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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04966234
Recruitment Status : Recruiting
First Posted : July 19, 2021
Last Update Posted : July 19, 2021
Sponsor:
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

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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Aspergillosis Drug: Posaconazole 100 MG [Noxafil] Drug: Posaconazole 40 MG/ML Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-label, randomized, multi-center study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Validation and Clinical Evaluation of a New Posaconazole Dosing Regimen for Children and Adolescents With Cystic Fibrosis and Aspergillus Infection
Actual Study Start Date : April 22, 2021
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.

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

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




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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


  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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)

  9. 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).

  10. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   8 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04966234


Contacts
Layout table for location contacts
Contact: Betty Polikar, PhD Op Coord +39-06-68594243 betty.polikar@opbg.net
Contact: Adilia Warris, MD,C.Inv. +44(0)1392 727593 a.warris@exeter.ac.uk

Locations
Show Show 31 study locations
Sponsors and Collaborators
Bambino Gesù Hospital and Research Institute
University of Exeter
Radboud University Medical Center
Consorzio per Valutazioni Biologiche e Farmacologiche
Investigators
Layout table for investigator information
Study Director: Adilia Warris, Prof University of Exeter
Publications:

Layout table for additonal information
Responsible Party: Bambino Gesù Hospital and Research Institute
ClinicalTrials.gov Identifier: NCT04966234    
Other Study ID Numbers: cASPerCF_2007_OPBG_2019
2019-004511-31 ( EudraCT Number )
First Posted: July 19, 2021    Key Record Dates
Last Update Posted: July 19, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All IPD that underlie results in a publication
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Starting 6 months after the availability of the CSR and therefore from April 2024

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bambino Gesù Hospital and Research Institute:
Posaconazole
Progressive lung damage
Recurrent infection
Persistent inflammation
Better tolerability
Paediatrics
Adolescents
Therapeutic drug monitoring
Pharmacokinetics
Cystic Fibrosis
Aspergillosis
Additional relevant MeSH terms:
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Infections
Aspergillosis
Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Mycoses
Bacterial Infections and Mycoses
Posaconazole
Antifungal Agents
Anti-Infective Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs