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

Cystic Fibrosis Clinical Trial

— cASPerCF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04966234
• Other study ID #: cASPerCF_2007_OPBG_2019
• Secondary ID: 2019-004511-31
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 22, 2021
• Est. completion date: November 2023

Study information

• Verified date: March 2021
• Source: Bambino Gesù Hospital and Research Institute
• Contact: Betty Polikar, PhD Op Coord
• Phone: +39-06-68594243
• Email: betty.polikar[@]opbg.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 135
• Est. completion date: November 2023
• Est. primary completion date: April 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Aspergillosis
• Cystic Fibrosis
• Fibrosis
• Infection

Intervention

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
• 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

Locations

Country	Name	City	State
Czechia	Motol University Hospital	Prague
France	Centre hospitalier universitaire Dijon Bourgogne	Bourgogne
France	Centre hospitalier universitaire Grenoble Alpes	Grenoble
France	Centre hospitalier universitaire de Montpellier	Montpellier
Germany	Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital	Bochum
Germany	Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin	Dresden
Germany	Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center	Essen
Germany	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
Greece	Cystic Fibrosis Department, "Agia Sofia" Children's Hospital	Athens
Greece	Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki	Thessaloniki
Ireland	Cork University Hospital	Cork
Italy	ASST Spedali Civili Paediatric department	Brescia
Italy	IRCCS Istituto Giannina Gaslini	Genoa
Italy	University of Parma Department of Medicine and Surgery	Parma
Italy	IRCCS Ospedale Pediatrico Bambino Gesù	Rome
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Netherlands	Radboud University Medical Center (RUMC)	Nijmegen
Netherlands	Erasmus Medical Center (EMC)	Rotterdam
Netherlands	University Medical Center Utrecht (UMCU)	Utrecht
Portugal	Centro Hospitalar Universitário Lisboa Norte EPE	Lisbon
Spain	Hospital Universitario Materno Infantil Reina Sofia	Córdoba
Spain	Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Switzerland	University Children's Hospital Zurich	Zürich
United Kingdom	Birmingham Women's and Children's NHS Foundation Trust	Birmingham
United Kingdom	University Hospital Nottingham (Queens Medical Centre)	Nottingham
United Kingdom	Sheffield Childrens NHS Foundation Trust	Sheffield
United Kingdom	University Hospital Southampton NHS FT	Southampton
United Kingdom	University Hospitals of North Midlands NHS Trust	Stoke-on-Trent

Sponsors (4)

Lead Sponsor	Collaborator
Bambino Gesù Hospital and Research Institute	Consorzio per Valutazioni Biologiche e Farmacologiche, Radboud University, University of Exeter

Countries where clinical trial is conducted

Czechia,  France,  Germany,  Greece,  Ireland,  Italy,  Netherlands,  Portugal,  Spain,  Switzerland,  United Kingdom, 

References & Publications (12)

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. — View 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. — View Citation

Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, Sermet-Gaudelus I, Southern KW, Barben J, Flume PA, Hodková 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. Review. — View Citation

Dolton MJ, Brüggemann 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. — View Citation

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. — View 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. Review. — View 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. — View 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. — View 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. — View 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. — View Citation

Tragiannidis A, Herbrüggen H, Ahlmann M, Vasileiou E, Gastine S, Thorer H, Fröhlich B, Müller 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. — View Citation

Welzen ME, Brüggemann 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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