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

NCT04966234 | Unknown Phase 2 DMC

• 2 other identifiers: cASPerCF_2007_OPBG_20192019-004511-31
• Study Type: interventional
• Target: 135
• Locations: 11 countries
• Sites: 31

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.

Conditions

Cystic Fibrosis; Aspergillosis

Keywords

Posaconazole; Progressive lung damage; Recurrent infection; Persistent inflammation; Better tolerability; Paediatrics; Adolescents; Therapeutic drug monitoring; Pharmacokinetics; Cystic Fibrosis; Aspergillosis

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (10)

• Pharmacokinetic parameters of posaconazole

  Day 21-35 and day 84 of treatment

• Pharmacokinetic parameters of posaconazole

  Day 21-35 and day 84 of treatment

• Pharmacokinetic parameters of posaconazole

  Day 21-35 and day 84 of treatment

• Pharmacokinetic parameters of posaconazole

  Day 21-35 and day 84 of treatment

• Pharmacokinetic parameters of posaconazole

  Day 21-35 and day 84 of treatment

Study Arms (2)

Posaconazole arm

EXPERIMENTAL

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]; Drug: Posaconazole 40 MG/ML

Control arm

NO INTERVENTION

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

Interventions

Posaconazole 100 MG [Noxafil] DRUG

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

Also known as: gastro-resistant tablets Noxafil® 100 mg

Posaconazole arm

Posaconazole 40 MG/ML DRUG

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

Also known as: 105 ml Noxafil® 40 mg/ml oral suspension

Posaconazole arm

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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 \[IMP\]

You may not qualify if:

• 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

Sponsors & Collaborators

• Bambino Gesù Hospital and Research Institute: lead
• University of Exeter: collaborator
• Radboud University Medical Center: collaborator
• Consorzio per Valutazioni Biologiche e Farmacologiche: collaborator

Study Sites (31)

Motol University Hospital

Prague, Czechia

NOT YET RECRUITING

Centre hospitalier universitaire Dijon Bourgogne

Bourgogne, France

NOT YET RECRUITING

Centre hospitalier universitaire Grenoble Alpes

Grenoble, France

NOT YET RECRUITING

Centre hospitalier universitaire de Montpellier

Montpellier, France

NOT YET RECRUITING

Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital

Bochum, Germany

NOT YET RECRUITING

Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin

Dresden, Germany

NOT YET RECRUITING

Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center

Essen, Germany

NOT YET RECRUITING

Medizinische Hochschule Hannover, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie

Hanover, Germany

NOT YET RECRUITING

Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin, Pädiatrische Pneumologie/Allergologie/Mukoviszidose-Zentrum

Jena, Germany

NOT YET RECRUITING

Cystic Fibrosis Department, "Agia Sofia" Children's Hospital

Athens, Greece

NOT YET RECRUITING

Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki

Thessaloniki, Greece

NOT YET RECRUITING

Cork University Hospital

Cork, Ireland

NOT YET RECRUITING

ASST Spedali Civili Paediatric department

Brescia, Italy

RECRUITING

IRCCS Istituto Giannina Gaslini

Genoa, Italy

NOT YET RECRUITING

University of Parma Department of Medicine and Surgery

Parma, Italy

NOT YET RECRUITING

IRCCS Ospedale Pediatrico Bambino Gesù

Rome, Italy

RECRUITING

University Medical Center Groningen (UMCG)

Groningen, Netherlands

NOT YET RECRUITING

Radboud University Medical Center (RUMC)

Nijmegen, Netherlands

NOT YET RECRUITING

Erasmus Medical Center (EMC)

Rotterdam, Netherlands

NOT YET RECRUITING

University Medical Center Utrecht (UMCU)

Utrecht, Netherlands

NOT YET RECRUITING

Centro Hospitalar Universitário Lisboa Norte EPE

Lisbon, Portugal

NOT YET RECRUITING

Hospital Universitario Materno Infantil Reina Sofia

Córdoba, Spain

NOT YET RECRUITING

Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario La Paz

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario Ramón y Cajal

Madrid, Spain

NOT YET RECRUITING

University Children's Hospital Zurich

Zurich, Switzerland

NOT YET RECRUITING

Birmingham Women's and Children's NHS Foundation Trust

Birmingham, United Kingdom

NOT YET RECRUITING

University Hospital Nottingham (Queens Medical Centre)

Nottingham, United Kingdom

NOT YET RECRUITING

Sheffield Childrens NHS Foundation Trust

Sheffield, United Kingdom

NOT YET RECRUITING

University Hospital Southampton NHS FT

Southampton, United Kingdom

NOT YET RECRUITING

University Hospitals of North Midlands NHS Trust

Stoke-on-Trent, United Kingdom

NOT YET RECRUITING

Related 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.

  PMID: 24914809 BACKGROUND

• 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.

  PMID: 30301819 BACKGROUND

• 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.

  PMID: 29554296 BACKGROUND

• 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.

  PMID: 21772229 BACKGROUND

• 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.

  PMID: 32682946 BACKGROUND

• 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.

  PMID: 27177733 BACKGROUND

• 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.

  PMID: 30805605 BACKGROUND

• 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.

  PMID: 25199779 BACKGROUND

• 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.

  PMID: 29506920 BACKGROUND

• 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.

  PMID: 30877757 BACKGROUND

• 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.

  PMID: 22833639 BACKGROUND

• 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.

  PMID: 31504563 BACKGROUND

MeSH Terms

Conditions

Cystic Fibrosis; Aspergillosis; Reinfection

Interventions

posaconazole; Suspensions

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Mycoses; Bacterial Infections and Mycoses; Infections; Recurrence; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Adilia Warris, Prof

  University of Exeter

  STUDY DIRECTOR

Central Study Contacts

Betty Polikar, PhD Op Coord

CONTACT

+39-06-68594243; betty.polikar@opbg.net

Adilia Warris, MD,C.Inv.

CONTACT

+44(0)1392 727593; a.warris@exeter.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label, randomized, multi-center study

Study Record Dates

• First Submitted: March 19, 2021
• First Posted: July 19, 2021
• Study Start: April 22, 2021
• Primary Completion: April 1, 2023
• Study Completion: November 1, 2023
• Last Updated: July 19, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Starting 6 months after the availability of the CSR and therefore from April 2024

Locations

DE (5); CZ (1); FR (3); GR (2); IT (4); GB (5); ES (4); CH (1); PT (1); NL (4); IE (1)