Cystic FibrosisPhase 2/3cASPerCFNCT04966234
A New Posaconazole Dosing Regimen for Paediatric Patients With Cystic Fibrosis and Aspergillus Infection
A Phase 2/3 study testing Posaconazole 100 MG [Noxafil] and Posaconazole 40 MG/ML in people with Cystic Fibrosis and Aspergillosis, run by Bambino Gesù Hospital and Research Institute at 31 sites in 11 countries.
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… Read more about this study
- Who is it for?
- Ages 8 to 17 years
- Conditions the study is for
- Cystic Fibrosis, Aspergillosis
- What is being tested?
- Posaconazole 100 MG [Noxafil] and Posaconazole 40 MG/ML
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 135 participants
- Where
- 31 sitesin 11 countries
- Study dates
- 22 Apr 2021to Nov 2023
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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%)
Show all 9Show fewer
- 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]
Who cannot join
- 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
Show all 24Show fewer
- 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
Trial locations and contacts
31 sites in 11 countries.
31 sites in 11 countries
Germany5 sites, 5 recruiting
- Not yet recruiting
Katholisches Klinikum Bochum gGMBH, Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum, St. Josef Hospital
Bochum
Folke Brinkmann, Dr.
- Not yet recruiting
Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Kinder- und Jugendmedizin
Dresden
Jutta Hammermann, Dr.
- Not yet recruiting
Universitätsklinikum Essen,Pediatric Pulmonology and Cystic Fibrosis Center
Essen
Florian Stehling, Dr.
- Not yet recruiting
Medizinische Hochschule Hannover, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
Hanover
Anna Maria Dittrich, Dr.
- Not yet recruiting
Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin, Pädiatrische Pneumologie/Allergologie/Mukoviszidose-Zentrum
Jena
Michael Lorenz, Dr.
United Kingdom5 sites, 5 recruiting
- Not yet recruiting
Birmingham Women's and Children's NHS Foundation Trust
Birmingham
Maya Desai, Dr.
- Not yet recruiting
University Hospital Nottingham (Queens Medical Centre)
Nottingham
Jayesh Bhatt, Dr.
- Not yet recruiting
Sheffield Childrens NHS Foundation Trust
Sheffield
Noreen West, Dr.
- Not yet recruiting
University Hospital Southampton NHS FT
Southampton
Gary Connett, Dr.
- Not yet recruiting
University Hospitals of North Midlands NHS Trust
Stoke-on-Trent
Francis Gilchrist, Dr.
Italy4 sites, 4 recruiting
- Recruiting
ASST Spedali Civili Paediatric department
Brescia
Raffaele Badolato, Prof.
- Not yet recruiting
IRCCS Istituto Giannina Gaslini
Genoa
Carlo Castellani, Dr.
- Not yet recruiting
University of Parma Department of Medicine and Surgery
Parma
Susanna Esposito, Prof.
- Recruiting
IRCCS Ospedale Pediatrico Bambino Gesù
Rome
Federico Alghisi, Dr.
Netherlands4 sites, 4 recruiting
- Not yet recruiting
University Medical Center Groningen (UMCG)
Groningen
Geread Koppelman, Prof.
- Not yet recruiting
Radboud University Medical Center (RUMC)
Nijmegen
Peter Merkus, Dr.
- Not yet recruiting
Erasmus Medical Center (EMC)
Rotterdam
Harm Tiddens, Prof.
- Not yet recruiting
University Medical Center Utrecht (UMCU)
Utrecht
Kors van der Ent, Prof.
Spain4 sites, 4 recruiting
- Not yet recruiting
Hospital Universitario Materno Infantil Reina Sofia
Córdoba
Javier Torres Borrego, Dr.
- Not yet recruiting
Hospital Universitario 12 de Octubre,Unidad Multidisciplinar Fibrosis Quística
Madrid
María del Carmen Luna Paredes, Dr.
- Not yet recruiting
Hospital Universitario La Paz
Madrid
Marta Ruiz de Valbuena Maiz, Dr.
