Clinical Trials Register

Summary
EudraCT Number:	2012-004170-26
Sponsor's Protocol Code Number:	1628/12
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:	2012-10-11
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

2012-004170-26

A.3

Full title of the trial

Randomized double blinde placebo controlled trial to evaluate the efficacy of N-acetylcystein in patients with chronic pancreatitis and primary sclerosing cholangitis.

Trial clinico randomizzato e controllato, in doppio cieco, per la valutazione dellÃƒÂƒÃ‚Â¢ÃƒÂ‚Ã‚Â€ÃƒÂ‚Ã‚Â™efficacia della terapia con N-acetilcisteina nei pazienti con pancreatite cronica e colangite sclerosante primitiva

A.3.1

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

Randomized double blinde placebo controlled trial to evaluate the efficacy of N-acetylcystein in patients with chronic pancreatitis and primary sclerosing cholangitis.

Trial clinico randomizzato e controllato, in doppio cieco, per la valutazione dell’efficacia della terapia con N-acetilcisteina nei pazienti con pancreatite cronica e colangite sclerosante primitiva

A.4.1

Sponsor's protocol code number

1628/12

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	POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI
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	Policlinico Gemelli
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	Policlinico Gemelli
B.5.2	Functional name of contact point	Medicina interna e gastroenterologi
B.5.3	Address:
B.5.3.1	Street Address	L.go Gemelli 8
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630156018
B.5.5	Fax number	06 30155923
B.5.6	E-mail	agasbarrini@RM.UNICATT.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	FLUIMUCIL*20CPR EFF 600MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ZAMBON ITALIA Srl
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.3.4	Pharmaceutical form	Effervescent 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	ACETYLCYSTEINE
D.3.9.1	CAS number	616-91-1
D.3.9.4	EV Substance Code	SUB05229MIG
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	600
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Effervescent tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic pancreatitis and primary sclerosing cholangitis

Pancreatite cronica e colangite sclerosante primitiva

E.1.1.1

Medical condition in easily understood language

Chronic pancreatitis and primary sclerosing cholangitis

Pancreatite cronica e clongite sclerosante primitiva

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10033649
E.1.2	Term	Pancreatitis chronic
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10008609
E.1.2	Term	Cholangitis sclerosing
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

a. Evaluate effect of NAC on quality of life of patients affected by chronic pancreatitis at EORTC-QLQ C30 and PAN28 questionnaire
b. Evaluate effect of NAC on quality of life of patients affected by primary sclerosing cholangitis at EORTC-QLQ C30 and BIL21 questionnaire

- Valutare gli effetti del trattamento con N-acetilcisteina sulla qualità di vita dei pazienti affetti da pancreatite cronica tramite questionari EORTC-QLQ C30 e PAN28
- Valutare gli effetti del trattamento con N-acetilcisteina sulla qualità di vita dei pazienti affetti da colangite sclerosante tramite questionari EORTC-QLQ C30 e BIL21

E.2.2

Secondary objectives of the trial

A – evaluate effect of NAC on pancreatic function measured by blood, fecal , sweet, breath markers and correlate them to clinical outcome
B – evaluate effect of NAC on hepatic cholestasis and necrosis evaluated by serum analisis and correlate them to clinical outcome
C – evaluate effect of NAC in mucus composition, ROS production by lynphocytes

- Analizzare gli effetti dell’ N-acetilcisteina sulla funzione pancreatica valutata in termini di variazione nei livelli di amilasemia, lipasemia, elastasi fecale e breath test ai trigliceridi misti (MTG breath test)
- Analizzare gli effetti dell’ N-acetilcisteina sulla colestasi e sull’epatocitonecrosi valutate in termini di FA, GGT, ALT
- Valutare se variazioni indotte dall’ N-acetilcisteina nella qualità del muco pancreatico o biliare, misurato indirettamente mediante dosaggio ionico nel test del sudore, siano associate ad un miglior outcome clinico
- Valutare l’efficacia dell’N-acetilcisteina in funzione di associazioni genetiche o profili genici
- Valutare l’effetto dell’ N-acetilcisteina sulla composizione del muco pancreatico o delle vie biliari, nella sottopopolazione di pazienti che per motivi clinici verranno sottoposti a brushing/biopsie delle vie biliari o pancreatiche

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 – male or female between 18 and 75 years at screening
2 – diagnosis of chronic pancreatitis or primary sclerosing cholangitis for at least 1 year
3 – written informed consent
4 – awareness of the protocol and willingness to adhere to protocol requests

1. Maschi e femmine di età ≥ 18 e < 75 al momento della visita di screening.
2. Diagnosi di pancreatite cronica da almeno 1 anno oppure diagnosi di colangite sclerosante da almeno 1 anno.
3. Consenso informato scritto firmato e datato prima dell’ammissione allo studio.
4. Il paziente deve essere in grado di comprendere e aderire alle richieste e alle istruzioni del protocollo.
5. Test di laboratorio al momento dello screening che non mostrino anormalità significative a parere del responsabile.

