This is a Phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS.

Condition	Treatment or Intervention	Phase
Multiple Sclerosis	Drug: Rituxan (rituximab)	Phase II Phase III

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Ability and willingness to provide written informed consent and to comply with the schedule of protocol assessments
• Age 18-65 years
• 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: IgG oligoclonal bands or Elevated CSF IgG index
• 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, Sjogren syndrome, Behcet 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-<beta>, 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
• Vitamin B12 level below the lower limit of normal
• Positive rapid plasma reagin
• Serum creatinine >1.4 mg/dL for women or >1.6 mg/dL for men
• Aspartate aminotransferase or alanine aminotransferase >2.5 x the upper limit of normal
• Platelet count <100,000/uL
• Hemoglobin <8.5 g/dL
• Neutrophils <1.5 x 10^3/uL
• Lymphocyte count <0.1 x 10^3/uL
• B-cell count <1.1% (reported as percent CD19)
• Serum IgG <5.65 mg/mL and serum IgM <0.55 mg/mL
• Findings on brain or cervical spinal cord MRI consistent with conditions other than MS
• Electrocardiogram (ECG) showing a significant cardiac abnormality that the principal investigator determines may jeopardize the subject's health by participation in this study

Recruitment Call Center      866-304-3060 

Arizona
      Barrow Neurology Clinics at St. Joseph's Hospital and Medical Center, Phoenix,  Arizona,  85013,  United States; Recruiting
      Mayo Clinic Scottsdale, Scottsdale,  Arizona,  85259,  United States; Recruiting
California
      East Bay Region Associates in Neurology, Berkeley,  California,  94705,  United States; Recruiting
      Multiple Sclerosis Center At UCSF, San Francisco,  California,  94117,  United States; Recruiting
      Sutter Gould Medical Foundation, Modesto,  California,  95355,  United States; Recruiting
      Neurological Research Institute of East Bay, Walnut Creek,  California,  94596,  United States; Recruiting
      USC Keck School of Medicine, Los Angeles,  California,  90033,  United States; Recruiting
Florida
      Axiom Clinical Research of Florida, Tampa,  Florida,  33609,  United States; Recruiting
      Neurology Associates, P.A., Maitland,  Florida,  32751,  United States; Recruiting
      Neurological Services of Orlando, Orlando,  Florida,  32806,  United States; Recruiting
      MS Center of Vero Beach, Vero Beach,  Florida,  32962,  United States; Recruiting
Georgia
      MS Center of Atlanta, Atlanta,  Georgia,  30327,  United States; Recruiting
      Shepherd Center, Atlanta,  Georgia,  30309,  United States; Recruiting
Illinois
      University of Chicago, Chicago,  Illinois,  60637-1470,  United States; Recruiting
Indiana
      Indiana University Medical Center, Indianapolis,  Indiana,  46202,  United States; Recruiting
Iowa
      Mercy Medical Center, Des Moines,  Iowa,  50314,  United States; Recruiting
Kansas
      University of Kansas Medical Center, Kansas City,  Kansas,  66160,  United States; Recruiting
Maryland
      Johns Hopkins Hospital, Baltimore,  Maryland,  21287,  United States; Recruiting
      University of Maryland Hospital MS Center, Baltimore,  Maryland,  21201,  United States; Recruiting
Massachusetts
      Neurocare, Inc., Newton,  Massachusetts,  02459,  United States; Recruiting
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States; Recruiting
      University of Massachusetts Memorial Medical Center, Worcester,  Massachusetts,  01655,  United States; Recruiting
Michigan
      Michigan State University MS Clinic, East Lansing,  Michigan,  48824-1313,  United States; Recruiting
      Henry Ford Hospital, Detroit,  Michigan,  48202,  United States; Recruiting
      Wayne State University, Detroit,  Michigan,  48201,  United States; Recruiting
