The primary objective of this trial is as follows:• To determine the pharmacokinetics of micafungin 300 mg given twice weekly on Mondays and Thursdays in patients at risk for developing an invasive fungal disease (patients who are being treated for…
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
An initial non-compartmental pharmacokinetic analysis will be performed using
Phoenix 64 (Pharsight Corporation, CA, USA).
Results from the noncompartmental analysis will be used as initial input in for
the compartmental analysis. A pharmacokinetic model will be fitted to the data
from all individuals simultaneously. Data will be analyzed using non-linear
mixed effects modelling (NONMEM). NONMEM is a one-stage analysis that
simultaneously estimates mean parameters, fixed effect parameters,
interindividual variability, and residual random effects. Since allowance can
be made for individual differ-ences, this method can be used with both
intensive sampling and sparse data (and in the occasion of missing values: an
unbalanced number of data points per patients.
Multiple compartment models with first-order or saturable elimination will be
tested. Between subject variability (BSV) and, when applicable, between
occasion variability (BOV) will be included on all pharmacokinetic parameters.
Residual unexplained variability (RUV) will be estimated with additive or
proportional error models. The first-order conditional estimation method with
interaction will be used, other estimation methods like SAEM of non-parametric
methods may be investigated. The effect of concomitant use of co-medication
will be included as dichotomous covariate on the appropriate parameters (i.e.
clearance). The log-likelihood ratio test will be used to assess significance
of this effect, with a p-value of 0.05 as significance cut-off. Other
co-variates will be tested in this analysis.
Finally, simulations may be performed to justify the appropriateness of this
dosing scheme for antifungal prophylaxis.
Secondary outcome
Safety of micafungin at alternate dosing strategies.
Background summary
Micafungin has been shown to be a reasonable option for treating invasive
as-pergillosis in HSCT recipients and has proven as effective as fluconazole
for pro-phylaxis. Whilst micafungin has much to offer, little is known about
its pharma-cokinetic profile in specific patient populations, specifically
concerning alternate dosing strategies with increased dosages over a prolonged
dosing interval. Suffi-cient data are lacking up to now for twice weekly
administration of micafungin as antifungal prophylaxis. Decreasing the dosing
frequency to two times weekly (Monday - Thursday) seems a reasonable approach
considering the long terminal elimination life (i.e. 10-17 h) and considering
the data available from murine models that support the use of less frequent
dosing with higher dosages. In addi-tion, this dosing will support ambulatory
care for this indication which becomes more important for patient convenience
and costs and sometimes is also possible for patients with graft versus host
disease.
The ultimate goal is to perform a monte carlo simulation providing the
necessary scientific background to support alternate dosing strategies in the
setting of pro-phylaxis. A first step is to define the pharmacokinetics in this
cohort of patients to provide the scientific justification for such an
alternate dosing scheme. It would be possible to determine pharmacokinetics of
micafungin in a single arm strategy. But the proposed setup comparing daily
micafungin to a twice weekly micafungin dosing regimen has some advantages. It
will enable us to characterize both the pharmacokinetics of micafungin in the
hematology cohort and directly compare the exposure to the alternate dosing
strategy. Therefore it seems prudent to conduct a trial in a cohort of patients
who have no evidence of invasive fungal diseases (IFD) but are at risk to IFD
describe their exposure to the drug in an al-ternative dosing regimen of
micafungin given twice weekly versus daily mica-fungin.
Study objective
The primary objective of this trial is as follows:
• To determine the pharmacokinetics of micafungin 300 mg given twice weekly on
Mondays and Thursdays in patients at risk for developing an invasive fungal
disease (patients who are being treated for acute or chronic graft versus host
disease; patients receiving reduced intensity conditioning for SCT; receiving
first remission induction chemotherapy for AML/MDS) compared to the
pharmacokinetics of micafungin 100 mg given daily to the same population
The secondary objective of this trial is as follows:
• To determine whether adequate exposure of micafungin is attained and to
perform Monte Carlo simulations to provide the scientific background for
al-ternate dosing strategies in the prophylactic setting
• To determine the safety of micafungin in this patient population
Study design
Open-label, multi-centre, phase-II, randomised, multiple-dose trial
Intervention
• 15 subjects (group A) will start with twice weekly 300 mg micafungin at 8.00
AM on Mondays and Thursdays. They can start on either Monday or Thursday with
the first dose. Micafungin will be infused over a 3 hour period. A total of 3
dosages will be ad-ministered to patients.
• 2 PK curves will be determined on days 4 or 5 (after 2 dosages; 4 in case of
start on Monday, 5 in case of start on Thursday) and 8 (after 3 dosages).
• Day 9-11: washout period to determine elimination of micafungin.
Study burden and risks
The risk-classification is assessed as negligible to the patient population
receiving study drug at the current regimens. The drug is licensed for the use
investigated in this protocol. Safety data on the use of higher dose are
published and very-well defined. There is no attributable risk for the
application of the study protocol to the hematology patients at risk for fungal
infections.
Geert Grooteplein 10
Nijmegen 6525GA
AF
Geert Grooteplein 10
Nijmegen 6525GA
AF
Listed location countries
Age
Inclusion criteria
1. Patient receives immunosuppressive therapy for acuteGvHD grade II-IV or reduced in-tensity conditioning regimens for allogeneic stem cell transplant, or patients receiving first remission induction chemotherapy for AML/MDS. ;2. Subject is at least 18 of age on the day of providing informed consent.;3. Has no signs or symptoms of invasive fungal disease;4. If a woman, is neither pregnant nor able to become pregnant and is not nursing an infant;5. Less than 1 week of immunosuppressive therapy for grade II-IV acute GvHD;6. Is managed with a central venous catheter (preferably a quadruple Ar-row-Howes* Quad-Lumen 8.5,5 French; Arrow International);7. Subject is able and willing to sign the Informed Consent before screening evaluations.
Exclusion criteria
1. Documented history of sensitivity to medicinal products or excipients similar to those found in the micafungin preparation;2. History of or current abuse of drugs, alcohol or solvents. ;3. Inability to understand the nature of the trial and the procedures re-quired.;4. Has not previously participated in this trial.
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 | EUCTR2013-002848-93-NL |
| CCMO | NL46527.091.13 |