Prospective validation and clinical evaluation of a new posaconazole dosing regimen for children and adolescents with cystic fibrosis and Aspergillus infection

Cystic fibrosis (CF) is the most common inherited life-limiting disease in
North European people affecting 90,000 people worldwide with about 45,000
registered in the Patient Registry of the European Cystic Fibrosis Society
(ECFS). Progressive lung damage caused by recurrent infection and persistent
inflammation is the major determinant of survival with a median age of death at
29 years. Approximately 60% of CF patients are infected with A. fumigatus [1],
a ubiquitous environmental fungus, and its presence is associated with
accelerated lung function decline. Half of the patients infected with
Aspergillus are < 18 years of age. Evidence to guide clinical management of
CF-related Aspergillus disease is lacking [2-4]. A recent survey showed
considerable variability in clinical practice among CF consultants [5].
Two-thirds would treat Aspergillus colonization in patients with CF and
two-thirds would use an azole antifungal in addition to steroids in the first
line treatment of CF-related allergic bronchopulmonary aspergillosis (ABPA).
The results of this survey underscore the limited evidence available to guide
management of Aspergillus infection in CF.
Posaconazole, being one of the 4 licensed triazole antifungals with good
efficacy against Aspergillus species has been chosen as the study drug as it
has a better tolerability compared to itraconazole, less toxicity and drug-drug
interactions compared to voriconazole, and can be administered once daily.
Posaconazole is licensed in Europe for the prevention of invasive aspergillus
in adult neutropenic patient populations and as salvage therapy for invasive
aspergillosis. A number of studies have reported on the safety and tolerability
of the use of posaconazole in children and adolescents with either
haematological malignancies, or chronic granulomatous disease, or those
undergoing haematopoietic stem cell transplantation [6-15]. Currently, no
dosing algorithm is available to guide posaconazole dosing in children and
adolescents with CF.
In clinical practice (based on feedback from individual centres), posaconazole
is often preferred above itraconazole if antifungal treatment is initiated in
children with CF. Nevertheless, the dosages prescribed are randomly chosen as
posaconazole is not licensed for use in patients < 18 yrs of age and it remains
unclear what the optimal dose for this age group will be.

- In silico definition of the most optimal posaconazole dose for children and
adolescents with CF aged 8 to 17 years.
- Assess the prevalence of Aspergillus infection in children and adolescents
with CF aged 8 -17 years.
- An intensive sampling pharmacokinetic study of posaconazole in a limited
number of children and adolescents with CF and Aspergillus infection aged 8 to
17 years to validate the model predicted dose and optimize the proposed dosing
algorithm.
- Prospective clinical evaluation of the defined posaconazole dosing regimen in
children and adolescents with CF and Aspergillus infection aged 8 to 17 year.
- Assess the tolerability and safety of posaconazole in children and
adolescents with CF and Aspergillus infection aged 8 to 17 years.
- Assess the clinical efficacy of posaconazole in terms of (1) clearance of
Aspergillus from the airways; (2) dampening airway inflammation, and (3)
clinical outcomes (as measured by pulmonary exacerbation rate, days on
antibiotics and corticosteroids, hospital admissions, change in FEV1, change in
BMI, CT-chest abnormalities)

