43 clinicians, pharmacists, researchers and parent representatives 
interested in FN research [29]. 
3.1.3 
ANC limits defining neutropenia for FN 
In contrast to these wide variations in the TLDF, the definition of neutropenia is nearly unanimous for 
both pediatric and adult FN: A peripheral blood ANC <0.5 G/L defines (severe) neutropenia. This 
definition is sometimes supplemented by either a leukocyte count <1.0 G/L if a differential leukocyte 
count is not done, or an ANC <1.0 G/L suspected to fall [28].  
In the expert panel mentioned above, there was no consensus reached for the definition of neutropenia 
neither. The majority of panel members, however, defined neutropenia as an ANC <0.5 G/L, or an 
ANC <1.0 G/L and expected to decline to <0.5 G/L in the next 48 hours [28,29].  
3.1.4 
Methods to measure temperature in pediatric oncology 
Ear temperature, measured by infrared tympanic thermometry, was shown to reliably and better  
(though not optimally)  reflect core temperature (mean difference, -0.09 ± 1.23°F) than axillary (-1.17 
± 1.13°F) and rectal or forehead measurements during increasing temperature, as well as during 
steady-state and decreasing temperature [30-32]. Results of ear temperature measurements are thus 
estimated to be around 1.08°F = 0.6°C higher than results of axillary measurements.  
In the three temperature limit surveys mentioned (see 3.1.2), temperature measurement methods were 
not recorded in the 21 UK institutions [12] (personal communication, B. Phillips), the majority (16 of 
28) of recent original publications on pediatric FN did not mention the method used [26] (unpublished 
data), and the majority (5 of 9) of SPOG institutions used different measurement methods in parallel 
(unpublished data). In everyday practice, the differences of results implied by using different methods 
are thus usually neglected. This may bias results in FN research, and thus may interfere with 
comparisons between centers, and with results of multi-center studies if not both the TLDF and the 
method of temperature measurement are standardized. 
3.1.5 
The impact of different TLDFs in FN: safety versus efficacy 
The choice of TLDF directly influences whether FN is diagnosed or not. The TLDF has thus 
important implications on individual patient management, health-related quality of life, resource 
utilization, costs, and potentially treatment-related mortality [16,17]. The choice of the optimal TLDF 
must weigh efficacy against safety. Emphasizing efficacy favors a high TLDF in order to avoid FN 
diagnoses in patients without relevant infections who will spontaneously defervesce, thus finally 
avoiding overtreatment [23,24]. Emphasizing safety favors a low TLDF in order to avoid delays in 
FN diagnosis and in start of empirical therapy. Such delays may increase morbidity and lethality in 
patients with bacterial infection [25].  
3.2 
Clinical evidence to date  
3.2.1 
Literature search 
A multi-modal search was performed on November 11, 2014, aiming to find published results of past 
or current research on the optimal TLDF for FN, on the effect of changing this TLDF, and on related 
topics.    
Search strategies used: 
1. Literature search in PubMed with 3 combinations of search terms: 
 
(fever OR febrile) AND (neutropenia OR neutropaenia) AND (definition OR limit), 146 
records screened, 1 relevant publication [23]. 
 
fever limit AND cancer, 99 records screened, 1 relevant publication [23]. 
 
fever definition AND cancer, 79 records screened, 1 relevant publication [23]. 
2. Search for ongoing or past prospective clinical trials on www.clinicaltrials.gov, using 7 different 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 16 of 37 
combinations of search terms:  
 
fever AND definition AND cancer, 58 records screened, 1 relevant project found [24]. 
 
fever AND definition AND neutropenia, 27 records screened, 1 relevant project found [24]. 
 
fever AND limit AND cancer, 57 records screened, 1 relevant project found [24]. 
 
fever AND limit AND neutropenia, 25 records screened, 1 relevant project found [24]. 
 
temperature AND limit AND cancer, 37 records screened, 1 relevant project found [24]. 
 
temperature AND limit AND neutropenia, 8 records screened, 1 relevant project found [24]. 
 
fever AND neutropenia AND cancer, 165 records screened, 1 relevant project found [24]. 
In sum, this search found no retrospective or prospective research project studying these topics in 
adult or pediatric FN, besides the two studies initiated by the Study Chair himself in Bern, 
Switzerland [23,24]. 
3.2.2 
Retrospective study in Bern and Zurich, 2004-2011 
In this retrospective two-center cohort study, 783 FN episodes occurring in 521 pediatric patients with 
cancer during 6009 months (501 years) of cumulative chemotherapy exposure time (CET) were 
studied [23]. Three different TLDFs had been used clinically during the 8 years studied: ear 
temperature ≥38.5°C persisting ≥2 hours (low, Zurich, 2004 to 2011), axillary temperature ≥38.5°C 
≥2 hours or ≥39.0°C once (middle, Bern, 2004 to 2007), and ear temperature ≥39.0°C once (high, 
Bern, 2007 to 2011). Mixed Poisson regression, with CET as rate multiplier, and with a random 
intercept per patient, was used for analysis [23].  
Regarding efficacy, FN rates per month of CET were 0.15 (95% CI, 0.13 to 0.16) for the low TLDF, 
0.13 (95% CI, 0.11 to 0.15) for the middle TLDF, and 0.10 (95% confidence interval [CI], 0.08 to 
0.11) for the high TLDF. Comparison of the high versus low TLDF resulted in a univariate rate ratio 
of 0.66 (95% CI, 0.45 to 0.97; p = 0.036). This finding of efficacy of the high versus low TLDF was 
not confirmed in multivariate analysis, accounting for diagnostic group, myelosuppressive intensity of 
chemotherapy, and bone marrow involvement (rate ratio, 0.94; 95% CI, 0.67 to 1.33; p = 0.74). This 
counter-intuitive result of no efficacy of a high TLDF was discussed to potentially be a false negative 
finding due to methodological limitations of the retrospective study design [23].  
Regarding safety, the high versus low TLDF was not associated with an increased rate of FN with 
bacteremia in univariate (rate ratio, 0.77; 95% CI, 0.25 to 2.37; p = 0.65) and multivariate (rate ratio, 
1.39; 95% CI, 0.53 to 3.62; p = 0.50) analyses [23].  
3.2.3 
Pediatric FN Definition 2012 Bern 
This small prospective single-center observational study (NCT01683370) was designed to assess only 
the efficacy, but not the safety, of the high TLDF used as clinical standard in Bern (ear temperature 
≥39.0°C once, called LimitStandard in the manuscript) [24]. It studied 43 FN episodes occurring in 39 
pediatric patients with cancer during 289 months of cumulative CET from 2012 to 2013. It simulated 
different lower TLDFs (called LimitLow) in silicon, and compared these with LimitStandard. This 
comparison resulted in three types of FN: simultaneous FN, diagnosed at both TLDFs within 1 hour; 
earlier FN, diagnosed >1hour earlier at LimitLow; and additional FN, not diagnosed at LimitStandard (see 
Figure 3.2). Again, mixed Poisson regression with CET as rate multiplier, and with a random 
intercept per patient, was used for analysis [24]. 
 
 
 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 17 of 37 
Figure 3.2. Types of FN diagnoses applying a low versus high TLDF  
(from ref. [24]) 
 
