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

• ClinicalTrials.gov Identifier: NCT04966234
• Recruitment Status: Unknown
• First Posted: July 19, 2021
• Last Update Posted: July 19, 2021
• Sponsor: Bambino Gesù Hospital and Research Institute
• Collaborators: University of Exeter; Radboud University Medical Center; Consorzio per Valutazioni Biologiche e Farmacologiche
• Information provided by (Responsible Party): Bambino Gesù Hospital and Research Institute

Tracking Information

• First Submitted Date: March 19, 2021
• First Posted Date: July 19, 2021
• Last Update Posted Date: July 19, 2021
• Actual Study Start Date: April 22, 2021
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2021)

• 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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: July 7, 2021)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A New Posaconazole Dosing Regimen for Paediatric Patients With Cystic Fibrosis and Aspergillus Infection
• Official Title: Prospective Validation and Clinical Evaluation of a New Posaconazole Dosing Regimen for Children and Adolescents With Cystic Fibrosis and Aspergillus Infection
• Brief Summary: This study will provide: (1) new insights in the prevalence of Aspergillus infection in children and adolescents with CF aged 8-17 yrs; (2) an in silico modelled dose of posaconazole for children and adolescents with CF and Aspergillus infection aged 8-17 yrs; (3) an intensive sampling PK study to define the optimal dose in a limited number of children and adolescents with CF and Aspergillus infection aged 8-17 yrs; (4) a prospective clinical validation to reduce the residual variability and to allow investigation into PK-PD; and (5) an efficacy evaluation of this dosing regimen to treat Aspergillus infection in children and adolescents with CF to inform future primary efficacy trials.

Detailed Description

Cystic fibrosis (CF) is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide with about 45,000 registered in the Patient Registry of the European Cystic Fibrosis Society (ECFS). Progressive lung damage caused by recurrent infection and persistent inflammation is the major determinant of survival with a median age of death at 29 years. Approximately 60% of CF patients are infected with A. fumigatus, a ubiquitous environmental fungus,and its presence is associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. Evidence to guide clinical management of CF-related Aspergillus disease is lacking. A recent survey showed considerable variability in clinical practice among CF consultants. Two-thirds would treat Aspergillus colonization in patients with CF and two-thirds would use an azole antifungal in addition to steroids in the first line treatment of CF-related allergic bronchopulmonary aspergillosis (ABPA). The results of this survey underscore the limited evidence available to guide management of Aspergillus infection in CF.

Posaconazole, being one of the 4 licensed triazole antifungals with good efficacy against Aspergillus species has been chosen as the study drug as it has a better tolerability compared to itraconazole, less toxicity and drug-drug interactions compared to voriconazole and can be administered once daily. Posaconazole is licensed in Europe for the prevention of invasive aspergillus in adult neutropenic patient populations and as salvage therapy for invasive aspergillosis. Several studies have reported on the safety and tolerability of the use of posaconazole in children and adolescents with either haematological malignancies, or chronic granulomatous disease, or those undergoing haematopoietic stem cell transplantation. Currently, no dosing algorithm is available to guide posaconazole dosing in children.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Open-label, randomized, multi-center study

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Cystic Fibrosis
• Aspergillosis

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

  Other Name: 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 Name: 105 ml Noxafil® 40 mg/ml oral suspension

Study Arms

• 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.

  Interventions:

  • Drug: Posaconazole 100 MG [Noxafil]
  • Drug: Posaconazole 40 MG/ML
• 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

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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: July 7, 2021): 135
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2023
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Diagnosed with cystic fibrosis (genetic diagnosis and/or abnormal sweat test and clinical phenotype of lung disease)
2. Age ≥ 8 yrs and < 18 yrs
3. Body weight ≥20 kg
4. Presence of Aspergillus infection as defined for this study
5. Clinically stable condition without a significant change in lung function (FEV1 +/- 10%) or significant worsening of respiratory symptoms over the previous month
6. Able to perform lung function test (FEV1%)
7. Able to produce a sputum sample (spontaneous or induced sputum)
8. Informed Consent given
9. If female and of childbearing age must be using highly effective contraception (and must agree to continue for 7 days after the last dose of investigational medicinal product [IMP]

Exclusion Criteria:

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 8 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, France, Germany, Greece, Ireland, Italy, Netherlands, Portugal, Spain, Switzerland, United Kingdom

Administrative Information

• NCT Number: NCT04966234
• Other Study ID Numbers: cASPerCF_2007_OPBG_2019; 2019-004511-31 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

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

• Current Responsible Party: Bambino Gesù Hospital and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Bambino Gesù Hospital and Research Institute
• Original Study Sponsor: Same as current

Collaborators

• University of Exeter
• Radboud University Medical Center
• Consorzio per Valutazioni Biologiche e Farmacologiche

Investigators

• Study Director: Adilia Warris, Prof; University of Exeter

• PRS Account: Bambino Gesù Hospital and Research Institute
• Verification Date: March 2021