Clinical Trials Register

Summary
EudraCT Number:	2011-004681-15
Sponsor's Protocol Code Number:	KIMCL_TS_2011-09
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-10-19
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2011-004681-15

A.3

Full title of the trial

Effects of the activation of peroxisome proliferator-activated receptors in patients with primary biliary cirrhosis

Wirkung von Aktivierung von Peroxisom-Proliferator-aktivierten Rezeptoren bei PatientInnen mit primär biliärer Cirrhose

A.3.1

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

Effects of the activation of PPARs in the orphan hepatic disease primary biliary cirrhosis

Wirkung von PPARs-Aktivierung auf die seltene Lebererkrankung primär biliäre Zirrhose

A.3.2

Name or abbreviated title of the trial where available

Effects of the activation of PPARs in patients with PBC

Wirkung von PPARs-Aktivierung bei PBC PatientInnen

A.4.1

Sponsor's protocol code number

KIMCL_TS_2011-09

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	Medizinische Universität Graz
B.1.3.4	Country	Austria
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	Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medical University of Graz
B.5.2	Functional name of contact point	MUG
B.5.3	Address:
B.5.3.1	Street Address	Auenbruggerplatz 15
B.5.3.2	Town/ city	Graz
B.5.3.3	Post code	8036
B.5.3.4	Country	Austria
B.5.4	Telephone number	+43316385 80442
B.5.5	Fax number	+43316385 13430
B.5.6	E-mail	tatjana.stojakovic@medunigraz.at

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	Bezafibrat "Genericon" retard 400 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Genericon Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Bezafibrat
D.3.2	Product code	1-20190
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.3.8	INN - Proposed INN	BEZAFIBRATE
D.3.9.1	CAS number	41859-67-0
D.3.9.4	EV Substance Code	SUB05810MIG
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	400
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.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.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Ursodeoxycholsäure
D.3.4	Pharmaceutical form	Capsule
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	128-13-2
D.3.9.3	Other descriptive name	URSODEOXYCHOLIC ACID
D.3.9.4	EV Substance Code	SUB11389MIG
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	250
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

Up to 67% of PBC patients have an incomplete biochemical response to UDCA and remain at increased risk for progression to cirrhosis and liver-related death. In this study we will prospectively examine the therapeutic effects of bezafibrate (a pan-agonist activating PPARalpha/delta/gamma) in patients with early-stage PBC with a specific focus on improvement of liver functions, inflammation, lipid profile, oxidative status and endothelial function.

Bis zu zwei Drittel der PBC PatientInnen sprechen nicht ausreichend auf UDCA an und weisen ein erhöhtes Risiko für eine Progression zur Leberzirrhose und dadurch bedingten Tod auf. In dieser prospektiven Studie sollen die therapeutischen Effekte von Bezafibrat (ein Panagonist, der PPARalpha/delta/gamma aktiviert) bei PatientInnen mit PBC im Frühstadium in Hinblick auf Verbesserung der Leberfunktion, Inflammation, Lipidprofil, oxidativer Status und Endothelfunktion untersucht werden.

E.1.1.1

Medical condition in easily understood language

Up to 67% of PBC patients have an incomplete biochemical response to UDCA. Effects of bezafibrate will be examined with a specific focus on improvement of laboratory parameters and vascular function.

Bis zu 2/3 der PBC PatientInnen sprechen nicht ausreichend auf UDCA an. Es sollen daher die Effekte von Bezafibrat in Hinblick auf Laborparameter und Gefäßfunktion untersucht werden.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

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

Our major hypothesis is that the treatment with bezafibrate will improve levels of AP in early-stage PBC patients with an incomplete biochemical response to UCDA through a combination of metabolic and anti-inflammatory effects.

Unsere Hypothese ist, dass die Therapie mit Bezafibrat die AP bei PBC PatientInnen im Frühstadium und unzureichendem Ansprechen auf UCDA aufgrund metabolischer und anti-inflammatorischer Effekte vebessert.

E.2.2

Secondary objectives of the trial

Moreover, we will focus on mechanistic effects on markers of liver function, chronic low-grade inflammation, dyslipidemia, oxidative stress and endothelial function.