Regarding efficacy, the FN rate observed in reality was 0.15 per month (95% CI, 0.11 to 0.20). In 32 
(74%) of the 43 FN episodes, LimitStandard had been reached. For clinical reasons, 11 (26%) FN 
episodes were diagnosed and treated at lower temperatures. In contrast, FN was not diagnosed twice 
despite fever ≥39.0°C during severe neutropenia. Virtually applying LimitStandard thus resulted in 34 
(32 + 2) FN diagnoses. The predefined efficacy measure of a relevantly (≥15%) increased FN rate 
was reached at LimitLow 38.4°C, with totally 44 FN, 23 of them simultaneous, 11 earlier, and 10 
additional (Poisson rate ratioAdditional/Standard, 0.29; 95% lower confidence bound, 0.16). In 9 of the 10 
additional FN episodes spontaneous temperature decrease without specific therapy was observed in 
reality. Applying an alternative LimitLow of 38.5°C resulted in 41 FN, 24 of them simultaneous, 10 
earlier, and 7 additional [24].  
Regarding safety, no definite conclusions were possible, because this study was not powered for 
safety. Combining information from indirect safety-related findings (relevant numbers of FN 
diagnosed below LimitStandard, and of earlier FN), it was concluded that a TLDF of 39.0°C as used in 
Bern might prove unsafe in larger studies. The fact that the responsible PHO was free to diagnose FN 
below LimitStandard for clinical reasons lessened this risk [24].  
3.2.4 
 Summary 
As detailed above (see 3.1.2, 3.1.4, 3.1.5), there is no consensus on the optimal choice of TLDF 
weighing efficacy (no overtreatment, high TLDF) against safety (no adverse events, low TLDF) 
[7,29]. This reflects the fact that currently there is insufficient evidence how to rationally determine 
an optimal TLDF, balancing the risks of overtreatment versus efficacy and safety, in pediatric 
oncology. Specifically, a high TLDF of 39.0°C ear temperature has been recently shown to be 
efficacious when compared to lower temperatures around 38.5°C. It remains open, however, if this 
high TLDF is as well safe, i.e., if it does not lead to an increased rate of FN with safety-relevant  
events (SRE). The fact that the responsible PHO is free to diagnose FN below the TLDF for clinical 
reasons lessens this potential safety risk [24]. 
3.3 
Explanation for choice of TLDFs to be compared  
The high TLDF (39.0°C) is the current standard in Bern for all patients except those with acute 
myeloid leukemia (AML). The low TLDF (38.5°C) is the current standard for patients with AML in 
Bern, and for all patients in the vast majority of other SPOG sites. The efficacy of the high versus low 
TLDF has been recently shown, see 3.2.3 [24].  
3.4 
Risks and benefits  
Study participation of non-AML patients treated in Bern (current standard, high TLDF of 39.0°C) will 
lead to a higher rate of telephone calls by the parents throughout the study (see 9.2.1), and to a higher 
rate of FN diagnoses when the low TLDF is currently active (see 9.2.2). This is considered to be a 
small drawback regarding more frequent hospitalization for FN, with a small risk to acquire a 
nosocomial infection. Should the high versus low TLDF prove to be inferior regarding safety, study 
participation for these patients will increase safety when the low TLDF is currently active. 
Study participation of AML patients treated in Bern, and of all patients treated in the vast majority of 
other SPOG sites (current standard, low TLDF of 38.5°C) will not influence the rate of telephone calls 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 18 of 37 
throughout the study (see 9.2.1), but to a lower rate of FN diagnoses when the high TLDF is currently 
active (see 9.2.2). This is considered to be a benefit. Should the high versus low TLDF prove to be 
inferior regarding safety, however, study participation for these patients will decrease safety regarding 
FN treatment when the high TLDF is currently active. It is yet known that this potential decrease in 
safety is not big, however [23,24]. 
Interim analyses are planned to reduce the risks mentioned above by allowing early stopping of the 
study both for success (non-inferiority proven) or for futility (non-inferiority not provable) (see 11.4.6) 
In sum, the potential risks and benefits for patients participating in the study seem to be acceptable and 
well-balanced.  
The main benefit of this study is the increase in knowledge, aiming at precision medicine in this 
context. This will help to optimize the future treatment of only a small minority of study participants, 
but of a large number of children and adolescents treated with chemotherapy for cancer in the future:  
If this study shows evidence of non-inferiority of a high versus low TLDF regarding safety this high 
TLDF can be used clinically in pediatric oncology centers in developed countries. This will lead to a 
reduction in the current overtreatment of pediatric FN, by reducing over-diagnosis. If there is no 
evidence of non-inferiority, however, centers currently using this high TLDF should revise their 
clinical practice. 
3.5 
Justification of choice of study population  
FN in children and adolescents is known to differ in many core characteristics from FN in adults [7]. 
This is the reason why the aims of this study can be reached only by the study of children and 
adolescents themselves despite them being especially vulnerable study participants. See 2.7 for 
information on the corresponding implications on the informed consent process. 
4. STUDY OBJECTIVES  
4.1 
Overall objective 
The overall objective of this study is to determine the safety and efficacy of a high versus low TLDF, 
for the definition of FN, in children and adolescents with cancer treated with myelosuppressive (not 
myeloablative) chemotherapy. 
4.2 
Primary objective 
The primary objective is to determine if a high TLDF is non-inferior to a low TLDF regarding safety. 
4.3 
Secondary objective 
The secondary objective is to determine if a high TLDF is superior to a low TLDF regarding efficacy. 
4.4 
Tertiary objective 
The tertiary objective is to make use of the data collected for development of risk prediction rules, and 
for external validation of published risk prediction rules. 
5. DEFINITIONS AND STUDY OUTCOMES  
5.1 
Definitions 
5.1.1 
Temperature measurement method and device, fever, and TLDFs 
Throughout the study, all temperatures are measured as ear temperatures by infrared tympanic 
thermometry using a Braun ThermoScan® 7 device (IRT 6520; Braun GmbH, Kronberg, Germany; 
steps displayed, 0.1°C; accuracy, ±0.2°C; clinical repeatability,±0.14°C) [24,30-33], or its successor 
device with comparable or better performance characteristics. All parents are trained in the correct use 
of this device at study entry.  

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 19 of 37 
Fever is defined as a single ear temperature at or above the current TLDF.  
The TLDFs used in this study are 38.5°C (low TLDF), and 39.0°C (high TLDF; see 8.1). 
5.1.2 
Severe chemotherapy-induced neutropenia 
Severe chemotherapy-induced neutropenia (called neutropenia here) is defined as an ANC <0.5 G/L, 
or an ANC <1.0 G/L and expected to decline to <0.5 G/L in the next 48 hours [28,29]. Neutropenia 
can be diagnosed from the start of chemotherapy until 21 days after the last dose of chemotherapy. 
The additional 21 days account for neutropenia, and thus risk of FN, developing after cessation of 
chemotherapy [4]. 
5.1.3 
Types of clinically defined FN episodes  
A clinically defined FN episode (FNClin) is defined as an episode of at least slightly elevated 
temperature (≥38.0°C) and severe neutropenia, during which the responsible local PHO diagnoses FN, 
and/or starts FN therapy (including but not restricted to emergency hospitalization for outpatients, plus 
empirical intravenous antimicrobial therapy). In rare exceptions, to be discussed individually with the 
Study Chair / Study Vice Chair, this limit can be further lowered to 37.5°C in patients repeatedly 
receiving antipyretics despite neutropenia, a practice strongly discouraged by this protocol. 
An FNClin can thus be diagnosed at/above the currently effective TLDF for a specific patient (then 
called FNTLDF), or below this TLDF (then called FNBelow). This definition reflects the fact that the 
responsible local PHO is always free to diagnose FN and treat the patient correspondingly for clinical 
reasons even if the TLDF is not reached (see 8.2) [24]. 
The temperature used for defining FNClin, and for distinguishing between FNTLDF an FNBelow, is the first 
temperature at or above the currently active TLDF for FNTLDF, or the highest temperature reported by 
the patients or parents, or measured at presentation with FN, before the start of empirical antimicrobial 
therapy for FNBelow [6].  
The TLDF currently active at the time when this temperature defining FNClin is measured determines 
TLDF linked to this FNClin for analysis. 
5.1.4 
Types of FN episodes comparing high versus low TLDF 
When the high TLDF is currently active, the comparison with virtually applying the low TLDF results 
in three types of FN (see Fig. 5.1, ref [24]): Simultaneous FN is diagnosed without relevant delay (≤1 
hour) from passing the low TLDF. Delayed FN is diagnosed with a relevant delay (>1 hour and ≤168 
hours) from passing the low TLDF, with continued neutropenia and continued fever (temperature 
measured at least once ≥38.0°C every 24 hours) during this delay time. Avoided FN diagnosis is 
defined by temperature passing the low, but not the high TLDF, within a timeframe of ≤168 hours 
with continued neutropenia and continued fever (temperature measured at least once ≥38.0°C every 24 
hours) [24]. 
 
