Clinical Trials Register

Summary
EudraCT Number:	2019-004511-31
Sponsor's Protocol Code Number:	cASPerCF_2007_OPBG_2019
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-10-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-004511-31

A.3

Full title of the trial

Prospective validation and clinical evaluation of a new posaconazole dosing regimen for children and adolescents with cystic fibrosis and Aspergillus infection.

Validazione prospettica e valutazione clinica di un nuovo dosaggio di posaconazolo per bambini e adolescenti con fibrosi cistica e con infezione da Aspergillus.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Prospective validation and clinical evaluation of a new posaconazole dosing regimen for children and adolescents with cystic fibrosis and Aspergillus infection.

Validazione prospettica e valutazione clinica di un nuovo dosaggio di posaconazolo per bambini e adolescenti con fibrosi cistica e con infezione da Aspergillus.

A.3.2

Name or abbreviated title of the trial where available

cASPerCF

A.4.1

Sponsor's protocol code number

cASPerCF_2007_OPBG_2019

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	IRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Innovative Medicines Initiative 2
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	European Union’s Horizon 2020
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS OSPEDALE PEDIATRICO BAMBINO GESU'
B.5.2	Functional name of contact point	A.R. INFETTIVOLOGIA E SVILUPPO DI F
B.5.3	Address:
B.5.3.1	Street Address	P.zza S.Onofrio, 4
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00165
B.5.3.4	Country	Italy
B.5.6	E-mail	betty.polikar@opbg.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	NOXAFIL - 40 MG/ML SOSPENSIONE ORALE USO ORALE FLACONE (VETRO) 105 ML 1 FLACONE
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP e DOHME LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Posaconazolo
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Noxafil
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POSACONAZOLO
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Noxafil
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POSACONAZOLO
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg/h milligram(s)/kilogram/hour
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POSACONAZOLO
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	NOXAFIL - 40 MG/ML SOSPENSIONE ORALE USO ORALE FLACONE (VETRO) 105 ML 1 FLACONE
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP e DOHME LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POSACONAZOLO
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Noxafil
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP e DOHME LIMITED
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Noxafil
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Posaconazolo
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cystic Fibrosis and Aspergillus infection.

Fibrosi cistica e con infezione da Aspergillus.

E.1.1.1

Medical condition in easily understood language

Cystic Fibrosis and Aspergillus infection.

Fibrosi cistica e con infezione da Aspergillus.

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10003488
E.1.2	Term	Aspergillosis
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

- In silico definition of the most optimal posaconazole dose for children and adolescents with CF aged 8 to 17 years.
- Assess the prevalence of Aspergillus infection in children and adolescents with CF aged 8 -17 years.
- An intensive sampling pharmacokinetic study of posaconazole in a limited number of children and adolescents with CF and Aspergillus infection aged 8 to 17 years.
- Prospective clinical evaluation of the defined posaconazole dosing regimen in children and adolescents with CF and Aspergillus infection aged 8 to 17 year.
- Assess the tolerability and safety of posaconazole in children and adolescents with CF and Aspergillus infection aged 8 to 17 years.
- Assess the clinical efficacy of posaconazole in terms of (1) clearance of Aspergillus from the airways; (2) dampening airway inflammation, and (3) clinical outcomes (as measured by pulmonary exacerbation rate, days on antibiotics and corticosteroids, hospital admissions, change in FEV1, change in BMI, CT-ches

Definire con modello in silico la dose di posaconazolo per bambini ed adolescenti con FC di età tra 8 e 17 anni.
Valutare la prevalenza dell'infezione da Aspergillus in bambini ed adolescenti con FC di età tra 8 e 17 anni.
Effettuare uno studio farmacocinetico di campionamento intensivo di posaconazolo in un numero limitato di bambini ed adolescenti con infezione da FC e Aspergillus da 8 a 17 anni .
Effettuare la convalida clinica prospettica del regime di trattamento con posaconazolo definito in bambini ed adolescenti affetti da infezione da FC e Aspergillus da 8 a 17 anni.
Valutare la tollerabilità e la sicurezza di posaconazolo in bambini ed adolescenti con infezione da FC e Aspergillus da 8 a 17 anni.
Valutare l'efficacia clinica del posaconazolo in termini di (1) clearance di Aspergillus dalle vie aeree; (2) riduzione dell'infiammazione delle vie aeree e (3) risultati clinici (incluso FEV1, esacerbazioni polmonari, giorni di trattamento con antibiotici e steroidi)

