Clinical Trials Register

Summary
EudraCT Number:	2015-001590-41
Sponsor's Protocol Code Number:	CLJN452X2201
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

Germany - BfArM

A.2

EudraCT number

2015-001590-41

A.3

Full title of the trial

A multi-part, randomized, double-blind, placebo-controlled study to assess the safety, tolerability and efficacy of tropifexor (LJN452) in patients with primary biliary cholangitis

A.3.1

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

A multi-part, double blind study to assess safety, tolerability and efficacy of tropifexor (LJN452) in PBC patients

A.3.2

Name or abbreviated title of the trial where available

Multi-part, double blind study to assess safety, tolerability and efficacy of LJN452 in PBC patients

A.4.1

Sponsor's protocol code number

CLJN452X2201

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+491802232300
B.5.5	Fax number	+4991127312160
B.5.6	E-mail	infoservice.novartis@novartis.com

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	No
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.3.2	Product code	LJN452, 0,01 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	tropifexor
D.3.9.2	Current sponsor code	LJN452
D.3.9.3	Other descriptive name	LJN452
D.3.9.4	EV Substance Code	SUB174477
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	0.01
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	No
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.3.2	Product code	LJN452, 0,03 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	tropifexor
D.3.9.2	Current sponsor code	LJN452
D.3.9.3	Other descriptive name	LJN452
D.3.9.4	EV Substance Code	SUB174477
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	0.03
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: 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	No
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.3.2	Product code	LJN452, 0,1 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	tropifexor
D.3.9.3	Other descriptive name	LJN452
D.3.9.4	EV Substance Code	SUB174477
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	0.1
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	Capsule, hard
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

primary biliary cholangitis

E.1.1.1

Medical condition in easily understood language

primary biliary cholangitis

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10036680
E.1.2	Term	Primary biliary cirrhosis
E.1.2	System Organ Class	100000004871

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 determine the safety and tolerability of daily dosing of LJN452 in patients with Primary Biliary Cholangitis
• To determine the effect of LJN452 on cholestatic markers in patients with Primary Biliary Cholangitis. More specifically, in Part 2 to determine the dose-response relationship of LJN452 on GGT following 12 weeks of treatment

E.2.2

Secondary objectives of the trial

•To determine the change in the itch domain of PBC40 questionnaire
•To evaluate the change in overall disease specific quality of life
•To evaluate the change in itch based on 100 mm visual analog score (VAS)
•To evaluate the pharmacokinetics (PK) of LJN452 in patients with PBC
• Part 2: To determine the dose-response relationship of LJN452 on ALP in patients with PBC following 12 weeks of treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

●Diagnosis of PBC as demonstrated by the presence of ≥ 2 of the
following 3 diagnostic criteria: -History of Alkaline Phosphatase elevated
above upper limit of normal for at least 6 months
- Positive anti-mitochondrial antibodies (AMA) titer or if AMA negative or
in low titer (<1:80) PBC specific antibodies (anti- GP210 and/or anti-
SP100 and/or antibodies against the major M2 components (PDC-E2, 2-
oxo-glutaric acid dehydrogenase complex)
- Previous liver biopsy consistent with PBC
●At least 1 of the following markers of disease severity: - ALP ≥ 1.67×
upper limit of normal (ULN) -  Total bilirubin > ULN but < 1.5 × ULN
In addition, patients must meet the following biochemical criteria at
enrollment
 ALT/AST ≤5 × ULN
 Total bilirubin ≤1.5 × ULN
 INR ≤ ULN
●Subjects must weigh at least 40 kg to participate in the study, and
must have a body mass index (BMI) within the range of
18 - 40 kg/m^2. BMI = Body weight (kg) / [Height (m)]^2.
●Able to communicate well with the investigator, to understand and
comply with the requirements of the study.

E.4

Principal exclusion criteria

● Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception for 30 days before randomization, during
dosing and for 30 days following the end of treatment.
Presence of other concomitant liver diseases.
● Cirrhosis with complications, including history or presence of:
● Variceal bleed
● Uncontrolled ascites
● Encephalopathy
● Spontaneous bacterial Peritonitis
● Significant hepatic impairment as defined by Child-Pugh classification
of B or C, history of liver transplantation, current placement on a liver
transplant list or current Model for End Stage Liver Disease (MELD)
score ≥15.
● History of conditions that may cause increases in ALP (e.g., Paget's
disease).
● Use of investigational drugs or immunosuppressive drugs at the time of
enrollment, or within 5 half-lives or 30 days of randomization, whichever
is longer; or longer if required by local regulations. Use of high dose oral
steroids to treat co-morbid conditions (e.g., airways disease) will be
allowed but must be properly documented as such in concomitant
medications.
● Currently taking obeticholic acid or have taken obeticholic acid within
30 days of randomization
● Previous participation in CLJN452X2201 and received study medication
within three months of randomization (or longer if required by local
regulations).

E.5 End points

E.5.1

Primary end point(s)

1. Change in cholestatic markers from baseline
2. Number of patients with adverse events, serious adverse events and death

E.5.1.1

Timepoint(s) of evaluation of this end point

1. 28 days
2. 86 days

E.5.2

Secondary end point(s)

1. Change from baseline in disease specific quality of life
2. Change from baseline in itch as determined by the itch domain in the PBC-40
3. Change from baseline in itch as determined by 10mm VAS
4. Area under the plasma concentration-time profile (AUCtau)
5. Maximum plasma concentration of LJN452 (Cmax)
6. Minimum plasma concentration of LJN452 (Cmin)
7. Average steady state plasma concentration following multiple doses of LJN452 (Cav,ss)
8. Time to reach maximum concentration after drug administration (Tmax)
9. Apparent systemic clearance from plasma (CL/F)
10. Accumulation ratio of LJN452 (Racc)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. BL, 28 days
2. BL, 28 days
3. BL, 28 days
4. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
5. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
6. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
7. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
8. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
9. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56
10. Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

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

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

Canada

China

Germany

Poland

Russian Federation

United Kingdom

United States

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

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:

123

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

152

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 in part 1 of the trial take ursodeoxycholic acid (UDCA) additionally, however, it will not have a sufficient effect on the treatment. Patient in part 2 will not take UDCA during the trial, but they can start a treatment with UDCA as soon as the visit on day 56 has been done.
Generally further treatment is left to the physician to assess the best adequate treatment for each patient.

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

2015-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-08-02

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