A New Posaconazole Dosing Regimen for Paediatric Patients With Cystic Fibrosis and Aspergillus Infection
- Conditions
- Cystic FibrosisAspergillosis
- Interventions
- Registration Number
- NCT04966234
- Lead Sponsor
- Bambino Gesù Hospital and Research Institute
- Brief 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.
- Detailed 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 135
- 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]
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Posaconazole arm Posaconazole 40 MG/ML 90 patients (out of the 135 total patients, therefore with a 2:1 randomization ratio) will receive posaconazole for 12 weeks. Patients in the posaconazole arm will be stratified for body weight and positive sputum cultures for Aspergillus species. Patients will be followed-up for a total of 12 months post-randomization. Posaconazole arm Posaconazole 100 MG [Noxafil] 90 patients (out of the 135 total patients, therefore with a 2:1 randomization ratio) will receive posaconazole for 12 weeks. Patients in the posaconazole arm will be stratified for body weight and positive sputum cultures for Aspergillus species. Patients will be followed-up for a total of 12 months post-randomization.
- Primary Outcome Measures
Name Time Method Pharmacokinetic parameters of posaconazole At steady state, day 5-10 of treatment The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Half-life
Aspergillus isolation from sputum cultures 3 months after randomisation For evaluating the clinical efficacy of posaconazole, the outcome measure that will be analysed is the number of children with negative sputum sample for Aspergillus 3 months after randomisation.
- Secondary Outcome Measures
Name Time Method Pharmacokinetic parameters of posaconazole Day 21-35 and day 84 of treatment The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Half-life
Patients with a favourable clinical response and no signs of Aspergillus infection 3, 6 and 12 months after randomisation Percentage of patients who have a favourable clinical response (defined by pulmonary exacerbation rate, days on antibiotics and corticosteroids, hospital admissions, change in FEV1, change in BMI, CT-chest abnormalities, QoL)
The proportion of participants experiencing AEs and SAEs Up to 1 year after randomisation Assessed according to the Division of AIDS (DAIDS), Table for Grading of the NIAID, NIH, and the US Department of Health and Human Services.
Patients with no signs of Aspergillus infection 3, 6 and 12 months after randomisation Percentage of patients who have no signs of Aspergillus infection (defined by negative sputum cultures and negative serology).
Trial Locations
- Locations (31)
University Medical Center Groningen (UMCG)
🇳🇱Groningen, Netherlands
University Children's Hospital Zurich
🇨🇭Zürich, Switzerland
Centro Hospitalar Universitário Lisboa Norte EPE
🇵🇹Lisbon, Portugal
University Medical Center Utrecht (UMCU)
🇳🇱Utrecht, Netherlands
Centre hospitalier universitaire Dijon Bourgogne
🇫🇷Bourgogne, France
Motol University Hospital
🇨🇿Prague, Czechia
Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital
🇩🇪Bochum, Germany
Radboud University Medical Center (RUMC)
🇳🇱Nijmegen, Netherlands
Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin
🇩🇪Dresden, Germany
Erasmus Medical Center (EMC)
🇳🇱Rotterdam, Netherlands
IRCCS Istituto Giannina Gaslini
🇮🇹Genoa, Italy
Cystic Fibrosis Department, "Agia Sofia" Children's Hospital
🇬🇷Athens, Greece
Centre hospitalier universitaire Grenoble Alpes
🇫🇷Grenoble, France
University Hospital Southampton NHS FT
🇬🇧Southampton, United Kingdom
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
University Hospital Nottingham (Queens Medical Centre)
🇬🇧Nottingham, United Kingdom
University Hospitals of North Midlands NHS Trust
🇬🇧Stoke-on-Trent, United Kingdom
University of Parma Department of Medicine and Surgery
🇮🇹Parma, Italy
IRCCS Ospedale Pediatrico Bambino Gesù
🇮🇹Rome, Italy
Centre hospitalier universitaire de Montpellier
🇫🇷Montpellier, France
Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center
🇩🇪Essen, Germany
Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki
🇬🇷Thessaloniki, Greece
ASST Spedali Civili Paediatric department
🇮🇹Brescia, Italy
Cork University Hospital
🇮🇪Cork, Ireland
Hospital Universitario Materno Infantil Reina Sofia
🇪🇸Córdoba, Spain
Birmingham Women's and Children's NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Sheffield Childrens NHS Foundation Trust
🇬🇧Sheffield, United Kingdom
Medizinische Hochschule Hannover, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
🇩🇪Hannover, Germany
Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin, Pädiatrische Pneumologie/Allergologie/Mukoviszidose-Zentrum
🇩🇪Jena, Germany
Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística
🇪🇸Madrid, Spain