Clinical Trials Register

Summary
EudraCT Number:	2013-002082-19
Sponsor's Protocol Code Number:	LAQ-MS-306
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:	2013-11-06
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

2013-002082-19

A.3

Full title of the trial

A Multinational, Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Control (Rater Blinded) Study, to Evaluate the Efficacy, Safety and Tolerability of 2 Doses of Oral administration of Laquinimod (0.6 mg/day or 1.2 mg/day) compared to Interferon β-1a administered Intra Muscular Once Weekly in Subjects with Relapsing Remitting Multiple Sclerosis (RRMS)

A.3.1

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

A clinical study in subjects with relapsing-remitting multiple sclerosis (RRMS) to assess the efficacy, safety and tolerability of two oral doses of laquinimod either of 0.6 mg/day or 1.2mg/day (experimental drug) as compared to Interferon β-1a (Avonex, authorised drug) administered once weekly.

A.3.2

Name or abbreviated title of the trial where available

LIBRETTO

A.4.1

Sponsor's protocol code number

LAQ-MS-306

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	Teva Pharmaceutical Industries, Ltd.
B.1.3.4	Country	Israel
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	Teva Pharmaceutical Industries, Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Teva Pharma GmbH
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Waldeckerstrasse 7
B.5.3.2	Town/ city	Moerfelden-Walldorf
B.5.3.3	Post code	64546
B.5.3.4	Country	Germany
B.5.4	Telephone number	000000000000
B.5.5	Fax number	000000000000
B.5.6	E-mail	Info-era-clinical@teva.de

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	Laquinimod capsules 0.6 mg
D.3.2	Product code	TV-5600
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	LAQUINIMOD
D.3.9.1	CAS number	248281-84-7
D.3.9.2	Current sponsor code	TV-5600
D.3.9.3	Other descriptive name	Laquinimod Sodium (USAN)
D.3.9.4	EV Substance Code	SUB25236
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	0.6
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	Comparator
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	Avonex
D.2.1.1.2	Name of the Marketing Authorisation holder	BIOGEN IDEC LIMITED
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INTERFERON BETA-1A
D.3.9.1	CAS number	220581-49-7
D.3.9.2	Current sponsor code	INTERFERON BETA-1A
D.3.9.3	Other descriptive name	INTERFERON BETA-1A
D.3.9.4	EV Substance Code	SUB12440MIG
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Relapsing remitting multiple sclerosis

E.1.1.1

Medical condition in easily understood language

Relapsing-remitting multiple sclerosis is a chronic inflammatory disease that affects the central nervous system

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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 overall study objective is to assess the efficacy, safety, and tolerability of 2 laquinimod doses, 0.6 mg/day or 1.2 mg daily (QD), in a double-blind design compared to Avonex® (rater blinded) once weekly (QW)
Study objectives:
• To evaluate the effect of 2 laquinimod doses (0.6 mg/day or 1.2 mg/day) compared to Avonex® QW on brain atrophy.
• To evaluate the effect of 2 laquinimod doses (0.6 mg/day or 1.2 mg/day) on new T2 lesions.

E.2.2

Secondary objectives of the trial

• To assess the effect of 2 laquinimod doses (0.6 mg/day or 1.2 mg/day) compared to Avonex® on the following patient reported outcomes (PRO):
- Physical and psychological well-being (Multiple Sclerosis Impact Scale; MSIS-29)
- General health status (36-Item Short Form Health Survey; SF 36)
- Treatment satisfaction (Treatment Satisfaction Questionnaire for Medication; TSQM-9)
- Cognitive performance (Symbol Digit Modalities Test; SDMT)
- Disability (Patient-Determined Disease Step; PDDS)
- Effect on work (Work Productivity and Activities Impairment – General Health; WPAI-GH)
• To assess
- the rate of influenza-like symptoms in the 2 laquinimod doses compared to Avonex®
- the effect of 2 laquinimod doses compared to Avonex® on thalamic volume, cortical volume, and white matter (WM) volume
- the dose-response effect of 2 laquinimod doses on magnetic resonance imaging (MRI) and clinical parameters
- the safety and tolerability of 2 laquinimod doses

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Sub-studies included within the main protocol dated 24 June 2013:
• Pharmacokinetic (PK) study: Blood samples for analysis of laquinimod plasma concentrations will be collected from the laquinimod treated subjects at Months 1, 6, and 12 (Termination).If a subject discontinues treatment prematurely, PK samples will be taken up to and including the ETD visit and in no subsequent visit.
• Pharmacogenomic (PGx) and biomarker assessment: Blood samples for PGx analysis (DNA and RNA) will be collected at Baseline (or if not possible at the next possible visit) from all subjects that sign the informed consent form. The objective of this study is to collect and store DNA and RNA samples for possible association analysis of genetic polymorphisms, and/or gene expression profiles with clinical or paraclinical (MRI) treatment responses to laquinimod doses, in comparison with Avonex. In addition, these data will be used to assess potential safety signals that may arise during the study.