Desweiteren werden wir die mechanistischen Effekte in Bezug auf Leberfunktion, chronische niedriggradige Inflammation, Dyslipidämie, oxidativer Stress und Endothelfunktion untersuchen.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Incomplete responders to standard UDCA therapy (AP > 1.5x ULN after one year)
PBC stage I – II (biopsy proven and/or positive AMA)
Male or female gender
Age 18 – 70 years
Normal kidney function
Signed informed consent

inkomplette Responder auf Standard UDCA Therapie (AP >1.5x ULN nach 1 Jahr)
PBC Stadium I-II (entsprechende Leberhistologie und/oder AMA positiv)
männliches oder weibliches Geschlecht
Alter 18-70 Jahre
normale Nierenfunktion
schriftliche Einwilligung der PatientInnen

E.4

Principal exclusion criteria

PBC stage III – IV
Age > 70 years
Decompensated liver disease (Child-Pugh class B/C, presence of ascites, esophageal varices)
Cholelithiasis
ALT or AST > 3x ULN
CK > 5x ULN or CK >3x ULN with muscle pain, tenderness or weakness
Pregnancy or breastfeeding
Premenopausal women without certain contraception
Known hypersensitivity to fibrates
Current treatment with lipid-lowering drugs, immunosuppressants, coumarin-based anticoagulants, monoamine oxidase inhibitors

PBC Stadium III-IV
Alter >70 Jahre
dekompensierte Lebererkrankung (Child-Pugh B/C, Ascites, Oesophagusvarizen)
Cholelithiasis
ALT oder AST >3x ULN
CK >5x ULN oder CK >3x ULN mit Muskelschmerzen oder Muskelschwäche
Schwangerschaft oder Stillen
prämenopausale Frauen ohne sichere Kontrazeption
bekannte Hypersensitivität gegenüber Fibraten
laufende Behandlung mit lipidsenkenden Medikamenten, Immunsuppressiva, Antikoagulantien vom Cumarintyp, Monoaminooxidase-Hemmer

E.5 End points

E.5.1

Primary end point(s)

alkaline phosphatase (AP)

alkalische Phosphatase (AP)

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening (within 4 weeks prior to baseline visit), at weeks 0 (baseline), 4, 8

Screening (innerhalb 4 Wochen vor Baseline Visite), Woche 0 (Baseline), Woche 4, Woche 8

E.5.2

Secondary end point(s)

Liver enzymes
Composition and concentrations of VLDL, IDL, LDL and HDL particles
Cholesterol precursors and metabolites
Markers of inflammation and oxidative stress
Vascular morphology and function

Leberenzyme
Zusammensetzung and Konzentration von VLDL, IDL, LDL und HDL Partikeln
Cholesterinvorläufer und Metabolite
Marker für Inflammation und oxidativen Stress
Gefäßmorphologie und -funktion

E.5.2.1

Timepoint(s) of evaluation of this end point

Liver enzymes at screening, at weeks 0, 4, 8
Composition and concentrations of VLDL, IDL, LDL and HDL particles at weeks 0, 4, 8
Cholesterol precursors and metabolites at weeks 0, 4, 8
Markers of inflammation and oxidative stress at weeks 0, 4, 8
Vascular morphology and function at weeks 0, 8

Leberenzyme: Screening, Woche 0, 4, 8
Zusammensetzung and Konzentration von VLDL, IDL, LDL and HDL Partikeln: Woche 0, 4, 8
Cholesterinvorläufer und Metabolite: Woche 0, 4, 8
Marker für Inflammation und oxidativen Stress: Woche 0, 4, 8
Gefäßmorphologie und -funktion: Woche 0, 4, 8

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

E.8.1.1

Randomised

E.8.1.2

Open

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

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.8.6 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

End of the trial = last patient out

Ende der Studie = letzte(r) PatientIn abgeschlossen

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

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

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)

After the end or discontinuation of the trial the patient will be further supervised in the liver clinic. Depending on the findings of this trial a follow-up study to investigate the long-term efficacy and safety of bezafibrate in PBC will be planned.

Nach Abschluß bzw. bei vorzeitiger Beendigung der Studie wird der/die PatientIn in der Leberambulanz weiterbetreut. Abhängig von den Ergebnissen dieser Studie ist eine Folgestudie geplant, bei der die Sicherheit und Wirksamkeit von Bezafibrat bei PBC näher untersucht werden soll.

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

2011-11-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-14

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IMP with orphan designation in the indication
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