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

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

Official Title
-----------------
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)

Conditions
-----------------
Cancer, Pediatrics, Fever, Neutropenia, Fever in Neutropenia

Intervention / Treatment
-----------------
* Other: 39.0°C temperature limit defining fever
* Other: 38.5°C temperature limit defining fever


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chemotherapy treatment because of any malignancy for at least 2 months at time of recruitment for myelosuppressive therapy, or at least 1 cycle of myeloablative chemotherapy followed by autologous hematopoietic stem cell transplantation Age ≥12 months and <18 years at time of recruitment Written informed consent from patients and/or parents Exclusion Criteria: Infants <1 years old (reason: differences in temperature measurement method) Past allogeneic hematopoietic stem cell transplantation Denied written informed consent from patients and/or parents

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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