Figure 5.1. Types of FN diagnoses applying a high versus low TLDF (modified from [24]) 
 
 
 
 
 
 
 
5.1.5 
Duration of FN episodes  
The duration of antimicrobial therapy for FN defines the duration of FN episodes. Restarting 
antimicrobial therapy within 7 days and with persistent neutropenia is considered to belong to the 
same FN episode. Start of intravenous chemotherapy immediately ends an FN episode, overruling the 
Time
FN Type           Simultaneous FN       Delayed FN         Avoided FN     Fever, no FN 
      
    High TLDF -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --  
 
    Low TLDF --  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -  -   
Neutropenia 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 20 of 37 
preceding definition. Correspondingly, all outcomes are tracked onward for 7 days after the end of 
antimicrobial therapy for FN, as long as neutropenia persists and intravenous chemotherapy has not 
been started [6,24].  
5.1.6 
Chemotherapy intensity  
Chemotherapy is classified into four levels of intensity according to the expected duration of severe 
neutropenia [4,34]: 
 
Intensity 1: no severe neutropenia expected (e.g., maintenance therapy for acute lymphoblastic 
leukemia) 
 
Intensity 2: severe neutropenia expected ≤10 days (e.g., therapy for most solid tumors) 
 
Intensity 3: severe neutropenia expected >10 days (e.g., non-maintenance therapy for AML) 
 
Intensity 4: myeloablative chemotherapy, hematopoietic stem cell therapy required 
The study center will verify reported chemotherapy intensities (see 12.2.4). 
5.1.7 
Chemotherapy exposure time 
The CET equals the length of study participation of a specific patient, and refers to myelosuppressive 
(intensity 1 to 3), but not to myeloablative chemotherapy (intensity 4). The start is the day of the first 
dose of chemotherapy (or of recruitment into the study, whichever comes later). The end is 21 days 
after the last dose of chemotherapy (or end of study for other reasons, whichever comes earlier; see 
5.1.2) [4].  
5.1.8 
Safety-relevant event 
A composite endpoint is chosen for the primary outcome [29,35,36]. Specifically, a safety relevant 
event (SRE) is defined as bacteremia detected, and/or a serious medical complication (SMC) reported.  
Bacteremia is defined according to a recent consensus definition [29,37] as the culture of a recognized 
pathogen from one or more blood cultures (includes viridans group streptococci in the setting of 
concomitant mucosal barrier injury). Common commensals should be cultured from two or more 
blood cultures drawn on separate occasions. Where only a single blood culture is taken, and in the 
presence of a long term vascular catheter, common commensals cultured once may be included if an 
alternative source of infection is not identified. (Blood cultures drawn from different sites including 
different venepunctures or different lumens of the same central line, should undergo separate 
decontamination and are therefore considered drawn on “separate occasions.” A complete list of 
common commensals is available via the online Centre for Disease Control and Prevention resource 
[37]).  
In this study, it is not required to draw blood cultures from venepunctures in addition to blood cultures 
drawn from central lines. 
A serious medical complication is defined according to a recent consensus definition [29] as  
 
death due to any cause during FN [modified from ref. 29], or 
 
admission to intensive care unit (ICU), high dependency unit or other critical care unit for 
organ support, or 
 
severe sepsis (including septic shock) according to established definitions [38] 
In view of these non-trivial definitions, the study center will verify SREs and potential SREs reported 
by the study sites (see 5.2, 12.2.4). 
5.2 
Primary outcome and its assessment 
The primary outcome is the Poisson rate of FNClin with at least one SRE per CET. It is assessed per 
patient during the entire study duration in patient charts, and reported monthly by the study sites to the 
study center. The study center verifies the SRE status of FN episodes (see 5.1.8, 12.2.4). 
The primary outcome refers to SRE during FNClin, not during FNTLDF. Reporting only FNTLDF with 
SRE as events would lead, by definition, to non-reporting of FNBelow with SRE, which would not 
reflect clinical reality. This underreporting would be, again by definition, more important for the high 
TLDF than for the low TLDF. This bias would thus finally lead to a falsely low rate ratio , with the 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 21 of 37 
risk of falsely declaring the high TLDF as safe. 
5.3 
Secondary outcomes and their assessment 
The secondary safety-related outcomes are 
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) 
B. AE: clinically / microbiologically documented infection, unexplained fever, sepsis / severe sepsis /  
     septic shock, relapse of primary infection (definitions see refs. 29, 38; assessed in patient charts,  
     reported per FN) 
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) 
The secondary efficacy-related outcomes are 
D. Poisson rate of FNClin per CET (assessed like primary outcome; main measure of efficacy) 
E. Poisson rate of FNTLDF and FNBelow per CET (assessed like primary outcome) 
F. Duration (days) of hospitalization, ICU treatment, i.v. antibiotics, p.o. antibiotics, any antibiotics,  
    delay of chemotherapy for FN (assessed in patient charts, reported per FN episode) 
G. Only for currently active high TLDF: simultaneous and avoided FN diagnosis (see 5.1.4) by  
     applying high vs. low TLDF (assessed from patients charts, reported monthly and per FN) 
6. STUDY DESIGN  
6.1 
General study design and justification of design  
This is a multi-center open-label cluster-randomized controlled parallel-group multiple-crossover non-
inferiority trial, with study sites as units of randomization, and patients as units of analysis.  
Every month, 1:1 randomizations between the two different TLDFs are repeated for each study site. 
This implies that the TLDF is identical for all study participants within each study site. Per-site instead 
of per-patient randomization was chosen for practical reasons, aiming to reduce assignment errors due 
to the repeated changes in the currently active TLFD. This leads to potential multiple cross-overs 
within patients. This scheme was chosen in order to decrease the target number of events (FNClin with 
SRE; see 5.2, 11.2), and thus the number of patients needed thanks to the increase in power reached by 
within-patient cross-over.  
6.2 
Methods of minimizing bias  
6.2.1 
Randomisation  
See 7.4. 
6.2.2 
Blinding procedures  
None, this is an unblinded study. 
6.2.3 
Other methods of minimizing bias  
 
Uniform method and device for temperature measurements (see 5.1.1). 
 
Verification of chemotherapy intensity and SREs by study center (see 5.1.6, 5.1.8, 9.3.1). 
 
Use of clinically defined FN (FNClin) with SRE as primary outcome (see 5.3). 
 
Use of mixed Poisson regression for analysis of primary and other outcomes (see 11.4.1). 
 
Analysis in the per protocol (PP) set for primary outcome (see 11.4.2) [39]. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 22 of 37 
7. STUDY POPULATION  
7.1 
Requirements for study sites 
Study sites must fulfill all of the following requirements: 
 
Member institution of SPOG  
 
Consistent temperature measurement method at home, in outpatients and inpatients: ear, 
infrared tympanic thermometry (see 5.1.1) 
 
Simple single TLDF (see 5.1.1)  
 
Empirical FN therapy: ≥1 dose i.v. antibiotics (see 9.2.3) 
 
Rules for diagnosis and management of FN predefined in standard operating procedure (SOP) 
or SOP-like documents (e.g., standard prescription, flowsheet). 
 
Board-certified pediatric oncologist on call 24 hours per day, 365 days per year 
 
Access to pediatric ICU 
 
Willingness to perform the study according to the protocol 
7.2 
Eligibility criteria for patients  
Patients fulfilling all of the following inclusion criteria are eligible for the study: 
 
Chemotherapy treatment because of any malignancy planned for at least 2 further 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, as documented by signature (see 2.6) 
The presence of any one of the following exclusion criteria will lead to exclusion of the patients: 
 
Infants <12 months (reason: difference in temperature measurement method) 
 
