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

Prospective Validation and Clinical Evaluation of a New Posaconazole Dosing Regimen for Children and Adolescents With Cystic Fibrosis and Aspergillus Infection

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.

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis; Aspergillosis
• Intervention / Treatment: Drug: Posaconazole 100 MG [Noxafil]; Drug: Posaconazole 40 MG/ML

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.

• Study Type: Interventional
• Enrollment (Anticipated): 135
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Betty Polikar, PhD Op Coord; Phone Number: +39-06-68594243; Email: betty.polikar@opbg.net
• Study Contact Backup: Name: Adilia Warris, MD,C.Inv.; Phone Number: +44(0)1392 727593; Email: a.warris@exeter.ac.uk

Study Locations

• Czechia
  • Prague, Czechia
    • Not yet recruiting
    • Motol University Hospital
    • Contact: Pavel Dřevínek, Prof.
• France
  • Bourgogne, France
    • Not yet recruiting
    • Centre Hospitalier Universitaire Dijon Bourgogne
    • Contact: Frédéric Huet, Prof.
  • Grenoble, France
    • Not yet recruiting
    • Centre Hospitalier Universitaire Grenoble Alpes
    • Contact: Isabelle Pin, Dr.
  • Montpellier, France
    • Not yet recruiting
    • Centre Hospitalier Universitaire de Montpellier
    • Contact: Raphaël Chiron, Dr.
• Germany
  • Bochum, Germany
    • Not yet recruiting
    • Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital
    • Contact: Folke Brinkmann, Dr.
  • Dresden, Germany
    • Not yet recruiting
    • Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin
    • Contact: Jutta Hammermann, Dr.
  • Essen, Germany
    • Not yet recruiting
    • Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center
    • Contact: Florian Stehling, Dr.
  • Hannover, Germany
    • Not yet recruiting
    • Medizinische Hochschule Hannover, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
    • Contact: Anna Maria Dittrich, Dr.
  • Jena, Germany
    • Not yet recruiting
    • Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin, Pädiatrische Pneumologie/Allergologie/Mukoviszidose-Zentrum
    • Contact: Michael Lorenz, Dr.
• Greece
  • Athens, Greece
    • Not yet recruiting
    • Cystic Fibrosis Department, "Agia Sofia" Children's Hospital
    • Contact: Ioanna Loukou, Prof.
  • Thessaloniki, Greece
    • Not yet recruiting
    • Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki
    • Contact: John Tsanakas, Prof.
• Ireland
  • Cork, Ireland
    • Not yet recruiting
    • Cork University Hospital
    • Contact: Muireann Ní Chróinín, Dr.
• Italy
  • Brescia, Italy
    • Recruiting
    • ASST Spedali Civili Paediatric department
    • Contact: Raffaele Badolato, Prof.
  • Genoa, Italy
    • Not yet recruiting
    • IRCCS Istituto Giannina Gaslini
    • Contact: Carlo Castellani, Dr.
  • Parma, Italy
    • Not yet recruiting
    • University of Parma Department of Medicine and Surgery
    • Contact: Susanna Esposito, Prof.
  • Rome, Italy
    • Recruiting
    • IRCCS Ospedale Pediatrico Bambino Gesù
    • Contact: Federico Alghisi, Dr.
• Netherlands
  • Groningen, Netherlands
    • Not yet recruiting
    • University Medical Center Groningen (UMCG)
    • Contact: Geread Koppelman, Prof.
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Radboud University Medical Center (RUMC)
    • Contact: Peter Merkus, Dr.
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Erasmus Medical Center (EMC)
    • Contact: Harm Tiddens, Prof.
  • Utrecht, Netherlands
    • Not yet recruiting
    • University Medical Center Utrecht (UMCU)
    • Contact: Kors van der Ent, Prof.
• Portugal
  • Lisbon, Portugal
    • Not yet recruiting
    • Centro Hospitalar Universitário Lisboa Norte EPE
    • Contact: Celeste Barreto, Dr.
• Spain
  • Córdoba, Spain
    • Not yet recruiting
    • Hospital Universitario Materno Infantil Reina Sofia
    • Contact: Javier Torres Borrego, Dr.
  • Madrid, Spain
    • Not yet recruiting
    • Hospital Universitario La Paz
    • Contact: Marta Ruiz de Valbuena Maiz, Dr.
  • Madrid, Spain
    • Not yet recruiting
    • Hospital Universitario Ramón y Cajal
    • Contact: Adelaida Lamas Ferreiro, Dr.
  • Madrid, Spain
    • Not yet recruiting
    • Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística
    • Contact: María del Carmen Luna Paredes, Dr.
• Switzerland
  • Zürich, Switzerland
    • Not yet recruiting
    • University Children's Hospital Zurich
    • Contact: Alexander Moeller, Prof.
• United Kingdom
  • Birmingham, United Kingdom
    • Not yet recruiting
    • Birmingham Women's and Children's NHS Foundation Trust
    • Contact: Maya Desai, Dr.
  • Nottingham, United Kingdom
    • Not yet recruiting
    • University Hospital Nottingham (Queens Medical Centre)
    • Contact: Jayesh Bhatt, Dr.
  • Sheffield, United Kingdom
    • Not yet recruiting
    • Sheffield Childrens NHS Foundation Trust
    • Contact: Noreen West, Dr.
  • Southampton, United Kingdom
    • Not yet recruiting
    • University Hospital Southampton NHS FT
    • Contact: Gary Connett, Dr.
  • Stoke-on-Trent, United Kingdom
    • Not yet recruiting
    • University Hospitals of North Midlands NHS Trust
    • Contact: Francis Gilchrist, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Posaconazole arm; 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.	Drug: Posaconazole 100 MG [Noxafil]; Posaconazole is a lipophilic, highly permeable triazole, which is practically insoluble in water. Posaconazole inhibits the enzyme CYP51a (also known as Erg11p or lanosterol demethylase). This enzyme is required for catalysation of an essential step in biosynthesis of ergosterol in filamentous fungi and yeasts. Posaconazole is favoured over itraconazole and voriconazole with respect to palatability, tolerability and toxicity profile; Other Names: gastro-resistant tablets Noxafil® 100 mg; Drug: Posaconazole 40 MG/ML; Posaconazole is a lipophilic, highly permeable triazole, which is practically insoluble in water. Posaconazole inhibits the enzyme CYP51a (also known as Erg11p or lanosterol demethylase). This enzyme is required for catalysation of an essential step in biosynthesis of ergosterol in filamentous fungi and yeasts. Posaconazole is favoured over itraconazole and voriconazole with respect to palatability, tolerability and toxicity profile; Other Names: 105 ml Noxafil® 40 mg/ml oral suspension
No Intervention: Control arm; 45 patients (out of the 135 total patients, therefore with a 2:1 randomization ratio) will not receive the active treatment. Patients will be followed-up for a total of 12 months post-randomization. If participants in the control arm are deteriorating during the first 3 months after randomization, it is up to the treating physician to consider treatment for the initial asymptomatic Aspergillus infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Cmax	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Cmin	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Tmax	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Area Under the Curve during 1 dosing interval and over 24 hours	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Clearance	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Distribution volume	At steady state, day 5-10 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Half-life	At steady state, day 5-10 of treatment
Aspergillus isolation from sputum cultures	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.	3 months after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Cmax	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Cmin	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Tmax	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Area Under the Curve	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Clearance	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Distribution volume	Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole	The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Half-life	Day 21-35 and day 84 of treatment
Patients with a favourable clinical response and no signs of Aspergillus infection	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)	3, 6 and 12 months after randomisation
Patients with no signs of Aspergillus infection	Percentage of patients who have no signs of Aspergillus infection (defined by negative sputum cultures and negative serology).	3, 6 and 12 months after randomisation
The proportion of participants experiencing AEs and SAEs	Assessed according to the Division of AIDS (DAIDS), Table for Grading of the NIAID, NIH, and the US Department of Health and Human Services.	Up to 1 year after randomisation