      Michigan Institute For Neurological Disorders, Farmington Hills,  Michigan,  48334,  United States; Recruiting
Minnesota
      Minneapolis Clinic of Neurology, Golden Valley,  Minnesota,  55422,  United States; Recruiting
Missouri
      Washington University School of Medicine, St. Louis,  Missouri,  63110,  United States; Recruiting
New Hampshire
      Dartmouth Hitchcock Medical Center, Lebanon,  New Hampshire,  03756,  United States; Recruiting
New Jersey
      Gimbel MS Center, Teaneck,  New Jersey,  07666,  United States; Recruiting
New York
      Albany Medical Center, Albany,  New York,  12208,  United States; Recruiting
      SUNY Upstate Medical University, Syracuse,  New York,  13202,  United States; Recruiting
      University of Rochester, Rochester,  New York,  14642,  United States; Recruiting
      Mount Sinai Medical Center-CGD MS Center, New York,  New York,  10029,  United States; Recruiting
North Carolina
      Raleigh Neurology Associates, Raleigh,  North Carolina,  27607-6520,  United States; Recruiting
      MS Center-Carolinas Medical Center, Charlotte,  North Carolina,  28207,  United States; Recruiting
Ohio
      The Ohio State University, Columbus,  Ohio,  43221,  United States; Recruiting
Oregon
      Oregon Health and Science University, Portland,  Oregon,  97239,  United States; Recruiting
Pennsylvania
      University of Pennsylvania Medical Center, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
      Geisinger Medical Center, Danville,  Pennsylvania,  17822,  United States; Recruiting
Rhode Island
      Neurology Foundation INC/ Rhode Island Hospitals, Providence,  Rhode Island,  02905,  United States; Recruiting
Tennessee
      Vanderbilt/Stallworth Rehab Hospital, Nashville,  Tennessee,  37212,  United States; Recruiting
Texas
      University of Texas, Houston,  Texas,  77030,  United States; Recruiting
      Neurology Clinic of San Antonio, San Antonio,  Texas,  78229,  United States; Recruiting
      University of Texas Southwestern Medical Center, Dallas,  Texas,  75390,  United States; Recruiting
      MS Center of Baylor College, Houston,  Texas,  77030,  United States; Recruiting
Vermont
      University of Vermont, Burlington,  Vermont,  05401,  United States; Recruiting
Virginia
      University of Virginia, Charlottesville,  Virginia,  22903,  United States; Recruiting
      Neurological Associates, Inc., Richmond,  Virginia,  23230,  United States; Recruiting
Washington
      Neurology and Nephrology Associates of Tacoma, Inc., P.S., Tacoma,  Washington,  98405,  United States; Recruiting
      Holy Family MS Center, Spokane,  Washington,  99208,  United States; Recruiting
      Virginia Mason Medical Center, Seattle,  Washington,  98101,  United States; Recruiting
Wisconsin
      St. Luke's Medical Center/Center for Neurological Disorders, Milwaukee,  Wisconsin,  53215,  United States; Recruiting
Canada, Alberta
      Foothills Medical Clinic, Calgary,  Alberta,  T2N 2T9,  Canada; Recruiting
Canada, British Columbia
      University of British Columbia, Vancouver,  British Columbia,  V6T 2B5,  Canada; Recruiting
Canada, Nova Scotia
      Dalhousie MS Research Unit, Halifax,  Nova Scotia,  B3H 1V7,  Canada; Recruiting
Canada, Ontario
      Ottawa Hospital, General Campus, Ottawa,  Ontario,  K1H 8L6,  Canada; Recruiting
      St. Michael's Hospital, Toronto,  Ontario,  M5B-1W8,  Canada; Recruiting
Canada, Quebec
      CHUM-Hospital Notre Dame, Montreal,  Quebec,  H2L 4M1,  Canada; Recruiting
      Hopital Charles LeMoyne, Greenfield Park,  Quebec,  J4V 2H1,  Canada; Recruiting
      CSSSG- Hull Hospital, Gatineau,  Quebec,  J8Y 1W7,  Canada; Recruiting
      Montreal Neurological Institute, Montreal,  Quebec,  H3A 2B4,  Canada; Recruiting

Study ID Numbers:  U2786g
Record last reviewed:  April 2005
Last Updated:  April 7, 2005
Record first received:  July 9, 2004
ClinicalTrials.gov Identifier:  NCT00087529
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08