Past allogeneic hematopoietic stem cell transplantation 
 
Denied written informed consent from patients and/or parents (see 2.6) 
Reason for inclusion of children/adolescents (vulnerable participants): important differences in core 
FN characteristics between children/adolescents and adults [7]. 
7.3 
Screening and recruitment  
Patients of the study sites are screened for eligibility and recruited by the teams of these sites. No 
specific screening procedures except verifying inclusion/exclusion criteria are needed. See Appendix 
A for a list of study sites. 
There will be no advertisements, and no payment given to study participants. 
7.4 
Assignment to study groups  
See 6.1 for basic information on randomized allocation of patients, via monthly repeated 1:1 
randomization of study sites, to the two different TLDFs (see 8.1).  
A randomization sequence covering 72 months is generated at study entry of each study site by the 
study center using computer-generated random numbers. These sequences are stored in the study 
center. In the middle of each month, the study center informs the study sites on the TLDF assignment 
of the next month, valid for all patients of the respective site.  
The TLDF thus changes over time for the study site, and thus as well for most of the patients. The 
currently active TLDF will decide on the clinical procedures to be performed (see 9.2.2). 
7.5 
Criteria for withdrawal / discontinuation / end of study of patients  
Patients are withdrawn from the study in case of withdrawal of informed consent, and when study 
participation is not in the best interest of the patient any more, including relevant non-compliance, as 
judged by the study site or the study center. The study ends regularly when patients have reached the 
age of 20 years, at the end of the study as such, at the first day of myeloablative chemotherapy before 
allogeneic hematopoietic stem cell transplantation, 21 days after the last dose of chemotherapy, or at 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 23 of 37 
the day of death from any cause.  
See 8.3 for follow-up, data collection and use of data for withdrawn patients. 
8. INTERVENTION  
8.1 
Intervention: temperature limit defining fever 
A distinction into a standard and an experimental intervention is not possible, because both TLDFs are 
in clinical use today (see 3.1.2). 
Two TLDFs used in this study are 38.5°C (low TLDF), and 39.0°C (high TLDF; see 5.1.1). See 7.4 
for assignment to study groups, and see 9.2.2 for the clinical procedures performed according to the 
currently active TLDF. 
8.2 
Compliance with study intervention  
The Sponsor will perform risk-adapted monitoring. 
Non-compliance apparent during monitoring or audit visits will be handled according to SPOG Office 
SOPs. The Study Chair informs the Sponsor about any non-compliance observed. 
Making a FNBelow diagnosis is not considered to be a protocol violation (see 9.2.2). 
8.3 
Data Collection and Follow-up for withdrawn participants  
No specific follow-up beyond the date of withdrawal (see 7.5) is performed. No data will be collected 
beyond the date of withdrawal. The information collected until this date will be used for analysis. This 
information will be fully anonymized after analysis (see 12.2.3). 
9. STUDY PROCEDURES AND ASSESSMENTS  
9.1 
Assessment of eligibility 
Eligibility of patients, according to inclusion and exclusion criteria (see 7.2) is assessed during a 
routine outpatient visit, or during routine hospitalization. Each study site assesses the eligibility of all 
patients treated at the site with chemotherapy. Coded information on sex, year of birth, diagnostic 
group, participation or reason for non-participation, and date of assessment of all these patients is 
transmitted to the study center via partial copies of the patient screening log. 
9.2 
Mandatory clinical procedures throughout the study 
The minimally required clinical procedures described below can be supplemented by additional 
procedures specific to the study site. Such additional procedures must not interfere with the minimally 
required clinical procedures, and they must not make distinctions between the two TLDFs. The 
minimally required and the additional procedures are described in a FN SOP or SOP-like document 
specific for each study site (see 7.1).  
The requirements for patients and/or parents (see 9.2.1) are additionally described in the respective 
information documents (see 17.2). 
9.2.1 
Mandatory procedures by patients and/or parents throughout the study 
In outpatients, the ear temperature is measured if fever is suspected (see 5.1.1 for technical details) 
[40]. If a temperature ≥38.5°C (low TLDF) is measured, or if the patient’s general performance is 
reduced, the responsible local PHO is immediately informed via the study site.  
In inpatients, the nurses act correspondingly. 
Parents are not obliged to document results of temperature measurements. Besides, it is not usually 
clinically needed to know the exact (as required here for secondary outcome A) results and time points 
of temperature measurements reported by parents. Thus, they are not reliably documented in patients’ 
charts. This is the reason why the exact results and time points of relevant temperature measurements 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 24 of 37 
(first temperatures ≥38.0°C, ≥38.5°C, and ≥39.0°C, respectively) made by parents are directly noted 
on the respective CRF. Measurements of inpatients and outpatients, however, are reliably and exactly 
noted in patients’ charts. 
9.2.2 
Mandatory procedures by the responsible local PHO in case of reported fever 
When the responsible local PHO knows of a patient with ear temperature ≥38.5°C (low TLDF), and/or 
with reduced general performance, he/she decides if an emergency complete blood count (CBC) must 
be performed in order to assess a potential neutropenia (last CBC >48 [72 in unequivocal situations] 
hours old, or suspected not to reflect the current ANC).  
In case of neutropenia and an ear temperature at or above the currently active TLDF (38.5°C, or 
39.0°C), FN must be diagnosed (FNClin, specifically FNTLDF) (see 9.2.3 for further procedures).   
In case of neutropenia and an ear temperature below the currently active TLDF, FN is not routinely 
diagnosed, thus no antibiotics and no antipyretics are given. FN can be diagnosed, however, for 
clinical reasons, if the ear temperature is ≥38.0°C (FNClin, specifically FNBelow, see 5.1.3) (see 9.2.3 for 
further procedures). Making a FNBelow diagnosis is not a protocol violation. 
In all other cases, FN is not diagnosed, and all diagnostic and therapeutic measures are at the 
discretion of the responsible local PHO. 
9.2.3 
Mandatory procedures at diagnosis of FN 
In case of any FN diagnosis (FNClin: FNTLDF or FNBelow), the following procedures must be performed: 
 
Emergency hospitalization 
 
Minimum set of observations, including 
- History 
- Physical examination 
- Blood culture from central venous access device (CVAD) to be analyzed in automated  
  system (blood culture from venepuncture only in patients without CVAD) 
- CBC (not to be repeated if performed within 12 hours at the study site),  
  International normalized ratio of coagulation, and serum creatinine, total bilirubin, alanine 
transaminase, 
  C-reactive protein 
 
Emergency start with empirical intravenous broad-spectrum antibiotics (Complete abstention 
from antimicrobial therapy [22] is not allowed in this study.) This antimicrobial therapy is 
specified by each study site. It must fulfill the following requirements [6]:  
- It must cover Gram-positive cocci (e.g., Staphylococcus aureus, Streptococcus pneumoniae, 
  other streptococci) except methicillin-resistant S. aureus, coagulase-negative staphylococci,  
  and enterococci. 
- It must cover Gram-negative bacteriae (e.g., Neisseria species, Haemophilus species,  
  Moraxella catarrhalis, enterobacteriaceae, Pseudomonas aeruginosa). 
- A specific anti-anaerobic coverage is not needed. 
- It must be adapted to the local resistance patterns.  
All further diagnostic and therapeutic measures (e.g. risk-adapted step-down strategies, switching 
antibiotics, adding antifungals, discharge) are performed according to the SOP or SOP-like documents 
(see 7.1) specific to the study sites, or at the discretion of the responsible local PHO if they are not 
covered by this document. The TLDF currently active at diagnosis of FN is as well used for decisions 
on diagnostics, supportive care incl. antibiotics, discharge, and other aspects depending on fever. 
9.3 
Assessments of outcomes  
See 5.2 for the assessment of the primary outcome, see 5.3 for assessment of the secondary outcomes, 
and see 5.2, 5.3 and 10 for the assessment of safety outcomes. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 25 of 37 
10. SAFETY  
Regarding safety, serious adverse event (SAE) reporting is used in parallel to the assessment and 
analysis of the primary outcome and a set of secondary outcomes (see 9.2.1, 9.2.2). 
10.1 Definition of serious adverse events 
A SAE is defined here as any untoward medical occurrence, occurring during a FNClin episode, that 
 
results in death, 
 
is life-threatening, 
 
results in persistent or significant disability/incapacity, or 
 
results in a congenital anomaly/birth defect. 
This definition is more restrictive than the general SAE definition [2] for two reasons: First, as every 
FN leads to hospitalization of undetermined length (see 9.2.2), the usual criterion of “requirement of 
in-patient hospitalization or prolongation of existing hospitalization” is not used as a criterion defining 
SAE in this study. Second, since the intervention in this study has potential implications on the time of 
FN diagnosis, but not on any aspect outside of FN, SAEs are restricted in this study, by definition, to 
events occurring during FNClin (see 5.1.5). 
Any event caused by progression of the underlying malignancy is not considered as SAE. In case of 
doubt, the investigator contacts the Study Chair.  
10.2 Reporting of SAE 
Every SAE must be documented and reported within 7 days (using the SAE form) by the study sites to 
the SPOG Office (safety@spog.ch) with a copy to the Study Chair (roland.ammann@insel.ch) and the 
Study Vice Chair (nicole.bodmer@kispi.uzh.ch) [2] 
An SAE for which a relationship with the intervention studied here cannot be excluded must be 
documented and reported within 24 hours (using the SAE form) by the study sites to the SPOG Office 
(safety@spog.ch) with a copy to the Study Chair (roland.ammann@insel.ch) and the Study Vice Chair 
(nicole.bodmer@kispi.uzh.ch) [2].  
Deaths during ongoing SAEs have to be reported within the same timelines specified above (24 hours 
or 7 days, respectively). 
Upon receipt of an SAE form the SPOG Office informs the Study Chair/Study Vice Chair about the 
reported SAE (double check). The Study Chair/Study Vice Chair checks SAE reports for medical 
consistency and for completeness, sends the respective queries to study sites where needed, and 
performs a plausibility check of the relatedness of the SAE to the intervention studied in this study. If 
a relatedness of the SAE to the intervention studied cannot be excluded the Sponsor informs the lead 
CEC and the respective local CEC on all SAEs within 15 days [2]. If Sponsor and Study Chair / Study 
Vice Chair cannot resolve discrepancies regarding the question of such relatedness, an external expert 
is asked for advice. 
Clinical follow-up after an SAE is performed as part of the clinical routine by the respective study site. 
10.3 Annual Safety Report 
The Study Chair writes an annual safety report (ASR) in cooperation with the SPOG Office. This 
report follows the standards for the executive summary defined by the ICH Guideline E2F 
supplemented with a line listing of all SAEs for which a relation with the intervention studied here 
cannot be excluded which have occurred during the reporting period of this ASR, and during the entire 
study. The yearly cut-off date refers to the date the study was approved by the leading CEC. The 
SPOG Office submits this report to the concerned local CECs, the leading CEC, and additionally to all 
involved PIs within 90 days from this yearly cut-off date. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 26 of 37 
10.3 Further safety issues 
If immediate safety and protective measures have to be taken during the conduct of the study, the 
Study Chair informs all participating PIs and the Sponsor immediately of these measures, and of the 
circumstances necessitating them. The Sponsor will notify the CECs of any safety issue within 7 days. 
See 11.3 regarding occurrence of deaths. 
 