- Not yet recruiting
Hospital Universitario Ramón y Cajal
Madrid
Adelaida Lamas Ferreiro, Dr.
France3 sites, 3 recruiting
- Not yet recruiting
Centre hospitalier universitaire Dijon Bourgogne
Bourgogne
Frédéric Huet, Prof.
- Not yet recruiting
Centre hospitalier universitaire Grenoble Alpes
Grenoble
Isabelle Pin, Dr.
- Not yet recruiting
Centre hospitalier universitaire de Montpellier
Montpellier
Raphaël Chiron, Dr.
Greece2 sites, 2 recruiting
- Not yet recruiting
Cystic Fibrosis Department, "Agia Sofia" Children's Hospital
Athens
Ioanna Loukou, Prof.
- Not yet recruiting
Cystic Fibrosis Center, 3rd Paediatric Dept, Aristotle University of Thessaloniki
Thessaloniki
John Tsanakas, Prof.
Czechia1 site, 1 recruiting
- Not yet recruiting
Motol University Hospital
Prague
Pavel Dřevínek, Prof.
Ireland1 site, 1 recruiting
- Not yet recruiting
Cork University Hospital
Cork
Muireann Ní Chróinín, Dr.
Portugal1 site, 1 recruiting
- Not yet recruiting
Centro Hospitalar Universitário Lisboa Norte EPE
Lisbon
Celeste Barreto, Dr.
Switzerland1 site, 1 recruiting
- Not yet recruiting
University Children's Hospital Zurich
Zurich
Alexander Moeller, Prof.
About this study
Official title: 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.
Read the 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.
- Conditions
- Cystic Fibrosis, Aspergillosis
- Being tested
- Posaconazole 100 MG [Noxafil], Posaconazole 40 MG/ML
- Keywords
- Posaconazole, Progressive lung damage, Recurrent infection, Persistent inflammation, Better tolerability, Paediatrics, Adolescents, Therapeutic drug monitoring, Pharmacokinetics, Cystic Fibrosis, Aspergillosis
- Medical subject headings
- Cystic Fibrosis, Aspergillosis, Reinfection
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Posaconazole 100 MG [Noxafil]Drug
Also called gastro-resistant tablets Noxafil® 100 mg
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/MLDrug
Also called 105 ml Noxafil® 40 mg/ml oral suspension
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic parameters of posaconazole
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Cmax
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 3 months after randomisation
Secondary outcomes (10)
Pharmacokinetic parameters of posaconazole
The following pharmacokinetic parameters will be calculated using non-compartmental pharmacokinetic analysis: Cmax
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Measured: 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).
Measured: 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.
Measured: Up to 1 year after randomisation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2021
- Study start22 Apr 2021
- Primary completionApr 2023 (estimated)
- Study completionNov 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Open-label, randomized, multi-center study
- Masking
- None (open label)
- Enrolment
- 135 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Bambino Gesù Hospital and Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- University of Exeter, Radboud University Medical Center, Consorzio per Valutazioni Biologiche e Farmacologiche
- Responsible party
- Sponsor
- Investigators
- Adilia Warris, Prof, Study director, University of Exeter
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04966234
- Sponsor's protocol ID
- cASPerCF_2007_OPBG_2019
- Other IDs
- 2019-004511-31, 2019
- Acronym
- cASPerCF
- Status last verified
- Mar 2021
- First submitted
- 19 Mar 2021
- Last updated
- 19 Jul 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD that underlie results in a publication
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.
PubMed 24914809Rowbotham 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.
PubMed 30301819Boyle 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.
PubMed 29554296Welzen 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.
PubMed 21772229Groll 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.
PubMed 32682946King 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.
PubMed 27177733Periselneris 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.
PubMed 30805605Dolton 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.
PubMed 25199779Castellani 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.
PubMed 29506920Patel 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.
PubMed 30877757Krishna 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.
