Clinical trial NCT04966234: A New Posaconazole Dosing Regimen for Paediatric Patients With Cystic Fibrosis and Aspergillus Infection
Official title: Prospective Validation and Clinical Evaluation of a New Posaconazole Dosing Regimen for Children and Adolescents With Cystic Fibrosis and Aspergillus Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Cystic Fibrosis
Aspergillosis
Keywords: Posaconazole
Progressive lung damage
Recurrent infection
Persistent inflammation
Better tolerability
Paediatrics
Adolescents
Therapeutic drug monitoring
Pharmacokinetics
Cystic Fibrosis
Aspergillosis
Lead sponsor: Bambino Gesù Hospital and Research Institute
Sponsor class: OTHER
Collaborators: name: University of Exeter
name: Radboud University Medical Center
name: Consorzio per Valutazioni Biologiche e Farmacologiche
First posted: 2021-07-19
Enrollment: 135
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, randomized, multi-center study
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Diagnosed with cystic fibrosis (genetic diagnosis and/or abnormal sweat test and clinical phenotype of lung disease)
2. Age ≥ 8 yrs and \< 18 yrs
3. Body weight ≥20 kg
4. Presence of Aspergillus infection as defined for this study
5. Clinically stable condition without a significant change in lung function (FEV1 +/- 10%) or significant worsening of respiratory symptoms over the previous month
6. Able to perform lung function test (FEV1%)
7. Able to produce a sputum sample (spontaneous or induced sputum)
8. Informed Consent given
9. 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:

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

Primary outcomes:
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: At steady state, day 5-10 of treatment
measure: Aspergillus isolation from sputum cultures
timeFrame: 3 months after randomisation
Secondary outcomes:
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Pharmacokinetic parameters of posaconazole
timeFrame: Day 21-35 and day 84 of treatment
measure: Patients with a favourable clinical response and no signs of Aspergillus infection
timeFrame: 3, 6 and 12 months after randomisation
measure: Patients with no signs of Aspergillus infection
timeFrame: 3, 6 and 12 months after randomisation
measure: The proportion of participants experiencing AEs and SAEs
timeFrame: Up to 1 year after randomisation
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Motol University Hospital
city: Bourgogne
country: France
facility: Centre hospitalier universitaire Dijon Bourgogne
city: Grenoble
country: France
facility: Centre hospitalier universitaire Grenoble Alpes
city: Montpellier
country: France
facility: Centre hospitalier universitaire de Montpellier
city: Bochum
country: Germany
facility: Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital
city: Dresden
country: Germany
facility: Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin
city: Essen
country: Germany
facility: Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin, Pädiatrische Pneumologie/Allergologie/Mukoviszidose-Zentrum
city: Athens
country: Greece
facility: Cystic Fibrosis Department, "Agia Sofia" Children's Hospital
city: Thessaloniki
country: Greece
facility: Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki
city: Cork
country: Ireland
facility: Cork University Hospital
city: Brescia
country: Italy
facility: ASST Spedali Civili Paediatric department
city: Genoa
country: Italy
facility: IRCCS Istituto Giannina Gaslini
city: Parma
country: Italy
facility: University of Parma Department of Medicine and Surgery
city: Rome
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù
city: Groningen
country: Netherlands
facility: University Medical Center Groningen (UMCG)
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center (RUMC)
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center (EMC)
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht (UMCU)
city: Lisbon
country: Portugal
facility: Centro Hospitalar Universitário Lisboa Norte EPE
city: Córdoba
country: Spain
facility: Hospital Universitario Materno Infantil Reina Sofia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Zürich
country: Switzerland
facility: University Children's Hospital Zurich
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: University Hospital Nottingham (Queens Medical Centre)
city: Sheffield
country: United Kingdom
facility: Sheffield Childrens NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS FT
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
Study officials:
affiliation: University of Exeter
name: Adilia Warris, Prof
role: STUDY_DIRECTOR
References:
citation: Armstead J, Morris J, Denning DW. Multi-country estimate of different manifestations of aspergillosis in cystic fibrosis. PLoS One. 2014 Jun 10;9(6):e98502. doi: 10.1371/journal.pone.0098502. eCollection 2014.
citation: Rowbotham NJ, Smith S, Prayle AP, Robinson KA, Smyth AR. Gaps in the evidence for treatment decisions in cystic fibrosis: a systematic review. Thorax. 2019 Mar;74(3):229-236. doi: 10.1136/thoraxjnl-2017-210858. Epub 2018 Oct 9.
citation: Boyle M, Moore JE, Whitehouse JL, Bilton D, Downey DG. The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice. Med Mycol. 2019 Feb 1;57(2):155-160. doi: 10.1093/mmy/myy014.
citation: Welzen ME, Bruggemann RJ, Van Den Berg JM, Voogt HW, Gilissen JH, Pajkrt D, Klein N, Burger DM, Warris A. A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease. Pediatr Infect Dis J. 2011 Sep;30(9):794-7. doi: 10.1097/INF.0b013e3182195808.
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citation: King J, Brunel SF, Warris A. Aspergillus infections in cystic fibrosis. J Infect. 2016 Jul 5;72 Suppl:S50-5. doi: 10.1016/j.jinf.2016.04.022. Epub 2016 May 11.
citation: Periselneris J, Nwankwo L, Schelenz S, Shah A, Armstrong-James D. Posaconazole for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. J Antimicrob Chemother. 2019 Jun 1;74(6):1701-1703. doi: 10.1093/jac/dkz075.
citation: Dolton MJ, Bruggemann RJ, Burger DM, McLachlan AJ. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis. Antimicrob Agents Chemother. 2014 Nov;58(11):6879-85. doi: 10.1128/AAC.03777-14. Epub 2014 Sep 8.
citation: Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, Sermet-Gaudelus I, Southern KW, Barben J, Flume PA, Hodkova P, Kashirskaya N, Kirszenbaum MN, Madge S, Oxley H, Plant B, Schwarzenberg SJ, Smyth AR, Taccetti G, Wagner TOF, Wolfe SP, Drevinek P. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018 Mar;17(2):153-178. doi: 10.1016/j.jcf.2018.02.006. Epub 2018 Mar 3.
citation: Patel D, Popple S, Claydon A, Modha DE, Gaillard EA. Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease. Med Mycol. 2020 Jan 1;58(1):11-21. doi: 10.1093/mmy/myz015.
citation: Krishna G, Ma L, Martinho M, Preston RA, O'Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012 Nov;67(11):2725-30. doi: 10.1093/jac/dks268. Epub 2012 Jul 24.
citation: Tragiannidis A, Herbruggen H, Ahlmann M, Vasileiou E, Gastine S, Thorer H, Frohlich B, Muller C, Groll AH. Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents. J Antimicrob Chemother. 2019 Dec 1;74(12):3573-3578. doi: 10.1093/jac/dkz359.