The Efficacy and Safety and Tolerability of Laquinimod in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) (CONCERTO)

• Number of Participants with Adverse Events [ Time Frame: 24 months (Period 1) ] [ Designated as safety issue: Yes ]
• Number of Participants with Abnormal Vital Signs [ Time Frame: 24 months (Period 1) ] [ Designated as safety issue: Yes ]
• Number of Participants with Abnormal ECG Findings [ Time Frame: 24 months (Period 1) ] [ Designated as safety issue: Yes ]
• Number of Participants with Abnormal Clinical Laboratory Parameters [ Time Frame: 24 months (Period 1) ] [ Designated as safety issue: Yes ]

This is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by active treatment, to evaluate the efficacy, safety and tolerability of two doses of oral administration of laquinimod 0.6 mg/day or 1.2mg/day in subjects with RRMS.

Eligible subjects with confirmed relapsing-remitting multiple sclerosis will be randomized in a 1:1:1 ratio into one of the following treatment arms: Laquinimod capsules 0.6 mg, Laquinimod capsules 1.2 mg and matching placebo. The study will be comprised of two treatment periods:

Period 1: Double-blind Placebo-controlled (DBPC) period: at least 15 months, but not more than 24 months of once-daily, oral administration of either laquinimod 0.6 mg, 1.2 mg or matching oral placebo.

The Sponsor will declare closing of Period 1 for all subjects when all ongoing enrolled subjects completed at least 15 months in Period 1.

Period 2: Active-treatment (AT) period: 24 months In this period, subjects who were assigned to either 0.6 mg or 1.2 mg daily oral laquinimod during Period 1 (DBPC) will continue with the same treatment assignment, whereas those who were assigned to placebo will receive 1.2 mg daily oral laquinimod.

• Drug: Laquinimod 0.6 mg
• Drug: Matching Placebo
• Drug: Laquinimod 1.2 mg

• Experimental: Laquinimod 0.6 mg
  Two capsules, one containing 0.6 mg laquinimod and the other containing matching placebo, to be administered orally once daily during both Periods 1 and 2.
  Intervention: Drug: Laquinimod 0.6 mg
• Experimental: Laquinimod 1.2 mg
  Two capsules containing 0.6 mg laquinimod to be administered orally once daily during both Periods 1 and 2.
  Intervention: Drug: Laquinimod 1.2 mg
• Placebo Comparator: Placebo
  Two capsules containing placebo (matching to the 0.6 mg) to be administered orally once daily during Period 1.
  Intervention: Drug: Matching Placebo

Inclusion Criteria:

• Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria, with relapse onset disease or a relapsing-remitting disease course.
• Subjects must be ambulatory with Kurtzke EDSS score of 0- 5.5 in both screening and randomization visits.
• Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization.
• Subjects must have experienced at least one documented relapse in the 12 months prior to randomization.
• Subjects must be between 18 and 55 years of age at screening, inclusive.
• Subjects must have disease duration of at least 6 months, but not more than 12 years (from the first symptom) prior to randomization.
• Women of child-bearing potential must practice an acceptable method of birth control until 30 days after the last dose of treatment was administered (acceptable methods of birth control include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive 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.
• Subjects with Neuromyelitis Optica (NMO).
• Use of experimental or investigational drugs (including dimethyl fumarate and Teriflunomide) and/or participation in drug clinical studies within 6 months prior to randomization.
• Use of immunosuppressive agents, including fingolimod (Gilenya®) or cytotoxic agents, including Cyclophosphamide within 6 months prior to randomization.
• Use of either of the following within 2 years prior to screening visit: natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab.
• Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or intravenous immunoglobulin (IVIG) within 2 months prior to randomization.
• Chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to randomization.
• Previous use of Mitoxantrone (Novantrone®), Cladribine, or alemtuzumab(CAMPATH-1H).
• Previous use of laquinimod.
• Previous total body irradiation or total lymphoid irradiation.
• Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
• Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to randomization.
• Use of inducers of CYP3A4 within 2 weeks prior to randomization.
• Pregnancy or breastfeeding.
• Serum levels ≥3xULN of either ALT or AST at screening.
• Serum direct bilirubin which is ≥2xULN at screening.

• 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. Such conditions may include:

  • A major cardiovascular event (e.g. myocardial infarction, acute coronary syndrome, de-compensated congestive heart failure, pulmonary embolism, coronary revascularization) that occurred during the past 6 months prior to randomization.
  • Any acute pulmonary disorder
  • A CNS disorder other than MS that may jeopardize the subject's participation in the study, including such disorders that are demonstrated on the baseline MRI.
  • A gastrointestinal disorder that may affect the absorption of study medication.
  • Renal disease.
  • Any form of acute or chronic liver disease.
  • Known human immunodeficiency virus positive status.
  • A history of drug and/or alcohol abuse.
  • Unstable psychiatric disorder.
  • Any malignancies, excluding basal cell carcinoma, in the 5 years prior to randomization.
• A known history of sensitivity to gadolinium (Gd).
• GFR ≤ 60 mL/min at the screening visit.
• Inability to successfully undergo MRI scanning.
• Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI)within 3 months prior to randomization.
• Known hypersensitivity that would preclude administration of laquinimod capsule, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.