PubMed 22833639Tragiannidis 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.
PubMed 31504563
Study at a glance
From the registry record, last updated by the sponsor on 19 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Validation and Clinical Evaluation of a New Posaconazole Dosing Regimen for Children and Adolescents With Cystic Fibrosis and Aspergillus Infection
- ClinicalTrials.gov ID
- NCT04966234
- Acronym / sponsor ID
- cASPerCF / cASPerCF_2007_OPBG_2019
- Conditions
- Cystic Fibrosis, Aspergillosis
- Keywords
- Posaconazole, Progressive lung damage, Recurrent infection, Persistent inflammation, Better tolerability, Paediatrics, Adolescents, Therapeutic drug monitoring
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 135 participants (estimated)
- Lead sponsor
- Bambino Gesù Hospital and Research InstituteUniversity, hospital or other
- Collaborators
- University of Exeter, Radboud University Medical Center, Consorzio per Valutazioni Biologiche e Farmacologiche
- Study start
- 22 Apr 2021 (actual)
- Primary completion
- Apr 2023 (estimated)
- Study completion
- Nov 2023 (estimated)
- First posted
- 19 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open-label, randomized, multi-center study
| Arm | Type | Receives |
|---|---|---|
| Posaconazole arm | Experimental | Drug: Posaconazole 100 MG [Noxafil], Drug: Posaconazole 40 MG/ML90 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. |
| 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 |
Who may qualify
- Ages
- 8 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (24 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Posaconazole 100 MG [Noxafil]Also: gastro-resistant tablets Noxafil® 100 mgPosaconazole 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 | Drug | Posaconazole arm |
| Posaconazole 40 MG/MLAlso: 105 ml Noxafil® 40 mg/ml oral suspensionPosaconazole 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 | Drug | Posaconazole arm |
Primary outcome
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Cmax
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Cmin
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Tmax
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Area Under the Curve during 1 dosing interval and over 24 hours
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Clearance
Pharmacokinetic parameters of posaconazole
Time frame: At steady state, day 5-10 of treatment
The following pharmacokinetic parameter will be calculated using non-compartmental pharmacokinetic analysis: Distribution volume
Pharmacokinetic parameters of posaconazole
Time frame: 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
Time frame: 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.
10 secondary outcomes
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Pharmacokinetic parameters of posaconazole
Time frame: Day 21-35 and day 84 of treatment
Patients with a favourable clinical response and no signs of Aspergillus infection
Time frame: 3, 6 and 12 months after randomisation
Patients with no signs of Aspergillus infection
Time frame: 3, 6 and 12 months after randomisation
The proportion of participants experiencing AEs and SAEs
Time frame: Up to 1 year after randomisation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jul 2021.
- Background: PubMed 24914809Armstead 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.
- Background: PubMed 30301819Rowbotham 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.
- Background: PubMed 29554296Boyle 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.
- Background: PubMed 21772229Welzen 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.
- Background: PubMed 32682946Groll 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.
- Background: PubMed 27177733King 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.
- Background: PubMed 30805605Periselneris 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.
- Background: PubMed 25199779Dolton 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.
- Background: PubMed 29506920Castellani 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.
- Background: PubMed 30877757Patel 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.
- Background: PubMed 22833639Krishna 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.
- Background: PubMed 31504563Tragiannidis 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.
- Individual participant dataSharing planned: Yes. All IPD that underlie results in a publication
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adilia Warris, Prof study director
University of Exeter
31 sites in 11 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Posaconazole 100 MG [Noxafil] and Posaconazole 40 MG/ML in people with Cystic Fibrosis and Aspergillosis, run by Bambino Gesù Hospital and Research Institute at 31 sites in 11 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 sites in Germany, United Kingdom, Italy, Netherlands, Spain and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Betty Polikar, PhD Op Coord (+39-06-68594243, betty.polikar@opbg.net), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic parameters of posaconazole (time frame: At steady state, day 5-10 of treatment). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04966234, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jul 2021.