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria for the screening phase:
1. Diagnosed with cystic fibrosis (genetic diagnosis and clinical phenotype of lung disease)
2. Age = 8 yrs and < 18 yrs
3. Able to produce a sputum sample (spontaneous or induced sputum)
4. Informed Consent given
Inclusion criteria for the intervention phase:
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. Presence of Aspergillus infection as defined for this study
4. Clinically stable condition without a significant change in lung function (FEV1 +/- 10%) or significant worsening of respiratory symptoms over the previous month
5. Able to perform lung function test (FEV1)
6. Able to produce a sputum sample (spontaneous or induced sputum)
7. Informed Consent given

Criteri di inclusione per la fase di screening dello studio (n=1500)
I soggetti devono soddisfare i seguenti criteri per essere ammessi alla partecipazione alla fase di screening:
1. Diagnosi di FC (diagnosi genetica e fenotipo clinico della malattia polmonare)
2. Età =8 anni e <18 anni
3. Capacità di produrre un campione di espettorato (espettorato spontaneo o indotto)
4. Firma del Consenso Informato
Criteri di inclusione per la fase con posaconazolo (n=135)
1. Diagnosi di FC (diagnosi genetica e fenotipo clinico della malattia polmonare).
2. Età =8 anni e <18 anni.
3. Segni di infezione da Aspergillus come definito per questo studio (vedere sopra).
4. Condizione clinicamente stabile senza un cambiamento significativo nella funzionalità polmonare (FEV1 +/- 10%) o un peggioramento significativo dei sintomi respiratori nell'ultimo mese.
5. Capacità di eseguire test di funzionalità polmonare (FEV1%).
6. Capacità di produrre un campione di espettorato (espettorato spontaneo o indotto)
7. Firma del Consenso informato.

E.4

Principal exclusion criteria

Exclusion criteria for the trial:
1. Age < 8 yrs or = 18 yrs
2. Unable to perform lung function test (FEV1)
3. Unable to produce a sputum sample (spontaneous or induced sputum)
4. Clinically unstable condition with significant change in lung function or significant worsening of respiratory symptoms
5. Unable to tolerate oral medication
6. Known hypersensitivity to the drug/excipients
7. On active transplant list or transplant recipient
8. Azole resistant Aspergillus sp. cultured
9. Patients receiving terfenadine, ergot alkaloids, astemizole, cisapride, pimozide, halofantrine, quinidine, or HMG-CoA reductase inhibitors metabolised through CYP3A4
10. Patients receiving omalizumab
11. Received systemic mould-active antifungals in the last month
12. Shortened or elongated QT interval
13. Cardiac failure
14. ALT = 200 U/L
15. AST = 225 U/L
16. Alkaline phosphatase = 460 U/L
17. Bilirubin = 50 umol/L
18. Pregnancy
19. Informed Consent not given

Criteri di esclusione per la fase di screening dello studio (n=1500)
1. Nessun disturbo polmonare associato alla fibrosi cistica
2. Età < 8 anni e =18 anni
3. Non in grado di fornire l’espettorato
4. Mancato rilascio del Consenso informato

Criteri di esclusione per la fase con posaconazolo (n=135)
1. Età <8 anni e =18 anni.
2. Impossibilità ad eseguire il test di funzionalità polmonare (FEV1%).
3. Impossibilità a produrre un campione di espettorato.
4. Condizione clinicamente instabile con cambiamenti significativi nella funzionalità polmonare o peggioramento significativo dei sintomi respiratori.
5. Impossibilità di tollerare farmaci per via orale.
6. Coltura di Aspergillus resistente all'azolo.
7. Ipersensibilità nota a itraconazolo/posaconazolo/eccipienti
8. Pazienti che ricevono inibitori della terfenadina, alcaloidi dell'ergot, astemizolo, cisapride, pimozide, alofantrina, chinidina o HMG-CoA reduttasi metabolizzati dal CYP3A4.
9. Pazienti che ricevono Omalizumab.
10. Trattamento con antifungini nell’ultimo mese
11. Intervallo QT ridotto o allungato.
12. Insufficienza cardiaca.
13. ALT = 200 U / L
14. AST = 225 U / L
15. Fosfatasi alcalina = 460 U / L
16. Bilirubina = 50 umol / L
17. Gravidanza
18. Inserimento nella lista dei trapianti o come destinatario di trapianti.
19. Mancato rilascio del Consenso informato.

E.5 End points

E.5.1

Primary end point(s)

- For the dosing algorithm: The number of children and adolescents with CF and Aspergillus infection aged 8 to 17 years reaching the pre-defined area under the concentration time curve (AUC) of posaconazole at the first assessment (between day 5 and 10) based on the adult reference concentrations for treatment of susceptible pathogens.
- For clinical efficacy: The number of children with negative sputum sample for Aspergillus infection at 3 months.

