Primary Objectives 1. To evaluate the pharmacokinetics of fluconazole and micafungin both administered after randomization in neonates with suspected or culture-proven Candidiasis in order to validate their optimal dosage and identify covariates…
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study parameters/outcome of the study: protocol pg. 21
- Time to reach the AUC breakpoint and the ratio of AUC/MIC90s in the two
treated groups.
- The theoretical MIC90s against the common pathogens responsible for the
infection to be treated will be used by opposition with the *real MIC90* of the
agent really involved that is rarely isolated.
Secondary outcome
Secondary study parameters/outcome of the study: protocol pg 21-25
Covariates collection:
The following procedures or evaluations will be performed on the days of PK
study and the data recorded as indicated:
1. Record study drug dosing information.
2. Record all concomitant antimicrobials including drug name and dosing
information.
3. Record nutrition information.
4. Weight, height, postnatal age, gestational age.
5. Associated pathology.
6. The following clinical laboratories values: a. Hematology: hematocrit,
hemoglobin, white blood cell count with differential, absolute neutrophil
count, platelet count b. Serum chemistry: creatinin, blood urea nitrogen,
sodium, potassium, chloride, calcium, magnesium, total protein, albumin c.
Liver function tests: aspartate transaminase (AST), alanine transaminase (ALT),
alkaline phosphatase, total bilirubin, conjugated bilirubin d. Renal function
tests: urine protein.
The tolerability and safety criteria evaluation will include the collection of:
Adverse Event/Adverse Reaction, reasons for withdrawal, global physical
examination, vital signs, laboratory test evaluations.
Background summary
The epidemiology of candidiasis is rapidly changing; recent estimates are that
nearly 50% of Candida bloodstream isolates are non-albicans Candida species
requiring the use of treatments active against them. Because of the high risk
associated with candida infection in premature babies, fluconazole prophylaxis
is now recommended in NICUs with a high incidence in fungal infections. Both
Fluconazole and Amphotericine B are routinely used in neonates when there is a
suspected or proven invasive Candidiasis. Micafungin is hardly prescribed in
neonates since Pk-data is limited. However, the main advantages is a better
sensitivity for non-albicans Candida-strains.
As candida infection is difficult to prove and requires an urgent treatment, in
particular to avoid CNS infection, treatment is often started in high risk
patients when the infection is only suspected, i.e. on clinical arguments
without waiting for positive cultures (10% of cases).
Fluconazole has not been approved for use in the treatment of neonatal
candidiasis. In contrast, the efficacy of echinocandins for the treatment of
invasive candidiasis has been suggested by pre-clinical and clinical studies.
Related to Micafungin, the available data support the idea that only dosages
that are greater than what currently recommended in infants (that is, 2 to 4
mg/kg/day) may ensure adequate coverage of the CNS given that ability of low
dosages of micafungin to penetrate the cerebrospinal compartment and to diffuse
in the cerebrospinal fluid is deemed suboptimal.
Therefore, the current study is designed to determine whether micafungin is as
efficacious as the current standard of fluconazole, as well as, compare the
safety of the drugs in the treatment of proven neonatal candidiasis. It is also
designed to further elucidate the pharmacokinetics of the two products in the
growing and developing neonate and premature infant.
The doses that will be administered are higher that currently used in order to
optimize efficacy. The concept of a loading dose is present in antifungal
treatment strategies for adults, but it has never been applied to infants and
preterm neonates. It will be used for both drugs in the present project.
The protocol should be able to recommend fluconazole for prophylaxis and
micafungin for the treatment of fungal infections in newborns.
Study objective
Primary Objectives
1. To evaluate the pharmacokinetics of fluconazole and micafungin both
administered after randomization in neonates with suspected or culture-proven
Candidiasis in order to validate their optimal dosage and identify covariates
that impact pharmacokinetics including drug interactions and pharmacogenetic
factors.
2. To compare the time to reach the target drug exposure, i.e. the area under
the concentration-time curve from 0 to 24 h (AUC0-24) for candidiasis by the
two randomly administered drugs.
Secondary Objectives
1. To evaluate the tolerability of fluconazole and micafungin in neonates with
suspected or culture-proven Candidiasis.
