Clinical Trials Register

Summary
EudraCT Number:	2015-005215-33
Sponsor's Protocol Code Number:	CLJN452A2202
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:	2016-06-28
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

2015-005215-33

A.3

Full title of the trial

A randomized, double-blind, placebo controlled, 3- part, adaptive design, multicenter study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR

A.3.1

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

A 2 part clinical study that will evaluate the safety and effectiveness of LJN452A to treat patients with fatty liver disease for a period of 12 weeks. The first part will be used for LJN452 dose selection for the second part of the study.

A.4.1

Sponsor's protocol code number

CLJN452A2202

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	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Stella-Klein-Löw-Weg 17
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	A-1020
B.5.3.4	Country	Austria
B.5.4	Telephone number	+43186657 0
B.5.5	Fax number	+43186657 6458

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.3.1	Product name	LJN452
D.3.2	Product code	LJN452
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	Not available yet
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	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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.3.1	Product name	LJN452
D.3.2	Product code	LJN452
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	Not available yet
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	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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.3.1	Product name	LJN452
D.3.2	Product code	LJN452
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	Not available yet
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	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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

Non-alcoholic Steatohepatitis (NASH)

E.1.1.1

Medical condition in easily understood language

Fatty liver disease not related to alcohol intake

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	22.0
E.1.2	Level	PT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
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

The primary objective of the study is to determine safety and tolerability of different doses of tropifexor by monitoring adverse events.
Moreover, the study will determine the dose-response relationship of tropifexor on markers of hepatic inflammation in NASH by changes in ALT and AST from baseline to Week 12
The study will also determine the dose-response relationship of tropifexor on liver fat content by changes from baseline to week 12 in quantitative MRI determined fat

E.2.2

Secondary objectives of the trial

Effect of different doses of tropifexor on weight, BMI, waist-to-hip
(WTH) ratio)
To determine the dose-response relationship of tropifexor on
- markers of target engagement
- liver fibrosis markers
- GGT
- fasting lipid profile
- PK of tropifexor
- Effect of tropifexor vs PBO regarding occurrence of potential itch based
on a visual analog scale (VAS)
- Effects of LJN452 on primary endpoints in the subset of patients with
historical biopsy data, both overall and by subsets defined by fibrosis
score and/or NAS score as feasible
Additional Secondary Endpoints for Part C:
- safety / tolerability of different doses of tropifexor by monitoring AEs.
- dose-response relationship of tropifexor on markers of hepatic
inflammation in NASH (baseline to wk 48).
- dose-response relationship of tropifexor on liver fat content (MRI)
baseline to wk 48
- efficacy of tropifexor in NASH and F2/F3 fibrosis as assessed by
histological improvement from baseline to wk 48 vs PBO

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Written informed consent must be obtained before any assessment is performed

Male and female patients 18 years or older (at the time of the screening visit)

Diagnosis of NASH:

Parts A&B:
Presence of NASH as demonstrated by ONE of the following:
- Histologic evidence of NASH based on liver biopsy obtained 2 years or less before randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, (i.e. fibrosis in the absence of established cirrhosis) no diagnosis of alternative chronic liver diseases

Part C (All patients): Adequate liver biopsy sample for evaluation by
Central Reader to confirm Histologic evidence of NASH based on liver
biopsy obtained during the Screening period or within 6 months before
randomization with a diagnosis consistent with NASH, fibrosis level F2 or
F3, and no diagnosis of alternative chronic liver diseases. Permitted
therapy must be stable as outlined in Table 5-5 (from 1 month prior to
biopsy up to and including screening)

AND (all parts)
ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)

OR (for Parts A and B only)
Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
o ALT ≥ 43IU/L (males) or ≥ 28 IU/L (females) AND
o BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or ≥23 kg/m2 (in patients with a self-identified Asian race)
AND
o Diagnosis of Type 2 diabetes mellitus by having either:
- HbA1C ≥ 6.5% or
- Drug therapy for Type 2 diabetes mellitus

Liver fat ≥ 10% at screening as determined by the central MRI laboratory

Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate in the study

E.4

Principal exclusion criteria

Previous exposure to an FXR agonist including tropifexor

Patients taking medications prohibited by the protocol

Pregnant or nursing (lactating) women

Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the AUDIT questionnaire ≥8
Uncontrolled diabetes defined as HbA1c ≥ 9.5% within 60 days prior to enrollment

Presence of cirrhosis on liver biopsy or clinical diagnosis

Clinical evidence of hepatic decompensation or severe liver impairment

Previous diagnosis of other forms of chronic liver disease

Patients with contraindications to MRI imaging

E.5 End points

E.5.1

Primary end point(s)

Safety (to be assessed in the SAF):
- Occurrence of SAE
- Occurrence of AE resulting in permanent discontinuation or dose reduction of study treatment
- Occurrence of AE of special interest

Efficacy (to be assessed in the FAS):
- Change from baseline to Week 12 in ALT
- Change from baseline to Week 12 in AST
- Relative change from baseline to Week 12 in percentage of fat in the liver assessed using MRI

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks of treatment

E.5.2

Secondary end point(s)

Absolute change from baseline to Week 12 in percentage of fat in the liver assessed using MRI

Weight, BMI, waist-to-hip (WTH) ratio

FGF19, C4

Liver stiffness (in kPa) by Fibroscan®, enhanced liver fibrosis panel (ELF) score, and score of fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)

GGT

Fasting lipids (total cholesterol, trigylcerides, LDL and HDL cholesterol, free glycerol, free fatty acids)

Itch VAS

At least a one point improvement of fibrosis stage without worsening of
steatohepatitis at Week 48 compared to baseline
Proportion of patients who have at least a two point improvement in
fibrosis without worsening of steatohepatitis at Week 48 compared to
baseline
Resolution of steatohepatitis without worsening of fibrosis stage at
Week 48 compared to baseline
Change of NAS from baseline to Week 48

Absolute and relative change from baseline to Week 48 in percentage of
fat in the liver assessed using MRI
Change from baseline to Week 48 of ALT and AST

E.5.2.1

Timepoint(s) of evaluation of this end point

12 respectively 48 weeks of treatment

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

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

Yes

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

Australia

Austria

Belgium

Canada

France

Germany

Italy

Korea, Republic of

Netherlands

Singapore

Slovakia

Spain

Taiwan

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

Last Visit Last Patient Last Site (LPLVLS)

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:

190

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

155

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

345

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)

Continuing care should be provided by investigator and/or referring physician based on patient availability for follow-up.

The investigator must provide follow-up medical care for all patients who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.

This continuing care for patients who complete 12 weeks of treatment may include enrollment in an extension study, if any, to allow for therapy beyond 12 weeks

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

2016-06-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-04-06

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