Ancillary studies:
• 3D T1-w acquisition of the cervical cord (to be performed in selected sites) will be assessed at Months 0 (Baseline), ETD (if applicable), and Months 6 and 12 (Termination).
• Spectral Domain Optical Coherence Tomography (SD-OCT) evaluation (to be performed in selected sites) is performed at Baseline, ETD (if applicable), and Month 12 to assess retinal nerve fiber layer thickness (RNFLT).
• Magnetization Transfer Ratio (MTR) MRI (to be performed at selected sites) is assessed at Months 0 (Baseline), ETD (if applicable), and Months 6 and 12 (Termination).
All subjects participate in ancillary studies, will sign a seperate informed consent form.

E.3

Principal inclusion criteria

1. Subjects must have a confirmed and documented RRMS diagnosis as defined by the Revised McDonald criteria, with relapse onset disease or a relapsing-remitting disease course.
2. Subjects must be ambulatory with an Kurtzke EDSS score of 0 5.5 at both at Screening and Baseline (randomization) visits.
3. Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization.
4. Subjects must have experienced at least 1 documented relapse in the last year prior to randomization or 2 relapses in the last 3 years prior to randomization.
5. Subjects must be between 18 and 55 years of age at screening, inclusive.
6. Women of child-bearing potential must practice an acceptable method of birth control until 30 days after the last dose of treatment was administered.
7. Subjects must be able to sign and date a written informed consent prior to entering the study.
8. Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

E.4

Principal exclusion criteria

1. Subjects with progressive forms of MS.
2. Subjects with Neuromyelitis Optica (NMO).
3. Use of experimental or investigational drugs and/or participation in drug clinical studies within 6 months prior to Baseline visit (randomization).
4. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azatioprine within 12 months prior to Baseline.
5. Prior use of monoclonal antibodies ever, except for:
- Natalizumab (Tysabri®) if given more than 6 months prior to randomization AND the subject is John Cunningham (JC) virus antibody test negative at Screening.
- Previous use of Rituximab, ocrelizumab, or ofatumumab is allowed if the B cell count (CD19) is higher than 80 cells /µL.
6. Previous treatment with glatiramer acetate (Copaxone® ), fingolimod (Gilenya®), BG-12 (Tecfidera), Teriflunomide (Aubagio®) or intravenous immunoglobulin (IVIG) within 2 months prior to Baseline.
7. Use of mitoxantrone (Novantrone) within 5 years prior to Screening. Use of mitoxantrone (Novantrone) >5 years before screening is allowed in subjects with normal ejection fraction and who did not exceed the total lifetime maximal dose.
8. Chronic systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to Baseline.
9. Previous use of cladribine.
10. Previous use of laquinimod or Avonex® IM.
11. Treatment with other Interferon-β (either 1a subcutaneous [SC] or 1b SC) within 60 days before baseline (earlier treatment will be allowed if the reason for discontinuation was not treatment failure or for Interferon-β related safety reasons. This decision will be taken by the investigator).
12. Previous total body irradiation or total lymphoid irradiation.
13. Previous stem cell treatment, autologous bone marrow transplantation, or allogenic bone marrow transplantation.
14. Acute infection within 2 weeks prior to Baseline visit.
15. Major trauma or surgery within 2 weeks prior to Baseline visit.
16. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to Baseline.
17. Use of inducers of CYP3A4 within 2 weeks prior to Baseline
18. Pregnancy or breast feeding.
19. Serum levels ≥3 times (x) upper limit of normal (ULN) of either ALT or AST at Screening.
20. Serum direct bilirubin ≥2xULN at Screening.
21. Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests MRI or chest X-ray. months prior to randomization.
22. Twenty or more gadolinium (Gd)- enhancing (E) lesions on baseline MRI.
23. A known history of sensitivity to gadolinium (Gd).
24. GFR ≤ 60 mL/min at the screening visit.
25. Inability to successfully/safely undergo MRI scanning.
26. Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI).
27. Known hypersensitivity that would preclude administration of laquinimod capsule, such as hypersensitivity to: mannitol, meglumine, or sodium stearyl fumarate.
28. A known history of hypersensitivity to natural or recombinant interferon β, human albumin, or any other component of the formulation of Avonex®
29. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals

E.5 End points

E.5.1

Primary end point(s)

Change in whole brain atrophy as defined by the percent change in total brain volume between laquinimod 0.6 mg versus Avonex® and laquinimod 1.2 mg versus Avonex®.

E.5.1.1

Timepoint(s) of evaluation of this end point

Change in whole brain atrophy from Month 0 (Baseline) to Month 12.

E.5.2

Secondary end point(s)

• The cumulative number of influenza-like symptoms experienced on the 2 doses of laquinimod (0.6 mg and 1.2 mg) versus Avonex®
• The cumulative number of new T2 lesions between the 2 laquinimod doses

E.5.2.1

Timepoint(s) of evaluation of this end point

• The cumulative number of influenza-like symptoms experienced from baseline to Month 3 on each dose of laquinimod (0.6 mg and 1.2 mg) versus Avonex®
• The cumulative number of new T2 lesions measured at Month 6 and Month 12 between the 2 laquinimod doses

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

E.6.11

Pharmacogenomic

Yes

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)

Yes

E.8.2.2

Placebo

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

132

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

Switzerland

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:

600

F.1.3

Elderly (>=65 years)

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

590

F.4.2.2

In the whole clinical trial

600

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

2013-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-11-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-02-19

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