11. STATISTICAL METHODS  
11.1 Hypothesis for the primary objective / primary outcome 
Statistical null hypothesis (H0): The rate ratio of FNClin with SRE (primary outcome for safety) is not 
non-inferior (non-inferiority margin 1.33) for a high versus low TLDF. The non-inferiority-margin is 
chosen more conservatively than the suggested de-facto standard of 1.50 [41] because the primary 
outcome is a safety outcome. 
Statistical alternative hypothesis (H1; corresponds to the clinical hypothesis, see 3.1, 4.2): The rate 
ratio of FNClin with SRE (primary outcome for safety) is non-inferior (non-inferiority margin 1.33) for 
a high versus low TLDF. 
11.2 Determination of sample size and study duration 
Sample size calculations and thus decisions when to perform interim and final analyses refer to events 
regarding the primary outcome, i.e., FNClin episodes with SRE (see 5.1). The number of events needed 
was determined by a series of 1000-fold random simulations, applying mixed Poisson regression on a 
set of retrospective data on 1164 FN episodes in 898 patients treated with myelosuppressive (but not 
myeloablative) chemotherapy in two centers, Bern 1993-2012, and Zürich 2004-2011 [4,23,42]. 
Specifically, the glmmPQL function from the nlme package in the MASS library [43] was used for 
mixed Poisson regression simulations in R 3.1.2 [44].  
Assuming an event rate ratio of 1.05 for high versus low TLDF, and applying monthly repeated 
randomization within patients leading to multiple crossover, a sample size of 116 events was found to 
yield a power of 80% (beta = 0.20) at alpha = 0.05 to detect non-inferiority. Accounting for the 3 
interim analyses (see 11.4.4) leads to a target sample size of 132 events (FNClin with SRE) [45].  
Assuming that SRE will occur in 24% of FNClin [9], these 132 events of FNClin with SRE correspond to 
approximately 550 FNClin episodes in total. Assuming a rate of 1.48 FNClin episodes per year of CET 
[4,23], these 550 FNClin episodes correspond to approximately 372 years of CET. It is assumed that 
SPOG institutions treating in total 2/3 of the pediatric cancer patients diagnosed in Switzerland will 
participate, and that 2/3 of the patients potentially eligible are recruited. Then, around 100 of the 220 
newly diagnosed and around 10 of the 20 relapsed pediatric cancer patients diagnosed in the annual 
mean in Switzerland [46] will be recruited per year. This corresponds to around 110 years of CET per 
year [1], resulting in an estimated study duration of 3.5 years after a 3 months run-in phase (see Table 
11.1). 
Table 11.1. Planned timetable (assuming study is not stopped at interim analyses, see 11.3, 11.4.4) 
2015, June 
Submission to pediatric IRB Bern 
2015, December 
Submission to CECs 
2016, February 
Setting up study center, start initiating study sites 
2016, March 
Recruitment of first patient 
2016, June 
End of run-in phase of patient recruitment 
2017, April 
Accrual for first interim analysis reached: 33 events of FNClin with SRE 
2018, February 
Accrual for second interim analysis reached: 66 events of FNClin with SRE 
2018, December 
Accrual for third interim analysis reached: 99 events of FNClin with SRE 
2019, October 
Target of 132 events of FNClin with SRE reached (last patient last visit) 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 27 of 37 
2020, January 
Data closure, clean data 
2020, April 
Data analyzed 
2020, October 
Manuscript with main results submitted 
11.3 Statistical criteria of termination of trial  
There are no statistically defined discontinuation criteria for individual participants. 
The study itself will be stopped when the boundary for proven inferiority or proven non-inferiority is 
crossed at an interim analysis (see 11.4.4), or when the target sample size of 132 FNClin with SRE 
reported and verified (see 12.2.4) by the study center has been reached. 
It is expected that in this study there will be multiple deaths due to FN. In a recent multicenter study 
on FN in Switzerland and Germany, the proportion of FN with death was 0.7% [9]. If this study is not 
stopped at an interim analysis, and the target size of 132 FNClin with SRE is reached, up to 10 deaths 
are expected (0.7% of 550 FN, see 11.2; corresponding estimate, 4; exact 95% Blyth-Still-Casella CI, 
1 to 10). The occurrence of deaths during FNClin is thus not a reason to stop the study.  
11.4 Planned statistical analyses  
11.4.1 General strategy of analysis, and datasets to be analysed 
For all outcomes, descriptive statistics using standard methods will be performed. For all outcomes 
except secondary outcomes C and G, analytical statistics will be performed as described below.  
Because multiple randomizations are performed per patient, via monthly randomizations of centers, 
the datasets to be analyzed do not refer to patients, but to randomization periods (maximum length, 1 
month) of patients. The intention-to-treat (ITT) dataset contains all periods of patients reported to be 
on study by a study site on beginning of a month (first day of month, 00.01 AM). The per-protocol 
(PP) dataset contains all periods of the ITT dataset, for which the study site had informed its pediatric 
oncology inpatient and outpatient departments and the emergency department on the result of 
randomization until beginning of the month. Diagnosis of FNBelow is possible according to the protocol, 
and does not lead to exclusion from the PP dataset (see 9.2.2). 
Mixed regression analyses, with random intercepts per patient nested within study site (three-level 
random intercept model) will be used to account for multiple entries / multiple FN per patient [47]. 
Specifically, mixed Poisson regression with CET as rate multiplier will be used for Poisson distributed 
events, mixed logistic regression for binary outcomes, and mixed linear regression for continuously 
distributed outcomes. 
If not otherwise stated, two-sided tests will be used, analyses will be performed at the end of the study, 
and in ITT dataset, p-values <0.05 will be considered significant, and correspondingly, 95% CI will be 
calculated. The current version of the R software [44] will be used for analysis. 
11.4.2 Primary objective safety: Main analysis 
The rate ratio of the primary outcome, FNClin with SRE per CET, for high versus low TLDF (see 5.2, 
9.3.1) will be analyzed using univariate mixed Poisson regression (see 11.4.1) in the PP dataset [39] at 
the end of the study. Past interim analyses will be accounted for in this final analysis [45].  
If a significant carry-over is detected (carry-over window of 24 hours after switch from high to low 
TLDF; mixed Poisson regression on carry-over; p<0.05), this univariate analysis is replaced by a 
bivariate analysis, adjusted for this carry-over effect. 
The estimate of the rate ratio and its (one-sided) 95% upper confidence bound (UCB) will be reported. 
If this UCB is below the non-inferiority margin, i.e., <1.33, non-inferiority of the high versus low 
TLDF regarding safety will be claimed. 
Three sensitivity analyses will be performed: First, a multivariate analysis in the PP dataset, adjusting 
for chemotherapy intensity, time since diagnosis, bone marrow involvement, type of CVAD and past 
FN [4]; second, a uni- or bivariate analysis in the ITT dataset; and third, a multivariate analysis in the 
ITT dataset. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 28 of 37 
11.4.3 Primary objective safety: Further analyses  
Secondary outcomes A: The durations, calculated as differences in time, will be analyzed for high vs. 
low TLDF by mixed linear regression (see 11.4.1.  
Secondary outcomes B: These binary outcomes will be analyzed in two ways for high versus low 
TLDF: First, by mixed logistic regression (see 11.4.1) to assess differences on the level of FNClin 
episodes; and second, by mixed Poisson regression (see 11.4.1) to assess differences on the CET level. 
11.4.4 Secondary objective efficacy: Main analysis  
The rate ratio of the secondary outcome D, FNClin per CET for high versus low TLDF, will be 
analyzed by uni-or bivariate (see 11.4.2) mixed Poisson regression (see 11.4.1) in the ITT set [39]. If 
the 95% UCB of the rate ratio is below the superiority margin, set at equality, i.e., if it is <1.00, 
superiority of the high versus low TLDF regarding efficacy will be claimed.  
Three sensitivity analyses will be performed: First, a multivariate analysis in the ITT set; second a 
univariate analysis in the PP set; and third, a multivariate analysis in the PP set. 
 