E.4

Principal exclusion criteria

Exclusion criteria
1 – acute pancreatitis at enrollement or needing of surgery
2 – acute cholangitis at enrollment or needing of surgery
3 – primary biliary cirrhosis
4 - Hyperthyroidism
5 – pregnancy and brestfeeding
6 – hypersensibility to fluimucil or its components
7 – peptic ulcers
8 – arterial hypertension
9 – laboratory findings at screening considered significantly abnormal from the physician
10 – withdraw of informed consent

1. Pazienti con pancreatite acuta all’arruolamento o necessitanti di terapia chirurgica.
2. Pazienti con colangite acuta all’arruolamento o necessitanti di terapia chirurgica/endoscopica.
3. Pazienti con cirrosi biliare primitiva.
4. Soggetti con ipertiroidismo.
5. Stato di gravidanza e/o allattamento.
6. Ipersensibilità ai componenti di Fluimucil e ad altre sostanze strettamente correlate dal punto di vista chimico.
7. Ulcera peptica attiva.
8. Ipertensione arteriosa.
9. Ritiro del consenso informato.

E.5 End points

E.5.1

Primary end point(s)

a) Valutare gli effetti del trattamento con N-acetilcisteina sulla qualità di vita dei pazienti affetti da pancreatite cronica tramite questionari EORTC-QLQ C30 e PAN28
b) Valutare gli effetti del trattamento con N-acetilcisteina sulla qualità di vita dei pazienti affetti da colangite sclerosante tramite questionari EORTC- QLQ C30 e BIL21

E.5.1.1

Timepoint(s) of evaluation of this end point

week 0/4/12/16

settimana 0/4/12/16

E.5.2

Secondary end point(s)

A - In patients with chronic pancreatitis,analize effect of NAC on pancreatic function evaluated by levels of amilases, lipases, fecal elastasis and mixed triglicerid breath test (MTG breath test)
B – in patient wth primary sclerosing cholangitis, analize the effect of NAC by alchaline phosphatase, g-glutmil transpeptidase, alanin amino transferase
C – efficacy of NAC in modulate electrolytes in sweet test
D – evaluate whether sweet electrolytes modulation is associated to better clinical outcome
E - Evaluate whether NAC modulates quality of pancreatic mucus
F - Evaluate whether NAC modulate ROS in peripheral blood lynphocytes

- Nei pazienti con pancreatite cronica, analizzare gli effetti dell’ N-acetilcisteina sulla flogosi e sulla funzione pancreatica, valutate in termini di variazione nei livelli di amilasemia, lipasemia, elastasi fecale e breath test ai trigliceridi misti (MTG breath test)
- Nei pazienti con colangite sclerosante primitiva, analizzare gli effetti dell’ N-acetilcisteina sulla colestasi e sull’epatocitonecrosi valutate in termini di FA, GGT, ALT;
- Efficacia della terapia con N-acetilcisteina nel modulare la concentrazione degli elettroliti determinata con il test del sudore
- Valutare se variazioni indotte dall’ N-acetilcisteina nella qualità del muco pancreatico o biliare, misurato indirettamente mediante dosaggio ionico nel test del sudore, siano associate ad un miglior outcome clinico (sub analisi dell’efficacia sulla qualità di vita nei pazienti con alterazioni del test del sudore al baseline)
- Valutare l’efficacia dell’N-acetilcisteina in funzione di associazioni genetiche o profili genici
- Valutare l’effetto dell’ N-acetilcisteina sulla composizione del muco pancreatico o delle vie biliari, nella sottopopolazione di pazienti che per motivi clinici verranno sottoposti a brushing/biopsie delle vie biliari o pancreatiche
- Valutare se il trattamento con N-acetilcisteina modifica l’espressione di ROS su linfociti del sangue periferico dei pazienti prima e dopo terapia
- Censire, nella popolazione di pazienti arruolati nello studio, le caratteristiche cliniche dei pazienti, correlate all’assetto genetico, di test funzionali e di laboratorio

E.5.2.1

Timepoint(s) of evaluation of this end point

week 0/4/12/16

settimana 0/4/12/16

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

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

E.8.4.1

Number of sites anticipated in 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

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

140

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-10-11.

Yes

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

200

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)

standard clinical care

normale pratica clinica

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

2012-12-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-09-09

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