Cancer, Fever, Fever in Neutropenia, Neutropenia, Pediatrics
Conditions
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.
Interventions
OTHER38.5°C temperature limit defining fever
Diagnosis of FN, correspondingly hospitalization and start of empirical intravenous broad-spectrum antimicrobial therapy. Further treatment according to treating physician.
OTHER39.0°C temperature limit defining fever
Diagnosis of FN, correspondingly hospitalization and start of empirical intravenous broad-spectrum antimicrobial therapy. Further treatment according to treating physician.
Sponsors
Swiss Pediatric Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of clinically defined FN with at least one safety relevant event | 1 year (estimated average) | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of FN diagnosed at/above TLDF (E) | 1 year (estimated average) | 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) |
| Duration of treatment (F) | 1 year (estimated average) | . Duration of hospitalization, ICU treatment, i.v. antibiotics, p.o. antibiotics, any antibiotics, delay of chemotherapy for FN (unit: days) |
| Simultaneous and avoided FN diagnoses (G) | 1 year (estimated average) | 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) |
| Times and delays of diagnosis and therapy (A) | 1 year (estimated average) | 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) |
| Adverse events (B) | 1 year (estimated average) | 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) |
| Delay from crossing low to high TLDF (C) | 1 year (estimated average) | 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) |
| Rate of clinically defined FN (D) | 1 year (estimated average) | 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) |
| Rate of FN diagnosed below TLDF (E) | 1 year (estimated average) | 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| External validation of rules predicting risk of FN during chemotherapy | 1 year (estimated average) | Validation of published risk prediction rules for clinically defined FN, clinically defined FN with bacteremia, with serious medical complication, and with safety relevant event during chemotherapy (units: sensitivity, specificity, positive and negative predictive value, area under receiver operating characteristic curve) |
| External validation of rules predicting risk of adverse events during FN | 1 year (estimated average) | Validation of published risk prediction rules for bacteremia, for serious medical complication, and for safety relevant event during FN (units: sensitivity, specificity, positive and negative predictive value, area under receiver operating characteristic curve) |
| Development of rules predicting risk of FN during chemotherapy | 1 year (estimated average) | Risk prediction rules for clinically defined FN, clinically defined FN with bacteremia, with serious medical complication, and with safety relevant event during chemotherapy, all based on multivariate mixed Poisson regression (stepwise forward variable selection procedure; unit: predictor) |
| Development of rules predicting risk of adverse events during FN | 1 year (estimated average) | Risk prediction rules for bacteremia, for serious medical complication, and for safety relevant event during FN, all based on multivariate mixed logistic regression (stepwise forward variable selection procedure; unit: predictor) |
Countries
Switzerland
Outcome results
None listed