11.4.5 Secondary objective efficacy: Further analyses  
Secondary outcomes E: The rate ratios of FNTLDF and of FNBelow will be analyzed like secondary 
outcome D, FNClin (see 11.4.4). 
Secondary outcomes F: These durations will be analyzed in two ways for high versus low TLDF: First, 
by mixed linear regression (see 11.4.1) to assess differences on the level of FNClin episodes; and 
second, by mixed Poisson regression (see 11.4.1), to assess differences on the level of CET. 
Secondary outcome G: The rate ratios of simultaneous FN and of avoided FN will be analyzed like 
secondary outcome D, FNClin (see 11.4.4), for periods with high TLDF only. 
11.4.6 Tertiary objective, risk prediction rules  
Rules predicting the risk to develop FN (FNClin, FNClin with bacteremia / SMC /SRE) during 
chemotherapy will be based on multivariate mixed Poisson regression (see 11.4.1), applying stepwise 
forward variable selection.  
Rules predicting the risk to develop AE (bacteremia / SMC /SRE) during FN will be based on 
multivariate mixed logistic regression (see 11.4.1), applying stepwise forward variable selection.  
The predictive performance of published rules predicting the risk to develop FN (FNClin, FNClin with 
bacteremia / SMC /SRE) during chemotherapy will be assessed by multivariate mixed Poisson 
regression (see 11.4.1).  
The predictive performance of published rules predicting the risk to develop AE (bacteremia / SMC / 
SRE) during FN will be assessed by multivariate mixed logistic regression (see 11.4.1). 
11.4.7 Interim analyses for the primary outcome 
For the primary outcome, a Power family scheme of group sequential one-sided tests is used, with a 
maximum of 3 equally spaced interim analyses, after 33 (25%), 66 (50%), and 99 (75%), events are 
reached, respectively. Specifically, O’Brian-Fleming-type boundaries defined by delta = 0 are used, 
with tests both for proven non-inferiority (success) and non-provable non-inferiority (futility) 
performed at each analysis. This scheme increases the maximum number of events by a factor of 
1.140, i.e., from 116 (100%) to 132 (114%). The expected number of events, however, is decreased to 
71 (61%) assuming non-inferiority (theta = 0), and to 90 (78%) assuming inferiority (theta = 1) [45].  
Table 11.2. Stopping boundaries at interim and final analyses, expressed as z-values 
Interim 1 
(33 events) 
Interim 2 
(66 events) 
Interim 3 
(99 events) 
Final 
(132 events) 
Consequence 
≥ 3.312 
≥ 2.342 
≥ 1.912 
≥ 1.656 
Stop study: proven non-inferiority 
-0.671 to 3.311 
0.465 to 2.341 
1.146 to 1.911 
- 
Continue study 
< -0.671 
< 0.465 
<1.146 
< 1.656 
Stop study: non-inferiority not provable 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 29 of 37 
The corresponding stopping boundaries, expressed as z-values, of the interim and final analyses are 
displayed in Table 11.2 [45]. At interim analyses and, if applicable, at the final analysis (see 11.4.2), 
z-values are calculated from the results of the univariate or bivariate (see 11.4.2) mixed Poisson 
regression analysis (see 11.4.1) in the PP dataset as z = (ln(1.33) – beta) / SEbeta.  
11.4.8 Safety analysis 
In addition to the analysis of the primary, safety-related outcome (see 11.4.2), and the analyses of the 
safety-related secondary outcomes (11.4.3), the number, proportion and nature of SAEs (see 10.1) will 
be reported. 
11.4.9 Deviations from the original statistical plan  
Deviations from the planned analyses for the primary endpoint and for the secondary endpoints will be 
justified and described in an amendment of the protocol, if the Study Committee decides so. In any 
case, deviations from the planned analyses for these endpoints will be described in the corresponding 
manuscripts if they are decided upon after the recruitment of the first patient. 
 
