Clinical Trials Register

Summary
EudraCT Number:	2013-001258-82
Sponsor's Protocol Code Number:	CFTRcysta1
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-07-29
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

2013-001258-82

A.3

Full title of the trial

A phase II pilot clinical study of experimental research to evaluate the
functional rescue of CFTR protein through proteostasis regulators

Studio clinico pilota di ricerca sperimentale di fase II, per valutare il recupero funzionale della proteina CFTR attraverso l’uso di regolatori della proteostasi

A.3.1

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

Phase II clinical study for the therapy of cystic fibrosis patients with a
specific mutation

Studio clinico di fase II per il trattamento di pazienti di fibrosi cistica con
una specifica mutazione

A.3.2

Name or abbreviated title of the trial where available

Proteostasis regulators effect in cystic fibrosis therapy

Effetto di regolatori della proteostasi in fibrosi cistica

A.4.1

Sponsor's protocol code number

CFTRcysta1

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	European Institute for Cystic Fibrosis Research (IERFC)
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	European Institute for Cystic Fibrosis Research (IERFC)
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	AOU Federico II, Clinical Department of Pediatrics
B.5.2	Functional name of contact point	Dept. of Translational Medicine
B.5.3	Address:
B.5.3.1	Street Address	Via S. Pansini, 5
B.5.3.2	Town/ city	Naples
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390817463501
B.5.5	Fax number	0039081 5469811
B.5.6	E-mail	bartoloni@unina.it

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	Cystagon
D.2.1.1.2	Name of the Marketing Authorisation holder	Orphan Europe
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	Yes
D.2.5.1	Orphan drug designation number	ORPHA131237
D.3 Description of the IMP
D.3.1	Product name	Cysteamine bitartrate (Cystagon)
D.3.2	Product code	EMEA/H/C/000125
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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 patients with F508del-CFTR in homozygous or compound heterozygous with Class I or II mutations

Pazienti con fibrosi cistica con mutazione F508del-CFTR in omozigosi o in eterozigosi composta con mutazioni di classe I/II

E.1.1.1

Medical condition in easily understood language

Cystic fibrosis

Fibrosi cistica

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the effectiveness in the functional rescue of CFTR protein and the safety in the use of proteostasis regulator (cysteamine bitartrate) in association with a flavonoid (epigallocatechine gallate)
with the aim to strenghten the beneficial effects of cysteamine on the
F508del-CFTR protein at the plasma membrane level, in cystic fibrosis
patients with F508del-CFTR in homozygous or compound heterozygous with Class I or II mutations aged at least 6 years old. The study has been temporally extended in order to asses the therapeutic efficacy as well as tolerability of cysteamine bitartrate in patients either patient homozygotes or heterozigotes for F508del-CFTR

Valutare l'efficacia nel recupero funzionale della proteina CFTR e la
sicurezza dell'uso sequenziale di un regolatore della proteostasi (la
cisteamina bitartrato) in associazione con un flavonoide
(EpiGalloCatechinGallato, EGCG), che ha lo scopo di rafforzare gli effetti benefici della cisteamina sulla stabilità della proteina F508delCFTR in membrana, in pazienti con Fibrosi Cistica con mutazione F508del-CFTR in omozigosi o in eterozigosi composta con mutazioni di classe I e IIdi età uguale o superiore ai 6 anni. Lo studio costituisce una estensione temporale allo scopo di valutare l'efficacia terapeutica e la tollerabilità della cisteamina bitartrato in pazienti omozigoti o eterozigoti per la mutazione F508-del CFTR.

E.2.2

Secondary objectives of the trial

not applyable

non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnosis of cystic fibrosis by sweat test with chloride level≥60 mEq/l and confirmed by genetic analysis in order to search cystic fibrosis F508del-CFTR homozigotic mutation or F508del-CFTR combined mutations of class I and II
- males or females aged at least 6 years old.
- fertile females should accept a contraceptive method.
- FEV1 ≥40% as compared to expected value for age and sex.
- At least 2 sweat tests within the 3 months before Meeting 1 to
establish the interindividual variation of chloride level in the sweat.
- Informed agreement
- All subjects must be able to understand the aim of the study

- Diagnosi di Fibrosi Cistica effettuata mediante test del sudore con Cloro ≥60 mEq/l e confermata da analisi genetica con ricerca di mutazioni per FC e con riscontro di F508del-CFTR in omozigosi o F508del-CFTR/mutazione di classe I o II o omozigoti o eterozigoti composta per mutazioni di classe I o II.
- Maschi o femmine di età uguale o superiore a 6 anni.
- Per le femmine in età fertile uso di contraccezione nel corso dello studio.
- FEV1 ≥40% del valore predetto per età e sesso.
- Almeno 2 test del sudore praticati entro 3 mesi precedenti la visita 1 al fine di valutare la variazione intraindividuale del valore del cloro nel sudore.
- Consenso informato per tutte le procedure legate allo studio.
- Soggetti in grado di comprendere correttamente le finalità dello studio.

