A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo
Condition: Primary Progressive Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Intervention: Placebo; Laquinimod; Placebo
Intervention description: Placebo; Laquinimod capsules in 0.5 mg and 0.6 mg strengths; Placebo capsules
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 374.0
Sex: All
Minimum age: 25 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: multiple sclerosis; primary progressive multiple sclerosis; oral immunomodulator

Summary:

      This Phase 2 study is intended to serve as a proof of concept for potential treatment with
      laquinimod in patients with PPMS. The study is also aimed at evaluating 2 doses of laquinimod
      in this population.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010
             Revised McDonald criteria

          2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in
             either or both brain and spinal cord

          3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5,
             inclusive, at both screening and baseline visits

          4. Documented evidence of clinical disability progression in the 2 years prior to
             screening.

          5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait
             impairment due to lower extremity dysfunction

          6. Patients must be between 25 to 55 years of age, inclusive

          7. Women of child-bearing potential must practice an acceptable method of birth control
             for 30 days before taking the study drug, and 2 acceptable methods of birth control
             during all study duration and until 30 days after the last dose of treatment is
             administered.

          8. Patients must sign and date a written informed consent prior to entering the study.

          9. Patients must be willing and able to comply with the protocol requirements for the
             duration of the study.

        Exclusion Criteria:

          1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses,
             including any episodes of optic neuritis.

          2. Progressive neurological disorder other than PPMS.

          3. Any MRI record showing presence of cervical cord compression.

          4. Baseline MRI showing other findings (including lesions that are atypical for PPMS)
             that may explain the clinical signs and symptoms.

          5. Relevant history of vitamin B12 deficiency.

          6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.

          7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior
             to baseline. Use of a currently marketed drug in a clinical study within 24 weeks
             prior to baseline would not be exclusionary, provided no other exclusion criteria are
             met.

          8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and
             azathioprine within 48 weeks prior to baseline.

          9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate
             (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β
             (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior
             to baseline.

         10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if
             active washout (with either cholestyramine or activated charcoal) was done 2 months or
             more prior to baseline.

         11. Prior use of monoclonal antibodies ever, except for:

               1. natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to
                  baseline AND the patient is John Cunningham (JC) virus antibody test negative (as
                  per medical history)

               2. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical
                  history) is higher than 80 cells/μL

         12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of
             mitoxantrone >5 years before screening is allowed in patients with normal ejection
             fraction and who did not exceed the total lifetime maximal dose.

         13. Previous use of laquinimod.

         14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS
             disease modification) systemic (intravenous, intramuscular or oral) corticosteroid
             treatment within 8 weeks prior to baseline.

         15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).

         16. Previous total body irradiation or total lymphoid irradiation.

         17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of
             any kind.

         18. Patients who underwent endovascular treatment for chronic cerebrospinal venous
             insufficiency (CCSVI) within 12 weeks prior to baseline.

         19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to
             baseline.

         20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.

         21. Pregnancy or breastfeeding.

         22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine
             aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.

         23. Serum direct bilirubin which is ≥2×ULN at screening.

         24. Patients with a clinically significant or unstable medical or surgical condition that
             (in the opinion of the Investigator) would preclude safe and complete study
             participation, as determined by medical history, physical examinations,
             electrocardiogram (ECG), laboratory tests or chest X-ray.

         25. A known history of hypersensitivity to gadolinium (Gd).

         26. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.

         27. Inability to successfully undergo MRI scanning, including claustrophobia.

         28. Known drug hypersensitivity that would preclude administration of laquinimod, such as
             hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.