11.5 Handling of missing data and drop-outs  
There will be no imputation for missing data (multiple imputation, last observation carried forward, 
and alike). No replacement of drop-outs is needed, because the target sample size refers to events, i.e., 
FNClin with SRE, not to patients. 
12. QUALITY ASSURANCE AND CONTROL  
12.1 Data handling and record keeping / archiving  
12.1.1 Case Report Forms  
All information collected during the study must be entered in case report forms (CRFs). CRF are 
completed either by the PI or a designated representative authorized by the PI. Authorisation of any 
local staff member to make CRF entries must be documented on the according staff list.  
Primarily, paper CRFs will be used, later replacement by electronic CRFs is possible.  
Study patients are not identified in the CRF by name, initials, or birth date. A combination of site 
acronym, participant number and year of birth (e.g., BE.001.2003) is used in the CRFs to decrease the 
risk of patient mistakes.  
12.1.2 Specification of source documents  
Source documents include the patients’ charts, which are stored at the site specific usual location for 
charts, plus study-specific documents (Informed Consent forms, randomization lists, subject 
identification logs, and relevant correspondence), which are filed in the Investigator Site File (ISF). 
The ISF is stored at a different study-specific location defined by the responsible investigator of the 
study site.  
12.1.3 Record keeping / archiving  
Source documents as well as the ISF have to be archived at each site for a minimum of 10 years after 
termination of the study. Each local principal investigator is responsible to archive source documents 
and the ISF according to site-specific procedures. 
The Study Master File is archived at SPOG Office according to the SPOG Office SOP on archiving.  
12.2 Data management  
12.2.1 Data Management System  
A current version of the RedCap software, or a comparable system fulfilling the legal requirements 
[1,2], will be used for data management at the study center. The Study Chair is responsible for its use.  
Before entry of the first patient into the study, it is extensively tested using fake data in all CRFs. 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 30 of 37 
12.2.2 Data security, access and back-up  
The Study Chair, and persons authorized by him, have access to data.  
The data management system chosen has built-in security and back-up functions fulfilling the legal 
requirements [1,2] (see 12.2.1). 
12.2.3 Analysis and archiving 
For interim and final analysis, data are extracted using built-in extraction procedures into a form 
readable by the software used for the statistical analysis (see 11.4.1). After analysis, data of withdrawn 
patients will be fully anonymized (see 8.3). The data are stored for a minimum of 10 years after 
termination of the study. 
12.2.4 Electronic and central data verification  
In the study center, CRFs are checked for completeness and consistency, and the primary outcome 
(SRE status of FN episodes, see 5.1.8, 5.2) and the chemotherapy intensity (see 5.1.6) are verified. 
The respective study sites are requested to provide missing information. Discrepancies are discussed 
with the study sites until resolved, and the written results of these discussions are stored in the study 
center. 
Data are then entered into the data management system (see 12.2.1), in which range checks and further 
consistency checks are implemented. Again, discrepancies are discussed with the study sites until 
resolved, and the written results of these discussions are stored in the study center.  
12.3 Monitoring  
The Sponsor will perform a risk-adapted monitoring according to its monitoring SOP. The source 
data/documents as well as the investigator site file are accessible to monitors and questions are 
answered during monitoring. The extent and nature of monitoring activities are described in a study 
specific monitoring plan written by the Sponsor. 
12.4 Audits and Inspections  
The SPOG routinely audits its member institutions. The study can be audited in the course of such 
audits. No additional audits are planned specifically for this study. The Sponsor and the authorities 
have the right to conduct audits and inspections. 
The study documentation and the source data/documents are accessible to auditors/inspectors, and 
questions are answered during inspections. All involved parties must keep the participant data strictly 
confidential. 
12.5 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purposes of monitoring (see 12.3), audits and 
inspections (see 12.4).  
The protocol is not confidential, it is intended to be made publicly available (see 13). 
The Sponsor has no access to non-coded patient data.  
The members of the Study Committee will have access to the anonymized dataset, the statistical code, 
and other relevant information during and after the study.  
A set of fully anonymized essential data can be made publicly available after publication of the main 
results. In the resulting publications, identification of participants will be impossible. 
13. PUBLICATION AND DISSEMINATION POLICY  
The main results of this study will be communicated to participants, their parent, and the involved 
healthcare professionals by a letter in lay language.  
The detailed results will be submitted for publication in peer-reviewed journals. The reporting 
requirements of the CONSORT statement, including its extension for reporting non-inferiority trials, 
will be fulfilled [37,48]. The current version of the ICMMJE recommendations [49] is applicable 
regarding authorship eligibility. The use of professional writers is not intended.  
The protocol is not confidential, it is intended to make it publicly available (see 12.5). A set of fully 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 31 of 37 
anonymized essential data can be made publicly available after publication of the main results. The 
Study Committee decides on all further aspects of publication. 
14. FUNDING AND SUPPORT  
Funding has been granted by Krebsliga Schweiz (KFS-3645-02-2015). This funding has no influence 
on study design, data collection and analysis, decision to publish, or preparation of the manuscript. 
Further support may be searched only from institutions that will have no influence on study design, 
data collection and analysis, decision to publish, or preparation of the manuscript. 
15. INSURANCE  
Insurance will be provided by the Sponsor in compliance with Swiss law. A copy of the certificate is 
filed in each study site file and the study master file. 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 32 of 37 
16. REFERENCES  
1. Bundesgesetz über die Forschung am Menschen (Humanforschungsgesetz, HFG) vom 30. September 2011. 
(http://www.bag.admin.ch/themen/medizin/00701/00702/07558/index.html?lang=de) 
2. Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische Versuche, KlinV) 
vom 20. September 2013. 
(http://www.bag.admin.ch/themen/medizin/00701/00702/12310/index.html?lang=de) 
3. Declaration of Helsinki, Version October 2013, 
(http://www.wma.net/en/30publications/10policies/b3/index.html )  
4. Wicki S, Keisker A, Aebi C, Leibundgut K, Hirt A, Ammann RA. Risk prediction of fever in neutropenia in 
children with cancer: a step towards individually tailored supportive therapy? Pediatr Blood Cancer 
2008;51:778-783. 
5. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for 
febrile patients with cancer and granulocytopenia. N Engl J Med 1971;284:1061-1065. 
6. Ammann RA, Bodmer N, Hirt A, Niggli FK, Nadal D, Simon A, et al. Predicting adverse events in children 
with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin 
Oncol 2010;28:2008-2014. 
7. Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, et al. Guideline for the management 
of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J 
Clin Oncol 2012;30:4427-4438.  
8. Hann I, Viscoli C, Paesmans M, Gaya H, Glauser M. A comparison of outcome from febrile neutropenic 
episodes in children compared with adults: results from four EORTC studies. Br J Haematol 1997;99:580-
588. 
9. Lüthi 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;59: 90-95. 
10. Lindblom A, Bhadri V, Soderhall S, Ohrmalm L, Wong M, Norbeck O, et al. Respiratory viruses, a common 
microbiological finding in neutropenic children with fever. J Clin Virol 2010;47:234-237. 
11. Santolaya ME, Farfan MJ, De La Maza V, Cocina M, Santelices F, Alvarez AM, et al. Diagnosis of 
bacteremia in febrile neutropenic episodes in children with cancer: Microbiologic and molecular approach. 
Pediatr Infect Dis J 2011;30:957-961. 
12. Phillips B, Selwood K, Lane SM, Skinner R, Gibson F, Chisholm JC. Variation in policies for the 
management of febrile neutropenia in United Kingdom Children's Cancer Study Group centres. Arch Dis 
Child 2007;92:495-498. 
13. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The Multinational Association 
for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile 
neutropenic cancer patients. J Clin Oncol 2000;18:3038-3051. 
14. Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, et al. Outpatient oral antibiotics 
for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol 
2006;24:4129-4134. 
15. Teuffel O, Ethier MC, Alibhai SM, Beyene J, Sung L. Outpatient management of cancer patients with febrile 
neutropenia: a systematic review and meta-analysis. Ann Oncol 2011;22:2358-2365. 
16. Teuffel O, Amir E, Alibhai SM, Beyene J, Sung L. Cost-effectiveness of outpatient management for febrile 
neutropenia in children with cancer. Pediatrics 2011;127:e279-286. 
17. Cheng S, Teuffel O, Ethier MC, Diorio C, Martino J, et al. Health-related quality of life anticipated with 
different management strategies for paediatric febrile neutropaenia. Br J Cancer 2011; 105: 606-611.  
18. Manji A, Beyene J, Dupuis LL, Phillips R, Lehrnbecher T, Sung L. Outpatient and oral antibiotic 
management of low-risk febrile neutropenia are effective in children--a systematic review of prospective 
trials. Support Care Cancer 2012;20:1135-1145. 
19. Phillips RS, Lehrnbecher T, Alexander S, Sung L. Updated systematic review and meta-analysis of the 
performance of risk prediction rules in children and young people with febrile neutropenia. PLoS One 
2012;7:e38300.  
20. Delebarre M, Macher E, Mazingue F, Martinot A, Dubos F. Which decision rules meet methodological 
standards in children with febrile neutropenia? Results of a systematic review and analysis. Pediatr Blood 
Cancer 2014;61:1786-1791. 
21. Gibson F, Chisholm J, Blandford E, et al. Developing a national 'low risk' febrile neutropenia framework for 
use in children and young people's cancer care. Support Care Cancer. 2013;21:1241-1251.  

