A New Posaconazole Dosing Regimen for Paediatric Patients With Cystic Fibrosis and Aspergillus Infection

  • STATUS
    Recruiting
  • End date
    Nov 26, 2023
  • participants needed
    135
  • sponsor
    Bambino Gesù Hospital and Research Institute
Updated on 26 July 2021
voriconazole
respiratory symptom
posaconazole
fibrosis
itraconazole
sweat test

Summary

This study will provide: (1) new insights in the prevalence of Aspergillus infection in children and adolescents with CF aged 8-17 yrs; (2) an in silico modelled dose of posaconazole for children and adolescents with CF and Aspergillus infection aged 8-17 yrs; (3) an intensive sampling PK study to define the optimal dose in a limited number of children and adolescents with CF and Aspergillus infection aged 8-17 yrs; (4) a prospective clinical validation to reduce the residual variability and to allow investigation into PK-PD; and (5) an efficacy evaluation of this dosing regimen to treat Aspergillus infection in children and adolescents with CF to inform future primary efficacy trials.

Description

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, 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. A recent survey showed considerable variability in clinical practice among CF consultants. 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. Several 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. Currently, no dosing algorithm is available to guide posaconazole dosing in children.

Details
Condition Lung Disease, Fungal Infections, Mycoses, Pancreatic disorder, Cystic Fibrosis, Aspergillosis, Systemic Fungal Infections, Pancreatic Disorders, Pulmonary Disease
Treatment Posaconazole 100 MG [Noxafil], Posaconazole 40 MG/ML
Clinical Study IdentifierNCT04966234
SponsorBambino Gesù Hospital and Research Institute
Last Modified on26 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Diagnosed with cystic fibrosis (genetic diagnosis and/or abnormal sweat test and clinical phenotype of lung disease)
Age 8 yrs and < 18 yrs
Body weight 20 kg
Presence of Aspergillus infection as defined for this study
Clinically stable condition without a significant change in lung function (FEV1 +/- 10%) or significant worsening of respiratory symptoms over the previous month
Able to perform lung function test (FEV1%)
Able to produce a sputum sample (spontaneous or induced sputum)
Informed Consent given
If female and of childbearing age must be using highly effective contraception (and must agree to continue for 7 days after the last dose of investigational medicinal product [IMP]

Exclusion Criteria

Non-CF lung disorder
Age < 8 yrs or 18 yrs
Body weight < 20 kg
Not able to perform lung function test (FEV1%)
Unable to produce a sputum sample (spontaneous or induced sputum)
Clinically unstable condition with significant change in lung function or significant worsening of respiratory symptoms
Unable to tolerate oral medication
Known hypersensitivity to itraconazole or posaconazole, or it's excipients
On active transplant list or transplant recipient
Azole resistant Aspergillus sp. cultured
Patients receiving terfenadine, ergot alkaloids, astemizole, cisapride, pimozide, halofantrine, quinidine, or HMG-CoA reductase inhibitors metabolised through CYP3A4 (eg. simvastatin, lovastatin, and atorvastatin)
Patients receiving omalizumab
Received systemic mould-active antifungals in the last month
Shortened or elongated QT interval
Cardiac failure
ALT 200 U/L
AST 225 U/L
Alkaline phosphatase 460 U/L
Bilirubin 50 umol/L
eGFR < 20 ml/min/1.73 m2 (calculated with the Schwartz formula)
Patients with known glucose-galactose malabsorption problems
Pregnancy2 or breastfeeding
Females of childbearing age who do not intend to use contraception measures
Informed Consent not given
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