Collaborators and Investigators

• Sponsor: Bambino Gesù Hospital and Research Institute
• Collaborators: Radboud University Medical Center; University of Exeter; Consorzio per Valutazioni Biologiche e Farmacologiche
• Investigators: Study Director: Adilia Warris, Prof, University of Exeter

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• Groll AH, Abdel-Azim H, Lehrnbecher T, Steinbach WJ, Paschke A, Mangin E, Winchell GA, Waskin H, Bruno CJ. Pharmacokinetics and safety of posaconazole intravenous solution and powder for oral suspension in children with neutropenia: an open-label, sequential dose-escalation trial. Int J Antimicrob Agents. 2020 Sep;56(3):106084. doi: 10.1016/j.ijantimicag.2020.106084. Epub 2020 Jul 17.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2021
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): November 1, 2023

Study Registration Dates

• First Submitted: March 19, 2021
• First Submitted That Met QC Criteria: July 7, 2021
• First Posted (Actual): July 19, 2021

Study Record Updates

• Last Update Posted (Actual): July 19, 2021
• Last Update Submitted That Met QC Criteria: July 7, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Adolescents; Pharmacokinetics; Cystic Fibrosis; Posaconazole; Therapeutic drug monitoring; Paediatrics; Aspergillosis; Progressive lung damage; Recurrent infection; Persistent inflammation; Better tolerability
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Bacterial Infections and Mycoses; Mycoses; Pancreatic Diseases; Fibrosis; Infections; Cystic Fibrosis; Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: cASPerCF_2007_OPBG_2019; 2019-004511-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: Starting 6 months after the availability of the CSR and therefore from April 2024
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No