Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multinational, Multicenter, Randomized, Double Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Once Daily Oral Administration of Laquinimod (0.6 or 1.5 mg) in Patients With Primary Progressive Multiple Sclerosis (PPMS)
Brief 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.


Options:
A: Inclusion Criteria:

* Definitive diagnosis of PPMS
* Disease duration of ≥ 1 year
* EDSS at baseline between 2.0 and 6.5 points, inclusive
* Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings
* Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months:
* For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug

Exclusion Criteria:

* Pregnancy or lactation
* Incompatibility with MRI
* Lack of peripheral venous access
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
* Known active bacterial, viral, fungal, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex infections) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening
* History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis)
* History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas)
* History of alcohol or drug abuse within 6 months prior to screening
* History of or currently active primary or secondary immunodeficiency
* Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
* Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation
* History or presence of MS relapse or exacerbation
* History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation)
* History or presence of myelopathy due to spinal cord compression by disk or vertebral disease
* History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression)
* History of intracranial or intraspinal tumor (e.g., meningioma, glioma)
* History or presence of potential metabolic cause of myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities)
* History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 \[HTLV-1\], or herpes zoster myelopathy)
* History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis)
* Neuromyelitis optica
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease)
* History or presence of sarcoidosis
* Previous treatment with rituximab (MabThera(R)/Rituxan(R))
* Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization
* Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization
* Receipt of a live vaccine within 30 days prior to randomization
* Systemic corticosteroid therapy within 30 days prior to randomization
* Treatment with IFN-\&#x3B2;, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization
* Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil \[MMF\], cyclosporine) within 90 days prior to randomization
* Statins or hormone replacement therapy started within 30 days prior to randomization
B: Key Inclusion Criteria (Part 1):

* Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations.
* SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by multiple sclerosis (MS) relapses for at least 2 years.
* EDSS score of 3.0 to 6.5, inclusive.
* Multiple Sclerosis Severity Score of 4 or higher.
* Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.

Key Exclusion Criteria (Part 1):

* Relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald Committee criteria.
* Clinical relapse (within 3 months) prior to randomization.
* T25FW test of \>30 seconds during the screening period.
* Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.
* Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.
* Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).
* History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.
* History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
* Known history of or positive test result for human immunodeficiency virus.
* Positive test result for hepatitis C virus (test for hepatitis C virus antibody or hepatitis B virus (test for hepatitis B surface antigen and/or hepatitis B core antibody).
* History of transplantation or any anti-rejection therapy.
* Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
* History of progressive multifocal leukoencephalopathy or other opportunistic infections.

Treatment History (Part 1)

* Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.
* Any prior treatment with natalizumab.
* Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.
* Treatment with intravenous or oral corticosteroids, intravenous immunoglobulin, or plasmapheresis for treatment of MS within the 3 months prior to randomization.
* Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.
* Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.

Key Inclusion Criteria (Part 2):

* Subjects must have participated in and completed Part 1 per protocol, and have documented assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing.

Key Exclusion Criteria (Part 2):

* Subjects with any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in this extension study. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment.
* Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infusions in Part 1.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
C: 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.
D: Inclusion Criteria:

* Prior history of relapsing remitting MS
* SPMS defined as progressive increase of disability over at least 6 months
* EDSS score of 3.0 to 6.5
* No relapse of corticosteroid treatment within 3 months

Exclusion Criteria:

* Women of child bearing potential must use reliable forms of contraception.
* Diagnosis of Macular edema during screening period
* Any medically unstable condition determined by investigator.
* Unable to undergo MRI scans
* Hypersensitivity to any study drugs or drugs of similar class

Answer: C