Clinical Trials Register

Summary
EudraCT Number:	2015-002560-16
Sponsor's Protocol Code Number:	747-303
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-10-13
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

UK - MHRA

A.2

EudraCT number

2015-002560-16

A.3

Full title of the trial

A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in Subjects with Nonalcoholic Steatohepatitis

A.3.1

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

A clinical trial where neither the doctor, patient or sponsor know whether a placebo or active medicine is being given to the patient with nonalcoholic fatty liver disease to see if the medicine is effective and safe in the treatment of that disease.

A.3.2

Name or abbreviated title of the trial where available

REGENERATE

A.4.1

Sponsor's protocol code number

747-303

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02548351

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	Intercept Pharmaceuticals Inc.
B.1.3.4	Country	United States
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	Intercept Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Covance Clinical and Periapproval Services Limited
B.5.2	Functional name of contact point	Global Regulatory Submissions
B.5.3	Address:
B.5.3.1	Street Address	Osprey House, Maidenhead Office Park, Westacott Way
B.5.3.2	Town/ city	Maidenhead
B.5.3.3	Post code	SL6 3QH
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	submissions@covance.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	Yes
D.2.1.1.1	Trade name	Ocaliva
D.2.1.1.2	Name of the Marketing Authorisation holder	Intercept Pharma International Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Obeticholic Acid
D.3.2	Product code	INT-747, OCA,
D.3.4	Pharmaceutical form	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	Obeticholic Acid
D.3.9.1	CAS number	459789-99-2
D.3.9.2	Current sponsor code	6-ECDCA
D.3.9.3	Other descriptive name	6α-ethylchenodeoxycholic acid (6-ECDCA), OCA, INT-747
D.3.9.4	EV Substance Code	SUB91981
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	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: 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	Obeticholic Acid
D.3.2	Product code	INT-747, OCA,
D.3.4	Pharmaceutical form	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	Obeticholic Acid
D.3.9.1	CAS number	459789-99-2
D.3.9.2	Current sponsor code	6-ECDCA
D.3.9.3	Other descriptive name	6α-ethylchenodeoxycholic acid (6-ECDCA), OCA, INT-747
D.3.9.4	EV Substance Code	SUB91981
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	25
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	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

Nonalcoholic steatohepatitis

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	LLT
E.1.2	Classification code	10029530
E.1.2	Term	Non-alcoholic fatty 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

Primary Objective assessed at the Months 18 Interim Analysis:
1.Evaluate the effect of OCA compared to placebo on liver histology in
non-cirrhotic NASH subjects with stage 2 or 3 fibrosis by assessing the
following endpoints:
a.The proportion of OCA treated patients relative to placebo achieving at
least one stage of liver fibrosis improvement with no worsening of NASH
OR
b.The proportion of OCA treated patients relative to placebo achieving
NASH resolution with no worsening of liver fibrosis
Primary objective assessed at the end of trial:
1.Evaluate the effect of OCA compared to placebo on all-cause mortality
and liver-related clinical outcomes as measured by the time of first
occurrence of any adjudicated events (clinical outcomes composite
endpoint)

E.2.2

Secondary objectives of the trial

Secondary objectives at the Months 18 Interim Analysis:
1. Evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing endpoints using NASH CRN scoring criteria
2. Evaluate the effect of OCA compared to placebo on liver biochemistry
and markers of liver function

Secondary objectives at end of study:
1. Evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing endpoints using NASH CRN scoring criteria
2. Evaluate the effect of OCA compared to placebo on liver biochemistry and markers of liver function

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH with a score of at least 1 for each and a combined score of 4 or greater out of a possible 8 points according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk fac-tors: obesity (BMI ≥30 kg/m2 ), type 2 diabetes diagnosed per 2013 American Diabetes Association criteria, or ALT >1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.

E.4

Principal exclusion criteria

Key Exclusion Criteria:
1. Model for End-stage Liver Disease (MELD) score >12
2. ALT ≥10x ULN
3. HbA1c >9.5%
4. Total bilirubin >1.5 mg/dL
5. Evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC)
6. History of liver transplant, or current placement on a liver transplant list
7. Current or history of significant alcohol consumption
8. Prior or planned ileal resection, or prior or planned bariatric surgery
9. Histological presence of cirrhosis.
10. History of biliary diversion
11. Known positivity for human immunodeficiency virus infection.
12. Acute cholecystitis or acute biliary obstruction.
13. BMI>45 kg/m².

E.5 End points

E.5.1

Primary end point(s)

At 18 months:
a. Improvement in fibrosis with no worsening of NASH OR
b.Resolution of NASH with no worsening of fibrosis

At the end of study:
a. Clinical outcomes composite endpoint

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months and 7 years

E.5.2

Secondary end point(s)

Secondary efficacy endpoints at the Month 18 Interim Analysis:
• Improvement of fibrosis by at lease 1 stage AND/OR resolution of NASH, without worsening of either
• No worsening of fibrosis AND no worsening of NASH
• Improvement in each histological feature of NASH by at least 1 point
• Improvement of fibrosis by at least 2 stages
• Improvement in NAS by at least 2 points with no worsening of fibrosis
• Improvement of fibrosis and resolution of NASH as a composite
endpoint and as defined by both endpoints being met in the same
subject
• Resolution of fibrosis
• Histological progression to cirrhosis
Secondary efficacy endpoints at EOS:
• Improvement in fibrosis by at least 1 stage with no worsening of NASH
• NASH resolution with no worsening of fibrosis
• Improvement of fibrosis by at lease 1 stage AND/OR resolution of NASH, without worsening of either
• No worsening of fibrosis AND no worsening of NASH
• Improvement in each histological feature of NASH by at least 1 point
• Improvement of fibrosis by at least 2 stages
• Improvement in NAS by at least 2 points with no worsening of fibrosis
• Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints being met in the same subject
• Resolution of fibrosis

E.5.2.1

Timepoint(s) of evaluation of this end point

18 months and 7 years

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

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

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

130

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

Denmark

Finland

France

Germany

Hungary

Israel

Italy

New Zealand

Poland

Portugal

Serbia

Spain

Sweden

Switzerland

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

Subjects who discontinue investigational product due to Investigator or
Sponsor decision are expected to be followed through to study closure (or at the discretion of the Sponsor).
Last patient last visit

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:

2170

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

135

F.4.2

For a multinational trial

F.4.2.1

In the EEA

671

F.4.2.2

In the whole clinical trial

2370

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 of care

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

2015-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-10

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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