This study has been transitioned to CTIS with ID 2023-506546-23-00 check the CTIS register for the current data. Objectives safety run-in: The primary objective is:• To assess the safety of i.v. teicoplanin prophylaxis three times per week with a…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety run-in:
The number of DLTs observed.
Randomized controlled trial:
The (first) occurrence of culture-proven BSIs with VGS during initial AML
treatment;
Date(s) of BSI(s) with VGS
Secondary outcome
Safety run-in:
PK parameters of teicoplanin, e.g.,
Css,max; Css,min; Tss,max; Area under the curve
T1/2; Clearance (inter-compartmental, total, renal fraction); Volume of
distribution (central and peripheral)
Randomized controlled trial:
1. the number of BSIs with culture-proven bacteria
2. Results of all positive blood cultures
3. Infection-related (pediatric) intensive care admissions;
4. The number of episodes/admissions with (neutropenic) fever; days with fever
(with or without neutropenia), days with FN, days with neutropenia
5. Infection-free survival time, i.e., time from diagnosis till first
culture-proven BSI;
6. Infection-related mortality;
7. Number of days until neutrophil recovery (ANC of >=0.5 x10^9/L following the
nadir)
8. Resistance patterns of pathogenic isolates from blood cultures;
9. Incidence of resistant bacteria in (routine) throat and rectal surveillance
cultures, e.g.,; VRE
10. AEs of special interest (see section 8.2.4),
11.Serious adverse events (SAEs) (see section 8.2.3);
12. Use of (other) antibiotics, antifungals and antivirals;
13. Serum creatinine levels
14. Serum levels of teicoplanin
15. Cumulative incident of relapse
16. Event-Free survival
17. Overall survival
Background summary
As a result of an impaired immune system and severely impaired mucosal barriers
due to chemotherapy (in particular high-dose cytarabine), pediatric patients
with AML are at high risk of developing severe infections. Viridans Group
Streptococci (VGS) are a prevalent cause of Gram-positive bloodstream
infections (BSIs) in pediatric AML patients, with an incidence up to 30%. BSIs
with VGS are associated with severe complications and often result in sepsis,
which is associated with intensive care admission rates up to 60% in some
series, and mortality rates up to 20%. Nonetheless, no antibiotic VGS
prophylaxis is recommended by (inter)national guidelines in pediatric AML
patients, because of the lack of supporting evidence.
Recently, a retrospective cohort study conducted by the
Berlin-Frankfurt-Münster (BFM)-AML-Austria Study Group (SG) reported a complete
eradication of VGS sepsis and a decrease of approximately 40% in episodes of
febrile neutropenia (FN) in pediatric AML patients whom received prophylactic
i.v. teicoplanin.
Is this study the results of the BFM-AML Austria SG will be validated
prospectively.
Study objective
This study has been transitioned to CTIS with ID 2023-506546-23-00 check the CTIS register for the current data.
Objectives safety run-in:
The primary objective is:
• To assess the safety of i.v. teicoplanin prophylaxis three times per week
with a two to three days interval in children with newly-diagnosed AML.
A patient will be considered evaluable for safety if they experience a DLT
during a prophylactic cycle with teicoplanin or, in case no DLT occurs, if
exposure to teicoplanin is either at least 2 consecutive weeks with at least 5
doses of teicoplanin or at least 3 weeks in total with at least 6 out of 9
doses of teicoplanin, or 8 out of 12 doses in case of 4 weeks, or 10 out of 15
doses in case of 5 weeks.
The secondary objective is:
• To (preliminary) characterize the PK parameters of teicoplanin in children
with newly-diagnosed AML.
Objectives randomized phase:
The primary objective is:
• To evaluate whether i.v. teicoplanin prophylaxis in children with
newly-diagnosed AML decreases the occurrence of culture-proven BSIs with VGS
during treatment.
See for the secondary objectives protocol section 2.2
Study design
Prospective, international, multicenter, open-label, randomized clinical trial,
preceded by a safety run-in. The design for the safety run-in includes the
Rolling 6 design based on dose-limiting toxicity (DLT). The number of patients
to be included in the safety run-in depends on the occurrence of DLTs and may
vary from 6 to 24 patients. The sample size for the randomized phase of the
study is 122 patients.
An interim analysis will be performed after inclusion of 75% of the evaluable
patients (n=92). See protocol section 9.4.
Intervention
Intervention group: The safety run-in cohort will receive i.v. teicoplanin
prophylaxis 20 mg/kg/once daily three times per week via the central venous
line (CVL), which all AML patients have. The interval between two
administrations should be no less than 48 hours and no longer than 72 hours
(e.g., Monday, Wednesday and Friday or Tuesday, Thursday and Saturday).
The start of a cycle with teicoplanin is planned to start within 24 hours after
the last day of a chemotherapy course (i.e. on the last day of a chemotherapy
course or within 72 hours thereafter), and will be continued until the first of
the following events: an absolute neutrophil count of >=0.5 x10^9/L following
the nadir and/or the start of the next chemotherapy course.
Consecutive eligible patients in the randomized phase allocated to the
intervention arm will continue with this dosing schedule if considered safe, or
with a de-escalated dose of 15 mg/kg/once daily three times per week if
toxicity occurs.
Control group: The control group will receive standard of care (SOC), which
does not include teicoplanin prophylaxis in accordance with local guidelines.
See protocol for details.
Study burden and risks
Consequences of study participation include the administration of teicoplanin,
the risk of adverse reactions and events, and the additional PK blood samples
drawn from the CVL. Considering the broad experience with therapeutic
teicoplanin in the treatment of both adults and children and its generally mild
toxicity profile, risk of participating in this study is considered low. The PK
sampling strategy is minimally invasive, since all pediatric AML patients
require a CVL.
Given the differences in pharmacodynamics, infection-risk, treatment protocols
and survival between adults and children with AML, a similar study conducted in
adults cannot be extrapolated to children. This rectifies the use of minors,
under the strict regulations that are available and will be applied.
See protocol section 12.
Heidelberglaan 25
Utrecht 3584 CS
NL
Heidelberglaan 25
Utrecht 3584 CS
NL
Listed location countries
Age
Inclusion criteria
- Newly diagnosed with AML
- Being registered and starting treatment according to the NOPHO-DBH AML 2012
study protocol, or a consecutive protocol
- Age 0-19 years
- Written informed consent by the patient and/or legal guardians (whatever
applicable according to the patients age)
Exclusion criteria
- Acute promyelocytic leukemia
- Secondary AML
- Down Syndrome
- Preexisting primary immunodeficiency
- Patients who receive regular antibiotic prophylaxis against Gram-positive
bacteria for other conditions than leukemia-related
- Patients with a history of an anaphylactic reaction (CTCAE grade >=3) to
teicoplanin and/or vancomycin
- Patients with an eGFR of <30 ml/min/1.73m2 at the start of the study
- Patients with a history of severe impaired hearing (CTCAE grade >=3)
- Pregnant or breast-feeding patients
- Patients that are participating in another clinical study with an IMP, that
interferes with the study objectives.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-506546-23-00 |
| EudraCT | EUCTR2020-000508-13-NL |
| CCMO | NL72779.041.20 |
| Other | NTR nummer: Trial NL8130 |