E.4

Principal exclusion criteria

- Treatment with glucocorticoids per os or via inhalationat Meeting 1 or within 4 weeks before meeting 1.
- Treatment with oxygen, over day or over night.
- Other experimental drugs.
- Hypersensitivity (local or general) to cysteamine or penicillamine.
- Modifications in the therapy with macrolides, ant-asmatic, mucolytic
drugs, Dornase alfa, and/or FANS, DHA within 28 days before Meeting 1.

However, ita can be accepted the use of some drugs (for example FANS).
- Lung/hepatic/other organ transplantation.
- Kidney or hepatic alterations at Meeting 1:
-AST, ALT > 5 fold normal value . -
Creatinine > 2 fold normal value (ULN).
- Pregnancy
- Nursing.
- No contraceptive method.
- Neurologic and psychiatric pathologies that, on the basis of the Researcher
experience, could interfere with protocol

- Uso corrente di corticosteroidi per os o per via inalatoria alla visita 1 o fino a 4 settimane precedenti la visita 1.
- Uso corrente di ossigeno continuo giornaliero o nelle ore notturne.
- Uso di eventuali farmaci in sperimentazione.
- Ipersensibilità locale o sistemica alla cisteamina o alla penicillamina.
- Introduzione o modifiche allo schema posologico nelle terapie con macrolidi, broncodilatatori, Dornase alfa, mucolitici, FANS, DHA nei 28 giorni precedenti la visita 1. Tuttavia, l’uso occasionale di farmaci (ad esempio FANS) può essere tollerato.
- Anamnesi positiva per trapianto polmonare/epatico/altro.
- Alterazione degli indici di funzionalità renale o epatica alla visita 1:
-AST, ALT > 5 volte il limite superiore del valore di normalità. -Creatinina > 2 volte il limite superiore del valore di normalità (ULN).
- Test di gravidanza positivo.
- Allattamento.
- Non uso di contraccezione per le femmine in età fertile nel corso dello studio.
- Patologie neurologiche e psichiatriche di qualsiasi tipo ed entità che, a parere dello sperimentatore, possano interferire con la aderenza al protocollo.

E.5 End points

E.5.1

Primary end point(s)

Sweat test: reduction of chloride of at leastl 15% as compared to the same
patient at the beginning of the study.
Brushing of the nose: experiments will be performed to a) evaluate the
chloride channel activity of CFTR by SPQ technique; b) the expression of
pro-inflammatory cytokines (TNFalpha, IL-8) by Polymerase Chain
Reaction (PCR) as compared to the same patient at the beginning of the
study.

Test del sudore: riduzione del valore di cloro nel sudore almeno del 15% rispetto al valore dello stesso paziente registrato all’inizio dello studio.
Brushing nasale: saranno valutati a) la funzione di canale ionico della CFTR mediante analisi del flusso di cloro attraverso la membrana mediante tecnica SPQ in fluorescenza b) i livelli di espressione di citochine infiammatorie (TNFalpha, IL-8) mediante Polymerase Chain Reaction (PCR) rispetto ai valori dello stesso paziente registrati all’inizio dello studio.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 4,8, 12, 20, 28, 36, 44 weeks

Dopo 4, 8, 12, 20, 28, 36, 44 settimane

E.5.2

Secondary end point(s)

In the sputum it will be evaluated a) the number of pro-inflammatory
cells; b) IL-8 and neutrophilic elastase levels as compared to the same
patient at the beginning of the study.

Espettorato: saranno valutati a) il numero delle cellule infiammatorie; b) i livelli di IL-8 e di elastasi neutrofilica, rispetto ai valori dello stesso paziente registrati all’inizio dello studio.

E.5.2.1

Timepoint(s) of evaluation of this end point

After 4, 8, 12, 20, 28, 36, 44 weeks from the beginning of the study

Dopo 4, 8, 12, 20, 28, 36, 44 settimane dall'inizio dello studio

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

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)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

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

nessun trattamento

no treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

Number of subjects for this age range:

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)

Yes

F.1.2.1

Number of subjects for this age range:

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Patients will be monitored every two months in order to evalaute their health, side effects as well as the beneficial effects from the treatment.

I pazienti saranno monitorati regolarmente (almeno ogni 2 mesi) allo scopo di valutare parametric clinici e di laboratorio e non solo eventuali effetti collaterali a seguito della sospensione della terapia ma soprattutto di effetti benefici sulla funzionalità polmonare e generale e sulla storia naturale della malattia.

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

2013-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-17

P. End of Trial
P.	End of Trial Status	Completed

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