A Multinational, Multicenter, Randomized, Parallel-Group study performed in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) to assess the efficacy, safety and tolerability of laquinimod over placebo in a double-blind design and of a reference arm of Interferon ß-1a (Avonex®) in a rater-blinded design - BRAVO

• Register: EUCTR
• Last refreshed on: 12 May 2014
• Main ID: EUCTR2007-005450-23-EE
• Date of registration: 11/02/2008
• Prospective Registration: Yes
• Primary sponsor: Teva Pharmaceutical Industries Ltd
• Public title: A Multinational, Multicenter, Randomized, Parallel-Group study performed in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) to assess the efficacy, safety and tolerability of laquinimod over placebo in a double-blind design and of a reference arm of Interferon ß-1a (Avonex®) in a rater-blinded design - BRAVO
• Scientific title: A Multinational, Multicenter, Randomized, Parallel-Group study performed in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) to assess the efficacy, safety and tolerability of laquinimod over placebo in a double-blind design and of a reference arm of Interferon ß-1a (Avonex®) in a rater-blinded design - BRAVO
• Date of first enrolment: 28/03/2008
• Target sample size: 1200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-005450-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Third arm comparator, rater-blinded If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: yes Other specify the comparator: Avonex 30 microgram/0.5 ml Solution for Injection

Countries of recruitment

Bulgaria, Czech Republic, Estonia, Germany, Italy, Lithuania, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
1.Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria [Ann Neurol 2005: 58:840-846], with a relapsing-remitting disease course.
2.Subjects must be ambulatory with Converted EDSS score of 0-5.5 in both screening and baseline visits.
3.Subjects must be in a stable neurological condition and free of corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] 30 days prior to screening (month -1) and between screening (month -1) and baseline (month 0) visits.
4.Subjects must have had experienced one of the following:
?At least one documented relapse in the 12 months prior to screening, or
?At least two documented relapses in the 24 months prior to screening or
?One documented relapse between 12 and 24 months prior to screening
with at least one documented T1-Gd enhancing lesion in an MRI performed
within 12 months prior to screening.
5.Subjects must be between 18 and 55 years of age, inclusive.
6.Women of child-bearing potential must practice an acceptable method of birth control [acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner’s vasectomy or a double-protection method (condom or diaphragm with spermicide)].
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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. An onset of relapse or any treatment with corticosteroids [intravenous (IV),
intramuscular (IM) and/or per os (PO)] or ACTH between month -1 (screening)
and 0 (baseline).
2. Subjects with progressive forms of MS.
3. Use of experimental or investigational drugs, and/or participation in drug clinical
studies within the 6 months prior to screening visit.
4. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic
agents within 6 months prior to the screening visit.
5. Previous use of either of the following: natalizumab (Tysabri®), cladribine,
laquinimod, Interferon beta-1a (Avonex® or Rebif®), Interferon beta-1b
(Betaseron®/Betaferon®) or any other experimental Interferon-beta for MS.
6. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 2 months
prior to screening visit.
7. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid
treatment within 2 months prior to screening visit.
8. Previous total body irradiation or total lymphoid irradiation.
9. Previous stem cell treatment, autologous bone marrow transplantation or allogenic
bone marrow transplantation.
10. A known history of tuberculosis.
11. Acute infection within two weeks prior to baseline visit.
12. Major trauma or surgery within two weeks prior to baseline visit.
13. Known human immunodeficiency virus (HIV) positive status.
14. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline visit (see Appendix 5)
15. Use of amiodarone within 2 years prior to screening visit.
16. Pregnancy or breastfeeding.
17. A =3xULN serum elevation of either ALT or AST at screening.
18. Serum direct bilirubin which is =2xULN at screening
19. A QTc interval which is > 450 msec (according to machine output), obtained from:
-Two ECG recordings at screening visit OR
- The mean value calculated from 3 baseline ECG recordings
20. Subjects with a clinically significant or unstable medical or surgical condition that,
in the Investigator's opinion, would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray. Such conditions may include:
- A cardiovascular or pulmonary disorder that cannot be well-controlled by
standard treatment permitted by the study protocol.
- A gastrointestinal disorder that may affect the absorption of study medication.
- Renal, metabolic or hematological diseases.
- Thyroid disease: A subject with hyperthyroidism is not permitted to participate
in the study. A subject with hypothyroidism may be permitted to participate in
the study provided that he/she is clinically euthyroid and considered stable.
- Liver disease, such as cirrhosis.
- A family history of Long-QT syndrome.
- A history of drug and/or alcohol abuse.
- A current major psychiatric disorder, including schizophrenia or severe
depression, with or without suicidal ideation.
- A history of seizure disorder, with the last convulsive episode occurring within
12 months prior to screening visit.
21. A known history of sensitivity to Gadolinium.
22. Inability to successfully undergo MRI scanning.
23. A known drug hypersensitivity that would preclude administration of laquinimod,
such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.
24. A known history of hypersensitivity to natural or recombinant interferon beta,
human albumin, or any other com

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsing Remitting Multiple Sclerosis (RRMS)
MedDRA version: 9.1 Level: LLT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis

Intervention(s)

Product Name: Laquinimod Capsules 0.6 mg
Product Code: TV-5600
Pharmaceutical Form: Capsule*
INN or Proposed INN: Laquinimod
CAS Number: 248282-07-7
Current Sponsor code: TV-5600
Other descriptive name: Laquinimod Sodium (USAN)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.6-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Avonex 30 microgram/0.5 ml Solution for Injection
Product Name: -
Product Code: -
Pharmaceutical Form: Solution for injection
INN or Proposed INN: interferon beta-1a
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 30-

Primary Outcome(s)

Main Objective: To assess the efficacy of 0.6 mg daily dose of laquinimod in patients with RRMS, as measured by the number of confirmed relapses during the treatment period.

Primary end point(s): The number of confirmed relapses during the treatment period.

Secondary Objective: -To assess the effect of 0.6 mg daily dose of laquinimod on the development of brain atrophy as defined by the percent brain volume change from baseline at the end of the treatment period.

-To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of physical disability as measured by the time to confirmed progression of EDSS during the treatment period.

-To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of disability, as assessed by the MSFC score at the end of the treatment period.

Secondary ID(s)

MS-LAQ-302

2007-005450-23-ES