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

Bambino Gesù Hospital and Research Institute

Status and phase: Unknown; Phase 3; Phase 2

Conditions: Aspergillosis; Cystic Fibrosis

Treatments: Drug: Posaconazole 40 MG/ML; Drug: Posaconazole 100 MG [Noxafil]

Study type: Interventional

Funder types: Other

Identifiers

NCT04966234

cASPerCF_2007_OPBG_2019

2019-004511-31 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 135 estimated patients

Sex: All

Ages: 8 to 17 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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135 participants in 2 patient groups

Posaconazole arm

Experimental group

Description:

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.

Treatment:

Drug: Posaconazole 100 MG [Noxafil]

Drug: Posaconazole 40 MG/ML

Control arm

No Intervention group

Description:

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