Clinical Trials Register

Summary
EudraCT Number:	2017-000488-34
Sponsor's Protocol Code Number:	PVTRIFA2017
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:	2021-06-08
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

2017-000488-34

A.3

Full title of the trial

RIFAXIMIN BLUNTED HIGHER LEVELS OF ENDOTOXIN IN CIRRHOSIS PATIENTS: A RANDOMIZED, DOUBLE BLIND, SHORT TERM INTERVENTIONAL TRIAL.

MODULAZIONE DEGLI ELEVATI LIVELLI DI ENDOTOSSINA NEI PAZIENTI CON CIRROSI EPATICA: STUDIO RANDOMIZZATO, DOPPIO-CIECO, A BREVE TERMINE CON RIFAXIMINA

A.3.1

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

Role of rifaximin in decreasing the circulating levels of endotoxin in patients with cirrhosis

Ruolo della rifaximina per ridurre gli alti livelli sanguigni di endotossina nei pazienti affetti da cirrosi epatica

A.3.2

Name or abbreviated title of the trial where available

Rifaximin in cirrhotic patient

Rifaximina nel paziente cirrotico

A.4.1

Sponsor's protocol code number

PVTRIFA2017

A.5.4

Other Identifiers

Name:

n.a

Number:

n.a

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	UMBERTO I - POLICLINICO 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	ALFA WASSERMANN S.p.A
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	Sapienza-Universit¿ di Roma
B.5.2	Functional name of contact point	Dip. Medicina Interna e Specialit¿
B.5.3	Address:
B.5.3.1	Street Address	Viale del Policlinico 155
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00161
B.5.3.4	Country	Italy
B.5.4	Telephone number	3393452523
B.5.5	Fax number	0649970893
B.5.6	E-mail	stefania.basili@uniroma1.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	TIXTELLER - 550 MG COMPRESSE RIVESTITE CON FILM 14 COMPRESSE IN BLISTER PVC/PE/PVDC/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	ALFA WASSERMANN S.P.A.
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	RIFAXIMINA
D.3.2	Product code	n.a
D.3.4	Pharmaceutical form	Film-coated 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.3.9.1	CAS number	80621-81-4
D.3.9.2	Current sponsor code	n.a
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	1100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated 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

PATIENTS WITH CIRRHOSIS CHILD PUGH B or C Classes

PAZIENTI AFFETTI DA CIRROSI EPATICA CLASSE CHILD-PUGH B or C

E.1.1.1

Medical condition in easily understood language

ADVANCED CHRONIC LIVER DISEASE

MALATTIA EPATICA CRONICA AVANZATA

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10009211
E.1.2	Term	Cirrhosis liver
E.1.2	System Organ Class	100000004871

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

TO ASSESS THE EFFECT OF A SHORT-TERM (14 DAYS) TREATMENT WITH RIFAXIMIN (1100 MG/DIE) ON SYSTEMIC LEVELS OF INTESTINAL ENDOTOXIN AND ON PLATELET AND COAGULATION MARKERS IN PATIENTS WITH DECOMPENSATED CIRRHOSIS

valutare l¿effetto di un trattamento a breve termine (14 giorni) di rifaximina (1100 mg/die) sui livelli sistemici di endotossina di origine intestinale e sui marcatori di funzione piastrinica e coagulatoria nel paziente affetto da cirrosi epatica in fase di scompenso

E.2.2

Secondary objectives of the trial

Not planned

Non previsti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria will be: (i) patients aged 18–75 years; (ii) those with decompensated liver cirrhosis, as confirmed by clinical symptoms and signs, laboratory results, ultrasound and spiral computed tomography (CT) (Child–Pugh grade B or C).

I criteri di inclusione saranno: (i) età dai 18 ai 65 anni; (ii) cirrosi epatica scompensata, come confermato da sintomi e segni clinici, risultati di laboratorio, ultrasonografici e tomografia spirale computerizzata (classi di Child Pugh B o C).