Open-label, randomized, multi-center study.
An open-label randomized clinical study design has been chosen as the primary
aim of the study is the validation of a paediatric posaconazole dosing regimen
and is not a primary efficacy trial. We also have taken into consideration the
already existing onerous treatment burden of children and adolescents with CF.
The study is powered to validate a new posaconazole dosing regimen. In
addition, we will collect clinical and laboratory data to evaluate if
posaconazole has a beneficial effect in terms of clearance of the Aspergillus
infection, dampening inflammation and clinical outcomes. These data will be
used to inform a future efficacy trial.
Currently, posaconazole is not licensed for paediatric patients. It remains
unclear what the optimal dose for this age group will be. The first stage of
the research proposal is to define in silico the optimal dose for patients with
CF aged 8 - 17 years. For this purpose the new solid oral formulation will be
used as this pharmaceutical formulation has the best oral bio-availability and
allows for treatment in an outpatient setting. In addition recommendations will
be made for the oral suspension. The likelihood of its use during the present
study is low as the company (MSD) is preparing a new oral solution with
optimized bioavailability. Nevertheless, some patients may not be able to
swallow the posaconazole tablets and will require the oral solution.
We will derive a posaconazole dosing algorithm, for both the oral solution as
well as the delayed release tablet, by use of in silico modelling which is a
preferred new tool to prevent extensive *old-fashioned* PK studies with a high
number of samples per patient being taken. The modelling and Simulation Working
Party (MSWP) of the EMA is dedicated to drive towards a greater integration of
modelling and simulation in the development and regulatory assessment of
medicines. The EMA considers this methodology a powerful tool to provide the
opportunity to improve the efficiency of medicine development. It is
specifically considered to be of value in the paediatric population.
[https://www.ema.europa.eu/en/committees/working-parties-other-groups/chmp/model
ling-simulation-working-party]. We will use state-of-the-art modelling
techniques to define the dose of posaconazole, which will be further improved
by full PK data in a small cohort (n=24) of patients. Consequently, the defined
optimal dose will be used in the study population for validation.
The care of children and adolescents with CF is well structured and this study
will take advantage of that. The screening phase of the study is characterized
by a low-intensity study and will make use of samples and clinical data being
collected during regular clinic visits. For the intervention study, the
majority of the study visits are designed to be combined with regular clinical
visits, so additional study visits are limited in number.

In the screening phase:
Sputum samples are obtained as part of the standard of care practices with
blood samples taken at least once a year during annual review. The sputum and
blood sample needed for the screening will be obtained jointly with the
sampling doing for clinical reasons.

In the intervention phase:
Group 1:
Patients in group 1 will be treated with posaconazole for 12 weeks. Patients
will be divided in 3 weight based groups (< 30 kg; 30-40 kg; > 40 kg) to
validate the model predicted dose. Twenty-four patients will undergo intensive
PK sampling between day 5-10 of treatment with oral posaconazole. The patients
will be admitted to the hospital for one day and they will have an IV, for
taking the bloodsamples.
All the patients receiving posaconazole will come in for additional visits
between day 5 and 10 and between day 21 and 35; and at end-of-treatment for
therapeutic drug monitoring (TDM) and safety bloods (e.g. haematology and
biochemistry bloods) (WP IIIb; limited TDM sampling strategy to further improve
the model and reduce residual variability). Additional TDM measurements will be
performed if exposure is insufficient at the 2 time points defined. At
end-of-treatment patients will undergo the following assessments: Lung function
(FEV1), blood sample for Aspergillus-IgE and -IgG, safety monitoring bloods,
fungal culture on sputum, sputum inflammatory markers, BMI, pulmonary
exacerbations, days on i.v. antibiotics & oral corticosteroids, quality of
life, patient reported outcomes, quality of life (QoL; CFQ-R age specific).
(CT-chest optional).

Group 2:
Patients in group 2 (no antifungal treatment) will come in at 12 weeks (+/- 2
weeks to allow for combining study visit with routine outpatient clinic
appointment) and undergo the following assessments: Lung function (FEV1), blood
sample for Aspergillus-IgE and -IgG, fungal culture on sputum, sputum
inflammatory markers, BMI, pulmonary exacerbations, days on i.v. antibiotics &
oral corticosteroids, quality of life (QoL: CFQ-R age specific), patient
reported outcomes. (CT-chest optional).

The burden of this study is low to moderate.
The vast majority of the study visits are designed to coincide with the regular
clinical assessments. As lung function tests and sputum cultures are taken as
part of the standard of care, those will not add to the burden of taking part
to the screening part of our study. Blood samples are taken at least annually
in children with CF, and we will aim to combine the blood samples needed for
the screening part of the study (Aspergillus serology) as much as possible
(screening of children and adolescents during clinical annual review visit).
For those patients randomized to receive posaconazole, an additional 3 study
visits are needed to assess posaconazole plasma concentrations and safety.
Twenty-four patients will undergo an 8-hrs PK curve which will include the
insertion of an i.v.-line and admission to the day-care unit of the hospital.