¿ Per l’algoritmo di dosaggio: la percentuale di bambini e adolescenti con CF e infezione da Aspergillus di età compresa tra gli 8 e i 17 anni che raggiungono l’area predefinita sotto la curva di concentrazione/tempo (AUC) di posaconazolo alla prima valutazione (tra il giorno 5 e il giorno 10), basato sulla concentrazione di riferimento per gli adulti per il trattamento di agenti patogeni sensibili.
¿ Per l’efficacia clinica: il numero di bambini con campione di espettorato negativo per infezione da Aspergillus a 3 mesi.

E.5.1.1

Timepoint(s) of evaluation of this end point

- For the dosing algorithm: between day 5 and 10
- For clinical efficacy: 3 months.

Per l’algoritmo di dosaggio:Tra il giorno 5 e il giorno 10

Per l’efficacia clinica: 3 mesi

E.5.2

Secondary end point(s)

-The number of children and adolescents with CF and Aspergillus infection aged 8 to 17 years reaching the pre-defined area under the concentration time curve (AUC) of posaconazole at the second and third assessment (day 21-35 and EOT) based on the adult reference concentrations for treatment of susceptible pathogens.
- To assess the safety and tolerability of posaconazole.
- To assess any relation between posaconazole exposure and toxicity.
- Forced expiratory volume (FEV1) at 3, 6 and 12 months post randomisation to evaluate if posaconazole is beneficial for CF-related Aspergillus infection.
- Aspergillus in the airways (positive sputum culture) 6 and 12 months post randomisation to evaluate if posaconazole is able to clear CF-related Aspergillus infection.
- Levels of Aspergillus specific IgG and IgE 3, 6 and 12 months post randomisation to evaluate if posaconazole is able to normalize those levels.
- Airway inflammation as measured by proteome profiling of sputum at baseline and 3 months post randomisation to evaluate if posaconazole is able to dampen inflammation in CF-related Aspergillus infection.
- Clinical disease severity (as measured by pulmonary exacerbation rate, days on antibiotics and corticosteroids, hospital admissions, change in FEV1, change in BMI) 3, 6 and 15 months post randomisation to evaluate if posaconazole has a beneficial clinical effect.
- Patient reported outcomes 3, 6 and 12 months post randomisation to evaluate if posaconazole has a beneficial effect on people’s life.

¿ Il numero di bambini ed adolescenti con infezione da FC e Aspergillus da 8 a 17 anni che raggiungono l'area predefinita sotto la curva di concentrazione/tempo (AUC) di posaconazolo alla seconda e terza valutazione (giorno 21-35, EOT) in base alle concentrazioni di riferimento per adulti per il trattamento di agenti patogeni sensibili.
¿ Valutare la sicurezza e la tollerabilità del posaconazolo.
¿ Valutare qualsiasi relazione tra l’esposizione al posaconazolo e tossicità.
¿ Misurazione del volume espiratorio forzato (FEV1) a 3, 6 e 12 mesi dopo la randomizzazione per valutare se il posaconazolo è efficace per il trattamento dell'infezione da Aspergillus correlata alla FC.
¿ Valutare la presenza di Aspergillus nelle vie aeree (cultura dell'espettorato positivo) a 3, 6 e 12 mesi dopo la randomizzazione per valutare se il posaconazolo è in grado di eliminare l'infezione da Aspergillus correlata alla FC.
¿ Misurare i livelli di IgG e IgE specifiche di Aspergillus a 3, 6 e 12 mesi dopo la randomizzazione per valutare se il posaconazolo è in grado di normalizzare tali livelli.
¿ Valutare l’infiammazione delle vie aeree misurata mediante profilazione del proteoma dell'espettorato al basale e 3 mesi dopo la randomizzazione, per valutare se il posaconazolo è in grado di attenuare l'infiammazione nell'infezione da Aspergillus correlata alla FC.
¿ Valutare la gravità della malattia clinica (misurata in base al tasso di esacerbazione polmonare, giorni di trattamento con antibiotici ecorticosteroidi, ricoveri ospedalieri, variazione del FEV1, cambiamenti del BMI, anomalie della TAC toracica) a 3, 6 e 12 mesi dopo la randomizzazione per valutare se il posaconazolo ha un effetto benefico.
¿ Valutare i risultati del questionario sulla qualità della vita compilato dai pazienti a 3, 6 e 12 mesi dopo la randomizzazione per valutare se il posaconazolo ha un effetto benefico (CFQR convalidato).

E.5.2.1

Timepoint(s) of evaluation of this end point

-Day 21-35
-3, 6 and 12 months post randomisation

-Giorno 21-35
-3, 6 e 12 mesi dopo la randomizzazione

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Czech Republic

France

Germany

Greece

Ireland

Italy

Netherlands

Portugal

Spain

Sweden

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

Bambini

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

115

F.4.2.2

In the whole clinical trial

135

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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