Clinical Trials Register

Summary
EudraCT Number:	2016-002833-31
Sponsor's Protocol Code Number:	CLMB763X2201
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-12-01
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

UK - MHRA

A.2

EudraCT number

2016-002833-31

A.3

Full title of the trial

A randomized, patient and investigator blinded, placebo-controlled, multicenter study to assess the safety, tolerability, pharmacokinetics and efficacy of LMB763 in patients with non-alcoholic steatohepatitis (NASH)

A.3.1

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

Safety, tolerability, pharmacokinetics and efficacy of LMB763 in patients with non-alcoholic steatohepatitis (NASH)

A.4.1

Sponsor's protocol code number

CLMB763X2201

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 Pharmaceuticals UK Limited
B.5.2	Functional name of contact point	Medical Information Services
B.5.3	Address:
B.5.3.1	Street Address	200 Frimley Business Park
B.5.3.2	Town/ city	Frimley, Camberley
B.5.3.3	Post code	GU16 7SR
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 1276 698370
B.5.6	E-mail	medinfo.uk@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	LMB763
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 established
D.3.9.1	CAS number	Not assigned
D.3.9.3	Other descriptive name	LMB763
D.3.9.4	EV Substance Code	SUB184024
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	5
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	LMB763
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 established
D.3.9.1	CAS number	Not assigned
D.3.9.3	Other descriptive name	LMB763
D.3.9.4	EV Substance Code	SUB184024
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.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	LMB763
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 established
D.3.9.1	CAS number	Not assigned
D.3.9.3	Other descriptive name	LMB763
D.3.9.4	EV Substance Code	SUB184024
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	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	20.1
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

- To determine the safety and tolerability of LMB763 during 12 weeks of treatment
- To determine the effect of LMB763 on circulating alanine aminotransferase (ALT) levels

E.2.2

Secondary objectives of the trial

- To evaluate the pharmacokinetics (PK) of LMB763 in NASH patients
- To determine the effect of LMB763 on intrahepatic lipid after 12 weeks of treatment
- To determine the effect of LMB763 on anthropometric assessments after 12 weeks of treatment
- To determine the effect of LMB763 on non-invasive markers of liver fibrosis
- To determine the effect of LMB763 on fasting lipid profile
- To determine the effect of LMB763 compared with placebo with respect to occurrence and impact of potential itch

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Cohort 1
- Male and female patients 18 years or older (at the time of the screening visit)
- Presence of NASH as demonstrated by ONE of the following:

EITHER:

1) 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, in the absence of a histological diagnosis of alternative chronic liver diseases AND ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)

OR

2) Phenotypic diagnosis of NASH based on the presence of ALL THREE of the following:
- ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND
- 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
- Diagnosis of Type 2 diabetes mellitus by having either: HbA1C ≥ 6.5% OR Symptoms of diabetes plus hyperglycemia as indicated by fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l), two hour plasma glucose concentration ≥200mg/dl (≥11.1 mmol/l, two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)
OR
Drug therapy for Type 2 diabetes mellitus

Cohort 2
- Male and female patients 18 years or older (at the time of the screening visit)
- Liver fat ≥ 10% at baseline as determined by the reading of the central MRI laboratory of locally produced images
- Presence of NASH as demonstrated by ONE of the following:
EITHER
3. 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, in the absence of a histological diagnosis of alternative chronic liver diseases
AND
ALT ≥ 43IU/L (males) or ≥ 28 IU/L (females)
OR
4. Phenotypic diagnosis of NASH based on the presence of ALL THREE of the following:
- ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) AND
- 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
- Diagnosis of Type 2 diabetes mellitus by having either:
- HbA1C ≥ 6.5%
OR
- Symptoms of diabetes plus hyperglycemia as indicated by
- fasting plasma glucose ≥126 mg/dl (≥ 7.0 mmol/l)
- two hour plasma glucose concentration ≥ 200mg/dl (≥ 11.1 mmol/l two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)
OR
- Drug therapy for Type 2 diabetes mellitus

E.4

Principal exclusion criteria

Cohort 1 and 2
- Current use of obeticholic acid (OCA)
- New initiation of GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide within 3 months of screening
- Patients on treatment with the following medicines UNLESS they are on a stable dose (± 25% of current dose) for at least 1 month before randomization: anti-diabetic medications, insulin (if ≥25% change in dose), beta-blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if doses > 200 IU/day; doses > 800 IU/day are prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen containing birth control. For oral anti-diabetic medications, no more than one step up in local prescribing guidelines will be allowed.
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 5 days (approximately 5 times the terminal half life) after stopping study medication
- 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 as administered by the site as part of the medical history
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and baseline. Marijuana use is not allowed if it is determined to be medically inappropriate by the investigator
- Calculated eGFR less than 60 mL/min (using the MDRD formula)
- Presence of cirrhosis on liver biopsy or clinical diagnosis
- Clinical evidence of hepatic decompensation or severe liver impairment
- History or presence of other concomitant liver diseases
- History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study
- Patients with contraindications to MRI imaging
- For those patients that have had a previous biopsy: Significant weight loss (>15%) or change in clinical status (in the opinion of the investigator) since the diagnostic liver biopsy

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in ALT

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

E.5.2

Secondary end point(s)

- Efficacy / Pharmacodynamics
- Pharmacokinetics
- Pharmacokinetic / pharmacodynamic interactions

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline to 12 weeks

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)

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

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

China

Georgia

New Zealand

Switzerland

United Kingdom

United States

Jordan

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:

144

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

192

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)

None.

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

2017-01-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-03-04

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