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 33 of 37 
22. Oude Nijhuis C, Kamps WA, Daenen SM, Gietema JA, van der Graaf WT, Groen HJ, et al. Feasibility of 
withholding antibiotics in selected febrile neutropenic cancer patients. J Clin Oncol 2005;23:7437-7444. 
23. Binz P, Bodmer N, Leibundgut K, Teuffel O, Niggli FK, Ammann RA. Different fever definitions and the 
rate of fever and neutropenia diagnosed in children with cancer: A retrospective two-center cohort study. 
Pediatr Blood Cancer. 2013;60:799-805. 
24. Ammann RA, Teuffel O, Agyeman P, Amport N, Leibundgut K. The influence of different fever definitions 
on the rate of fever in neutropenia diagnosed in children with cancer. PLoS ONE 2015;10: e0117528. 
25. Fletcher M, Hodgkiss H, Zhang S, Browning R, Hadden C, et al. Prompt administration of antibiotics is 
associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer 
2013;60:1299-1306.  
26. Ammann RA, Tissing WJ, Phillips B. Rationalising the approach to children with fever in neutropenia. Curr 
Opin Infect Dis 2012;25:258-265. 
27. de Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F. Management of febrile 
neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21 Suppl 5:v252-256. 
28. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. 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;52:e56-93. 
29. Haeusler GM, Phillips RS, Lehrnbecher T, Thursky KA, Sung L, Ammann RA. Core outcomes and 
definitions for pediatric fever and neutropenia research: A consensus statement from an international panel. 
Pediatr Blood Cancer 2014;62:483-489. 
30. Craig JV, Lancaster GA, Taylor S, Williamson PR, Smyth RL. Infrared ear thermometry compared with 
rectal thermometry in children: a systematic review. Lancet. 2002;360:603-609.  
31. Nimah MM, Bshesh K, Callahan JD, Jacobs BR. Infrared tympanic thermometry in comparison with other 
temperature measurement techniques in febrile children. Pediatr Crit Care Med 2006;7:48-55. 
32. Haugan B, Langerud AK, Kalvoy H, Froslie KF, Riise E, Kapstad H. Can we trust the new generation of 
infrared tympanic thermometers in clinical practice? J Clin Nursing 2013;22:698-709. 
33. Kaz Europe SA (2014) Braun Thermoscan® (IRT 6520 / IRT 6020 MNLA/WE) product description. P/N: 
31IM0620190. Lausanne, Switzerland. pp 2-13.  
34. Kern WV, Cometta A, De Bock R, Langenaeken J, Paesmans M, Gaya H. Oral versus intravenous empirical 
antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N 
Engl J Med 1999;341:312-318. 
35. Feld R, Paesmans M, Freifeld AG, et al. Methodology for clinical trials involving patients with cancer who 
have febrile neutropenia: updated guidelines of the Immunocompromised Host Society/Multinational 
Association for Supportive Care in Cancer, with emphasis on outpatient studies. Clin Infect Dis 
2002;35:1463-1468. 
36. Sankoh AJ, Li H, D'Agostino RB, Sr. Use of composite endpoints in clinical trials. Stat Med 2014;33:4709-
4714. 
37. Centre for Disease Control and Prevention (CDC). Central Line-Associated Bloodstream Infection 
(CLABSI) Event. URL http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf.  
38. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis 
and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. 
39. Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG. Reporting of noninferiority and equivalence 
randomized trials: extension of the CONSORT 2010 statement. JAMA 2012;308:2594-2604. 
40. Teng CL, Ng CJ, Nik-Sherina H, Zailinawati AH, Tong SF. The accuracy of mother's touch to detect fever in 
children: a systematic review. J Trop Pediatr 2008;54:70-73. 
41. Food and Drug Administration. Guidance for industry non-inferiority clinical trials. Draft guidance 2010. 
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). 
42. Zermatten M. Fever and neutropenia in children with cancer. Consolidation of databases for future research 
on the topic. M Med thesis, Medical Faculty, University of Bern, Switzerland, 2014, unpublished. 
43. Venables WN & Ripley BD. Modern applied statistics with S. 4th ed. 2002, Springer, New York. 
44. R Core Team. R: A language and environment for statistical computing. 2014, R Foundation for Statistical 
Computing, Vienna, Austria. (http://www.R-project.org). 
45. Jennison C & Turnbull BW. Group sequential methods with applications to clinical trials. 1999, CRC, Boca 
Raton. 
46. Swiss Childhood Cancer Registry. Annual Report 2009/2010. URL 
http://www.kinderkrebsregister.ch/fileadmin/KKR08/uploads/pdf/20110427_Annual_Report_FINAL.pdf 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 34 of 37 
47. Brown H & Prescott R. Applied mixed models in medicine. 2006, Wiley, Chichester. 
48. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines 
for reporting parallel group randomised trials. Brit Med J 2010;340:c869. 
49. International Committee of Medical Journal Editors. Recommendations for the conduct, reporting, editing, 
and publication of scholarly work in medical journals updated December 2014. www.icmje.org/icmje-
recommendations.pdf 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 35 of 37 
17. APPENDICES 
A. List of Study Sites and Local Principal Investigators  
An updated List of Study Sites and Local Principal Investigators is available from the SPOG Office 
(see 1.1) 
 
B. Model Patient/Parent Information and Informed Consent forms 
Model versions of the following forms, all in German and French versions, are available from the 
SPOG Office (see 1.1): 
 
Patient Information, patients 11 to 13 years old 
 
Patient information, patients ≥14 years old 
 
Parents’ information 
 
Informed Consent 
 
C. Case Report Forms  
A set of paper CRFs is available from the SPOG Office (see 1.1) 
 
D. Amendment 1 
See pages 36 to 37 for an overview of Protocol changes introduced in Amendment 1, from Protocol 
version 1.0 of March 07, 2016, to version 1.1 of November 23, 2016. 
 
 

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 36 of 37 
 
Appendix D: Protocol changes introduced in Amendment 1,  
from Protocol version 1.0 of March 07, 2016, to version 1.1 of November 23, 2016 
Deleted items are marked as deleted, new items are marked in bold. 
1. Correction of typos 
 
 
 
 
 
 
     Minor typos have been corrected throughout all documents. 
 
2. Formal updates  
     a) Change, address SPOG (protocol 1.1) 
  
“Effingerstrasse 40 33” 
     b) Change, mail-address Katrin Scheinemann (protocol p.1) 
  
“katrin.scheinemann@luksukbb.ch“ 
     c) Change, mail address Karin Zimmermann (protocol p.1) 
  
“karin.zimmermann@inselunibas.ch 
     d) Change, mail address Philipp Agyeman (protocol p.1) 
  
“philipp.agyeman@gmail.cominsel.ch 
     e) Change, version number and date (throughout protocol)  
  
“1.0 / March 07, 2016 1.1 / November 23, 2016” 
     f) New, SNCTP number (protocol p.2, Synopsis, 2.1) 
  
“www.kofam.ch: SNCTP000001776” 
3. Additional members in Study Committee 
     Reason: Include PIs of initial set of recruiting Swiss study sites 
     a) New, PI of Geneva, Marc Ansari (protocol p.1) 
 
  
“Marc Ansari, MD   marc.ansari@hcuge.ch    Ped. Oncology” 
     b) New, PI of Lucerne, Johannes Rischewski (protocol p.1) 
  
“Johannes Rischewski, MD   johannes.rischewski@luks.ch    Ped. Oncology” 
4. Clarifications in the protocol 
     a) Adjust definition of “slightly elevated temperature”, and thus possible FN, to situations with continued use 
         of antipyretics (protocol 5.1.3) 
 
 
  
“… at least slightly elevated temperature (≥38.0°C ) … . In rare exceptions, to be discussed  
  
individually with the Study Chair / Study Vice Chair, this limit can be further lowered to 37.5°C 
  
 in patients repeatedly receiving antipyretics despite neutropenia, a practice strongly discouraged  
  
by this protocol.”  
     b) Clarify duration of FN episodes, considering restart of i.v. chemotherapy, adjust corresponding duration of  
         outcome tracking (protocol 5.1.5) 
  
“… same FN episode. Start of intravenous chemotherapy immediately ends an FN episode,  
  
overruling the preceding definition. Correspondingly, all outcomes are tracked … therapy for FN, as  
  
long as neutropenia persists and intravenous chemotherapy has not been started.” 
     c) Adjust to clinical reality: time delay allowed since last CBC used for decision on potential FNClin 
         (protocol 9.2.2) 
  
“(last CBC >48 [72 in unequivocal situations] hours old, or…” 
     d) Clarification of duties in processing SAE reports and which SAEs need to be reported to CECs  
         (protocol 10.2) 
  
“The Study Chair / Study Vice Chair checks SAE reports for medical consistency and for  
  
completeness, sends the respective queries to study sites where needed, and performs a plausibility  
  
check …. In parallel If a relatedness of the SAE to the intervention studied cannot be excluded the  
  
Sponsor  informs…  . If Sponsor and Study Chair / Study Vice Chair cannot resolve discrepancies  

 
_________________________________________________________________________________ 
SPOG 2015 FN Definition 
Version 1.1 of November 23, 2016 
 
Page 37 of 37 
  
regarding the question of such relatedness, an external expert is asked for advice.” 
     e) Clarification of timelines for reporting deaths in ongoing SAEs (protocol 10.2) 
  
“Deaths during ongoing SAEs have to be reported within the same timelines specified above (24  
  
hours or 7 days, respectively)” 
 
5. Allow participation of patients in/after myeloablative therapy followed by autologous  
    hematopoietic stem cell transplantation (synopsis, protocol 7.2) 
     Reason: New consensus among transplanting sites reached that study is feasible in autologous transplant  
     setting   
     in “Inclusion criteria”  
  
“Myelosuppressive (not myeloablative only) cChemotherapy treatment because of any malignancy  
  
planned for at least 2 further  months at time of recruitment for myelosuppressive therapy, or at least  
  
1 cycle of myeloablative  chemotherapy followed by autologous hematopoietic stem cell  
  
transplantation”  
     in “Exclusion criteria” 
  
“Past autologous or allogeneic hematopoietic stem cell transplantation” 
 
6. Clarification of end of study criteria  
     Reason: Addition of mandatory criterion, and completing the list of criteria in protocol (protocol 7.5) 
  
“7.5 Criteria for withdrawal / discontinuation / end of study of patients 
  
Patients are withdrawn from the study in case of withdrawal of informed consent, and when study  
  
participation is not in the best interest of the patient any more, including relevant non-compliance,  
  
as judged by the study site or the study center. The study ends regularly when they patients have  
  
reached the age of 20 years, at the end of the study as such, at the first day of or when they receive  
  
myeloablative chemotherapy before allogeneic hematopoietic stem cell transplantation  
  
(chemotherapy intensity 4, see 5.1.6), 21 days after the last dose of chemotherapy, or at the day of  
  
death from any cause.