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:

* Written informed consent must be obtained before any assessment is performed
* Male and female patients 18 to 65 years of age, inclusive.
* Patients with RRMS, as defined by 2010 revised McDonald criteria.
* Patients must be neurologically stable with no onset of relapse within 30 days of randomization
* Patients with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years before randomization.
* Patients with an EDSS score of 0 to 6, inclusive, at Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk at least 100 meters with or without resting.

Exclusion criteria:

* Patients with a history of malignancy of any organ system (other than cutaneous basal cell carcinoma) in the last 5 years that do not have confirmation of absence of a malignancy prior to randomization
* Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren's syndrome, Crohn's disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency).
* Patients who have been treated with:
* High-dose intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization
* Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, cyclophosphamide, methotrexate) within 6 months before randomization
* Natalizumab within 2 months before randomization
* Previous treatment with lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab, ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization Previous treatment with mitoxantrone within 6 months before randomization
* Use of teriflunomide within 3.5 months prior to randomization, except if active washout (with either cholestyramine or activated charcoal) was done. In that case, plasma levels are required to be measured and be below 0.02 mg/L before randomization.

No washout period is necessary for patients treated with dimethyl fumarate, interferon (IFN) beta, or glatiramer acetate.

Patients being treated with dimethyl fumarate, glatiramer acetate, or IFN beta at the Screening visit can continue drug intake up to the day before Day 1 of this study (i.e., there is no need for a washout period).

* Patients who have been treated with systemic corticosteroids or adrenocorticotropic hormones in the past 30 days prior to the screening magnetic resonance imaging (MRI) procedure.
* Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin \>9%) or with diabetic neuropathy.
* Patients with a diagnosis of macular edema during Screening (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at Screening).
* Patients with severe active bacterial, viral, or fungal infections.
* Patients without acceptable evidence of immunity to varicella zoster virus (VZV) at randomization.
* Patients who have received any live or live-attenuated vaccines (including VZV, herpes simplex, or measles) within 1 month before randomization.
* Patients who have received total lymphoid irradiation or bone marrow transplantation.
* Patients with any unstable medical/psychiatric condition, as assessed by the primary treating physician at each site.
* Patients who in the last 6 months experienced any of the following cardiovascular conditions or findings in the screening electrocardiogram (ECG): myocardial infarction, unstable angina, stroke, transient ischemic attack or decompensated heart failure requiring hospitalization or Class III/IV heart failure.
B: 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.
C: Inclusion Criteria:

* Able to provide signed, written informed consent to participate in the study
* 18-55 years of age.
* Definite diagnosis of MS according to the 2010 revisions of the McDonald diagnostic criteria for MS \[Polman, 2011\].
* Subjects do not have any manifestation of another type of MS other than RRMS.
* Subjects must have a relapsing-remitting course of disease with at least one of the following prior to screening:
* At least one confirmed relapse within the previous year or
* At least two confirmed relapses within the previous 2 years or
* At least one relapse in the previous 2 years, with a GdE brain lesion on an MRI scan in the past year.
* Expanded Disability Status Scale (EDSS) score of 0-5.5 (inclusive) at screening.
* Neurologically stable with no evidence of relapse for at least 30 days prior to start of Screening and during the Screening Phase (subjects who relapse during the screening Phase can be re-screened, once the relapse has resolved).
* A female subject is eligible to enter the study if she is:
* Of non-childbearing potential
* Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy test at screening, and agrees to one of the following:
* Complete abstinence from intercourse for the period from consent into the study until 6 months after the last dose of investigational product; or,
* Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 6 months after the last dose of investigational product:

Oral contraceptives (either combined or progesterone only) Injectable progesterone Levonorgestrel implants Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of \<1% per year Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; this male must be the sole partner for the subject Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

A female is considered "Non-childbearing potential" if she is status-post hysterectomy, status-post surgical removal of both ovaries, has current, documented tubal ligation, or is postmenopausal and \>2 years without menses. Female subjects who are post-menopausal \<2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol levels.

A female is considered "childbearing potential" if she has functional ovaries, ducts, and uterus with no impairment that would cause sterility. This includes women with oligomenorrhea (even severe), and women who are perimenopausal or who have just begun to menstruate.

* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

* Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media, or who lack adequate peripheral venous access).
* Any clinically significant brain abnormality other than MS found on MRI.
* Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) or confirmed PML (see Appendix 4, Section 11.4, for PML monitoring algorithm).
* Subjects whom experience a relapse during the Screening Phase. These subjects may be eligible for re-screening after consultation with GlaxoSmithKline (GSK).
* History of clinically significant Central Nervous System (CNS) trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
* Prior treatment with any of the following:
* Systemic glucocorticoids or Adrenocorticotrophic hormone (ACTH) within one month prior to screening
* Receipt of a live vaccine within 6 weeks prior to screening
* Glatiramer acetate (Copaxone) or Interferon (IFN)-β (Betaferon, Betaseron, Avonex, or Rebif) within 3 months prior to screening
* Any immunomodulatory therapies, excluding glatiramer acetate or IFN-β, within 6 months prior to screening including natalizumab and fingolimod (Gilenya), immunoglobulin, or plasma exchange/plasmapheresis
* Any monoclonal antibodies at any time, other than natalizumab (Tysabri)
* Any lymphocyte-depleting therapies, including, but not limited to: cladribine, anti-Cluster of Differentiation 4 (CD4), total body irradiation, or bone marrow transplantation
* Any immunosuppressive agents, including, but not limited to: mitoxantrone, azathioprine, cyclosporine, cyclophosphamide, or tacrolimus
* Past or current history of medically significant adverse effects (including allergic reactions) from:
* Cetirizine (or equivalent)
* Paracetamol/acetaminophen
* Corticosteroids
* Known hypersensitivity to components of the investigational product.
* Past or current malignancy, except for
* Cervical carcinoma Stage 1B (cancer is present but has not spread) or less
* Non-invasive basal cell and squamous cell skin carcinoma
* Cancer diagnoses with a duration of complete response (remission) \>5 years
* A history of hematologic malignancy excludes a subject from participation, regardless of response.
* Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average QT interval for heart rate corrected using Bazett's Formula (QTcB) or QT interval for heart rate corrected using Fridericia's Formula (QTcF) interval \>/=450 msec (\>/=480 msec for subjects with a Bundle Branch Block) over 3 consecutive ECGs.
* Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which in the opinion of the investigator could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by this protocol.
* History of severe, clinically significant CNS trauma (e.g. cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
* Chronic or ongoing active infectious disease requiring long term systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C.
* Previous serious opportunistic or atypical infections.
* Positive polymerase chain reaction (PCR) screening for John Cunningham (JC) Virus as measured by plasma John Cunningham Virus (JCV) DNA.
* Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
* Prior history, or suspicion, of tuberculosis (TB)
* Known history of positive serology for HIV.
* Any of the following screening laboratory values:
* White blood cells (WBC) \<3.8 GI/L.
* Neutrophils \<2 x 109/L.
* Platelets \<1.3 x 105 GI/L.
* Circulating IgG, Immunoglobulin M (IgM), or Immunoglobulin A (IgA) levels \< lower limit of normal (according to central laboratory range)
* Alanine aminotransferase (ALT) \>2.0 times the upper limit of normal
* Aspartate aminotransferase (AST) \>2.0 times the upper limit of normal
* Alkaline phosphatase (ALP) \>1.5 times the upper limit of normal
* Bilirubin \>1.5 times the upper limit of normal
* CD4 count \<500 cells/mm3.
* CD19+ B-lymphocyte counts \< lower limit of normal (according to central laboratory range)
* Creatinine clearance \<60 mL/minute (by Cockcroft and Gault).
* Subjects known or suspected of not being able to comply with a trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder).
* A documented history of attempted suicide over the 6 months prior to the screening visit, presents with suicidal ideation of type 4 or 5 on the C-Suicide Severity Rating Scale (SSRS) at the Screening visit, OR if in the investigator's judgment, the subject is at risk for a suicide attempt.
* Use of an investigational drug or other experimental therapy for a condition other than MS within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening. Any prior use of an investigational drug or other experimental therapy for MS at any time should be discussed with the GSK Medical Monitor.
* Current participation in any other interventional clinical trial. Participation in a non-interventional trial requires approval of the protocol by the GSK Medical Monitor
* French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days
D: Inclusion criteria:

Participant had completed at least 48 months of the Extension Study CAMMS03409. Signed written informed consent form.

Exclusion criteria:

Participant participating in another investigational interventional study.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Answer: B