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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Cystic Fibrosis, Aspergillosis

Intervention / Treatment
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* Drug: Posaconazole 100 MG [Noxafil]
* Drug: Posaconazole 40 MG/ML


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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] Exclusion Criteria: 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 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

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, randomized, multi-center study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Posaconazole arm<br>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]<br>* 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<br>* Other names: gastro-resistant tablets Noxafil® 100 mg;Drug: Posaconazole 40 MG/ML<br>* 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<br>* Other names: 105 ml Noxafil® 40 mg/ml oral suspension;|
| No Intervention: Control arm<br>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 the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Posaconazole, Progressive lung damage, Recurrent infection, Persistent inflammation, Better tolerability, Paediatrics, Adolescents, Therapeutic drug monitoring, Pharmacokinetics, Cystic Fibrosis, Aspergillosis