Primary: Dose finding for a twice daily regimen for PSZ as prophylactic treatment in children with CGD, based on the exposure to PSZ measured by PSZ trough levels.Secondary:To determine the tolerability of PSZ as prophylactic treatment in children…
ID
Source
Brief title
Condition
- Immune system disorders congenital
- Immunodeficiency syndromes
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Individual trough PSZ plasma concentrations, on basis of which the PSZ dosage
for individual patients will be adjusted.
Base on the results a dosage for future prophylaxis with PSZ in children with
CGD will be defined.
Secondary outcome
Biochemical en hematological parameters of individual patients.
Information from patients and/or parents about possible side-effects
experienced during the trial.
Background summary
At this moment itraconazole is the drug of first choice in the prophylaxis of
fungal infections in children with chronic granulomatous disease (CGD).
Breakthrough fungal infections while on itra-conazole prophylaxis are described
in literature indicating the need for a drug with a broader antifungal
spectrum. Posaconazol (PSZ) might provide in this need. PSZ may also have a
clinical safety and tolerability advantage over other antifungal agents.
Because PSZ is metabolized through phase II glucuronidation it is less common
to be subject to drug interactions. PSZ is known to be a CYP3A4 inhibitor, but
does not inhibit other CYP enzymes, therefore it may exhibit fewer drug
interactions as com-pared with other azole antifungal agents.
Treatment of children from age 8 and older has been described in literatur, but
it is still off-label use. No data have been published to date on the exposure
of PSZ in children under the age of 8 or in children with CGD. Yet with the
possibility of breakthrough fungal infections in CGD patients while on
itraconazole prophylaxis, there is an urgent need to study the use of PSZ in
these young children. Furthermore, the current regimen for antifungal
prophylaxis requires a three times daily administration of PSZ. For this
specific purpose less complex dosing schedules are warranted thus defining the
need to examine a twice daily schedule.
As the tolerability and pharmacokinetics are unknown in patients under the age
of 8 years and only limited data are available for age groups 8 to 16 years, we
propose a feasibility study of a twice daily regimen of PSZ prophylaxis in CGD
patients. With this information available we can suggest a dosage for future
prophylaxis in this patient group.
Study objective
Primary:
Dose finding for a twice daily regimen for PSZ as prophylactic treatment in
children with CGD, based on the exposure to PSZ measured by PSZ trough levels.
Secondary:
To determine the tolerability of PSZ as prophylactic treatment in children with
CGD.
Study design
Open-label, non-randomised, non-controlled, multi-centre, phase II trial.
Patients receive posaconazole (PSZ) twice daily based on a PSZ dosing scheme
for children (see Clinical Trial Protocol, 3.2.1 Dosing scheme, page 14).
On Day 10 the PSZ trough level is determined:
- if exposure to PSZ is adequate, prophylactic treatment with PSZ is continued,
- if exposure to PSZ is not adequate, the PSZ dosage is adjusted on Day 11.
On Day 20 the PSZ trough level is determined:
- if exposure to PSZ is adequate, prophylactic treatment with PSZ is continued,
- if exposure to PSZ is not adequate, the PSZ dosage is adjusted on Day 21.
On Day 30 the PSZ trough level is determined:
- the investigator and patient can agree to continue prophylactic treatment
with PSZ instead of returning to itraconazole.
If the PSZ trough level is inadequate (i.e. lower than 0.5 mg/L) the PSZ dosage
will be increased by 100%. In addition to the adjustment of the dosage
instructions concerning the intake of PSZ with food should be given repeatedly.
If the PSZ trough level is higher than 3 mg/L the PSZ dosage will be lowered by
50%.
An interim analysis will be presented after inclusion of 8 patients. If at this
point more than 4 patients have an inadequate PSZ trough level at Day 10, the
scheme for determining the starting dosage of PSZ will be revised.
Additionally, if at this point more than 1 patient suffers from an invasive
fungal infection, the trial will be terminated. This would imply a higher
incidence of invasive fungal infections in these patients than under
itraconazole prophylaxis (approximately 1 infection per 10 patients per
year.2). At termination of the trial patients are to return to itraconazole as
prophylactic treatment.
Intervention
Patients will be screend before entering the trial during a regular visit to
the outpatient clinic. Blood samples will be taken and an ECG will be made.
On Day 10 and 20 after start of intake of PSZ blood samples will be taken and
patients will be asked about possible side-effects. Medication will be taken
twice daily together with a meal.
During a regular visit to the outpatient clinic on Day 30 after start of intake
of PSZ blood samples will be taken and the trial will be completed.
Study burden and risks
Possible side-effects of PSZ are headache, dizziness, somnolence, nausea,
gastrointestinal problems and rash. These are the most frequently reported
side-effects and appear in only 6% of populations of healthy volunteers and
patients.
If the PSZ trough level is not high enough, a patient could be inadequately
protected against invasive fungal infections. By regularly measuring the PSZ
trough level and adjusting the individual PSZ dosage based on the trough level
we prevent patients from being inadequately protected against invasive fungal
infections.
The patient benefits from participation in this trial because posaconazole has
a broader antifungal spectrum than itraconazole. The group of CGD patients
benefits from this trial because a dosingscheme is defined for this specific
patientgroup.
Geert Grooteplein 10
6525 GA Nijmegen
Nederland
Geert Grooteplein 10
6525 GA Nijmegen
Nederland
Listed location countries
Age
Inclusion criteria
1. Patient has CGD, rendering him/her at risk for invasive fungal infections hence requiring antifungal prophylaxis.
2. Patient is at least 2 years of age and younger than 17 years of age on the day of the first dosing.
3. Parents or legal representative, and children where appropriate, willing and able to give informed consent.
Exclusion criteria
1. Patient is suspected of an invasive fungal infection.
2. Therapy with any medicinal product for which an effect on posaconazol is expected (see Clinical Trial Protocol, appendix B, Table 1). If patient is undergoing therapy with any medicinal product which may be effected by posaconazol, the patient is included on condition that the investigator judges that the effects are not clinically relevant (see Clinical Trial Protocol, appendix B, Table 2). This should be clearly recorded.
3. Documented history of sensitivity/idiosyncrasy to posaconazol.
4. Results of serum biochemistry and hematology testing are not higher than 3x the upper limit of normal (see Clinical Trial Protocol, appendix A). If the results exceed these limits, the pa-tient is included on condition that the investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
5. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
6. Relevant history or presence of cardiovascular disorder or renal and hepatic dis-order.
7. History of or current abuse of drugs, alcohol or recreational substances.
8. Participation in a trial with an investigational drug within 60 days prior to the first dose.
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 |
|---|---|
| EudraCT | EUCTR2008-004518-28-NL |
| CCMO | NL24490.091.08 |