2. To describe short-term safety.
3. To describe short term outcome of treated episodes.
Study design
This is a phase 2-3, randomized, multicenter, parallel group comparing
pharmacokinetics and safety of fluconazole and micafungin. This study will have
2 arms, with 1 group randomized to fluconazole and 1 group randomized to
micafungin.
Intervention
• Treatment: Randomization (1:1): Fluconazole (25mg/kg loading dose; 12mg/kg or
20 mg/kg daily according to gestational and postnatal age) OR Micafungin
(15mg/kg loading dose; 10 mg/kg daily)
• Pharmacokinetics (fluconazole or micafungin treatment):
If the gestational age <= 32 weeks ( at the time of recording / randomization )
:
Group A: Hours of sampling on day 1 and day 5 of treatment: at 2 h &
12 h; Total blood volume: 400 µL
Group B: Hours of sampling on day 1 and day 5 of treatment: at at 2 h
& 18 h; Total blood volume: 400 µL
If the gestational age >= 32 +1 weeks ( at the time of recording / randomization
) :
Group C: Hours of sampling on day 1 and day 5 of treatment: at 2 h, 4 h
& 16 h; Total blood volume: 600 µL
Group D : Hours of sampling on day 1 and day 5 of treatment: at 2.5 h,
10 h & 24 h; Total blood volume: 600 µL
Pharmacokinetic samples at Day 1 and 5 will only be drawn if there is a central
line or if peripheral blood is taken for medical reasons
• Pharmacogenetic sample (protocol pg.36): It is aimed to extract DNA from the
cells left over after centrifugation of the plasma EDTA samples to reduce the
amount of blood taken from the neonate therefore no additional sample will be
required.
• Cerebrospinal fluid sample (CSF) (protocol pg.36): CSF sample will not
specifically be performed for the study. Only if it is performed for routine
diagnostic procedure, a sample (0,2 ml) will be taken for the study.
Study burden and risks
- The additional blood samples are drawn from a line (arterial line) already
in place for his treatment or if the child has to be already punctured for his
standard care.
- Fluconazole and Micafungin: Both drugs are used for many years in neonates:
fluconazole for over fifty years and micafungin more recently as this drug has
been approved for neonate use since 2008. Use of both drugs hold very little
risk. This risk includes biological abnormalities related to the liver, such as
an increase in the transmaminases.
rue de Tolbiac 101
Paris Cedex 13 75654
FR
rue de Tolbiac 101
Paris Cedex 13 75654
FR
Listed location countries
Age
Inclusion criteria
1. Neonates and infants between 24 up to 42 weeks gestational age AND with a post-natal age of 48 hours of life up to day of life (DOL) 120 at the time of culture acquisition.
2. Requiring antifungal therapy according to medical decision by the attending physician for microbiologically documented or clinically suspected candida infection independently from the availability of any positive culture for Candida spp (see protocol appendix 1)
3. Written informed consent from the parents or the legally authorized representative must be obtained prior to entry.
4. Infant must have sufficient venous access to permit administration of study medication and monitoring of safety variables.
Exclusion criteria
1. Infant exposed to fluconazole or micafungin prophylaxis prior to inclusion
2. Infant who has received more than 48 hours of systemic antifungal therapy (any product) prior to the first dose of study drug for treatment of the current Candida infection.
3. Infant with a concomitant medical condition, whose participation, in the opinion of the Investigator and/or medical advisor, may create an unacceptable additional risk.
4. Infant previously enrolled in this study.
5. Infant who is co-infected with a non-Candida fungal organism.
6. Neonates with isolated candiduria
7. Infant with any history of a hypersensitivity or severe vasomotor reaction to any echinocandin or fluconazole product
8. Infant with pre-existing hepatic or renal disease
9.Infants with baseline Candida spp. Isolate resistant to fluconazole or micafungin according to EUCAST/CLSI clinical breakpoints (see section 5.2.2 for interpretative MIC criteria) or with an isolate for which treatment with an alternative antifungal agent is indicated, i.e. there is insufficient evidence that the species in question is a good target for therapy with either fluconazole or micafungin.
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 | EUCTR2012-001916-41-NL |
| CCMO | NL45035.078.14 |