Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS)

Inclusion criteria

• 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.
• Subjects must be ambulatory with converted Kurtzke EDSS score of 0-5.5.
• 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).
• Subjects must have had experienced one of the following:

• At least one documented relapse in the 12 months prior to screening
• At least two documented relapses in the 24 months prior to screening
• 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.
• Subjects must be between 18 and 55 years of age, inclusive.
• Subjects must have disease duration of at least 6 months (from the first symptom) prior to screening.
• 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 double-barrier method (condom or diaphragm with spermicide).
• Subjects must be able to sign and date a written informed consent prior to entering the study
• Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion criteria

• Subjects with progressive forms of MS
• An onset of relapse, unstable neurological condition or any treatment with corticosteroids [intravenous (iv), intramuscular (im) and/or per os (po)] or ACTH between month -1 (screening) and 0 (baseline).
• Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
• Use of immunosuppressive including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
• Previous use of either of the following: natalizumab (Tysabri®), cladribine, laquinimod.
• Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or IVIG within 2 months prior to screening visit.
• Systemic corticosteroid treatment of ≥30 consecutive days duration within 2 months prior to screening visit.
• Previous total body irradiation or total lymphoid irradiation.
• Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
• A known history of tuberculosis.
• Acute infection two weeks prior to baseline visit.
• Major trauma or surgery two weeks prior to baseline
• A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis).
• A carrier state of factor V Leiden mutation (either homo- or heterozygous) as disclosed at screening.
• Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit.
• Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (1 month for fluoxetine) see detailed list in Appendix 5
• Use of amiodarone within 2 years prior to screening visit.
• Pregnancy or breastfeeding.
• Subjects with a clinically significant or unstable medical or surgical condition that 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 or metabolic diseases.
• Any form of chronic liver disease, including known non-alcoholic steatohepatitis.
• A ≥2xULN serum elevation of either of the following at screening: ALT, AST or direct bilirubin
• A QTC interval (obtained from either 2 ECG recordings at screening or from the mean value calculated from 3 measurements at baseline visit) which is >450msec.
• A family history of Long- QT syndrome.
• A history of drug and/or alcohol abuse.
• Major psychiatric disorder.
• A known history of sensitivity to Gd.
• Inability to successfully undergo MRI scanning.
• Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

Exclusion criteria

• Subjects who suffer from any form of progressive MS.
• Any condition which the investigator feels may interfere with participation in the study.
• Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation,
• Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening
• Previous treatment with immunomodulators within two months prior to screening
• Pregnancy or breastfeeding.