E.4

Principal exclusion criteria

Exclusion criteria will be: i) presence of overt infection or sepsis; ii) treatment with systemic or non-absorbable antibiotic, aspirin or other non-steroidal anti-inflammatory drugs, antidepressant drugs in the previous 30 days; iii) recent need of transfusion of platelets or plasma; iv) presence of extra-hepatic malignancy; v) active alcohol intake in the last 6 months; vi) pregnancy or breast feeding; (v) presence of overt HE, GI haemorrhage, SBP or other concurrent infections during the previous one month; (v) human immunodeficiency virus (HIV) infection; (vi) chronic renal and/or respiratory insufficiency, severe heart disease; (vii) allergy to rifaximin.active post-viral hepatitis requiring or on direct-acting antiviral (DAA) agents; (ix) previous or active intestinal obstruction.

I criteri di esclusione saranno: (i) presenza di infezione manifesta o sepsi; (ii) trattamento con antibiotico sistemico o non assorbibile, aspirina o altri farmaci anti-infiammatori non steroidei; iii) recente necessità di trasfusione di piastrine o plasma; iv) presenza di malignità extra-epatica; v) assunzione attiva di alcol negli ultimi sei mesi; vi) gravidanza o allattamento; (vii) presenza di encefalopatia epatica manifesta, emorragia GI, PBS o altre infezioni occorrenti durante il precedente mese; (viii) infezione da virus dell’immunodeficienza umana (HIV); (ix) insufficienza renale e/o respiratoria cronica, malattia cardiaca severa; (x) allergia alla rifaximina. (viii) epatite post virale attiva che richiede o è in trattamento con agenti antivirali ad azione diretta (DAA). (xi) ostruzione intestinale passata o in atto.

E.5 End points

E.5.1

Primary end point(s)

Significant decrease (-20%) in serum bacterial LPS (endotoxemia) after 14-day treatment with Rifaximin 550 mg b.i.d respect to the control group as well as after 30 and 60 days from the end of the treatment.

Significativa riduzione (-20%) dei livelli di endotoxinemia dopo 14 giorni di trattamento con Rifaximina (550 mg due volte al giorno) e dopo 30 e 60 giorni dalla sospensione del trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of the treatment as well as after 30 and 60 days after drug discontinuation

a fine trattamento e dopo 30 e 60 giorni dall’interruzione

E.5.2

Secondary end point(s)

Significant correlation between change in serum LPS and thrombin generation and/or platelet activation indexes in both group to support the role of LPS as trigger of clotting activation and platelet activation.; Number of participants with adverse events as a measure of safety and tolerability; Proportion of patients with clinical failure [acute on chronic liver failure: specific syndrome characterized by acute decompensation, organ failure, and high short-term mortality].

Correlazione significative tra i cambiamenti dell¿endotoxina sierica e gli indici di attivazione coagulatoria e/o piastrinica.; percentuale di pazienti con eventi avversi durante il trattamento.; percentuale di pazienti con peggioramento dello stadio di malattia (insufficienza epatica acuta su cronica: sindrome specifica caratterizzata da uno scompenso epatico acuto, insufficienza organo specifica e alto tasso di mortalit¿ a breve termine).

E.5.2.1

Timepoint(s) of evaluation of this end point

a fine trattamento e dopo 30 e 60 giorni dall¿interruzione ; During the interventional period.; at the end of the treatment as well as after 30 and 60 days after drug discontinuation.

a fine trattamento e dopo 30 e 60 giorni dall¿interruzione ; durante il periodo di intervento terapeutico. ; a fine trattamento e dopo 30 e 60 giorni dall¿interruzione

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

Yes

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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.1.1.1

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Periodic outpatient visits will be performed according with clinical good practice for the chronic disease.

I pazienti al termine dello studio continueranno ad effettuare controlli periodici ambulatoriali come richiesto dalla buona pratica clinica per la condizione da cui sono affetti.

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

2017-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-06-01

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IMP with orphan designation in the indication
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