Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-blind, Two-arm, Multicenter, Randomized Trial to Evaluate Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Recent Secondary Progressive Multiple Sclerosis: P.R.OM.E.S.S Study
Brief Summary: Preliminary not-controlled clinical studies of the efficacy of monthly intravenous cyclophosphamide administration in secondary progressive multiple sclerosis reported encouraging results, but no randomized controlled trial has been conducted so far. The primary objective of this trial is to evaluate the efficacy of IV cyclophosphamide as compared to IV methylprednisolone administered every 4 weeks during 1 year and every 8 weeks during 1 year, on the delay to confirmed disability deterioration as assessed by the Expanded Disability Status Scale (EDSS) in patients with secondary progressive multiple sclerosis. The secondary objectives are to evaluate safety, tolerability and efficacy at 2 years on the Multiple Sclerosis Functional Composite (MSFC), the percentage of patients with disability deterioration (EDSS) and the number of relapses. An intention-to-treat statistical analysis will be carried out.


Options:
A: Unless otherwise specified, to be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of the randomization:

Key Inclusion Criteria:

* Must have confirmed diagnosis of RRMS according to McDonald criteria #1-4
* Must have a baseline EDSS between 0.0 and 5.0, inclusive.
* Must have relapsing-remitting disease course.

Key Exclusion Criteria:

* Other chronic disease of immune system, malignancies, urologic, pulmonary, gastrointestinal disease
* Pregnant or nursing women

Note: Other protocol-defined inclusion/exclusion criteria may apply.
B: Key Inclusion Criteria:

* Inclusion Criteria for Part I:

  * Must have a diagnosis of Relapsing-Remitting Multiple Sclerosis (RRMS).
  * Must have a baseline Expanded Disability Status Scale (EDSS) score between 0.0 and 5.0, inclusive.

Key Inclusion Criteria for Part II:

• Subjects who participated in and completed Part I per protocol.

Key Exclusion Criteria:

* Other chronic disease of the immune system, malignancies, acute urologic, pulmonary, gastrointestinal disease.
* Pregnant or nursing women.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.
C: Inclusion Criteria:

* Ability and willingness to provide written informed consent and to comply with the schedule of protocol assessments
* Age 18--55 years, inclusive
* Diagnosis of relapsing MS, as defined by McDonald Criteria 1--4
* History of at least one relapse in the subject's medical records during the 1 year prior to randomization
* EDSS at screening between 0 and 5.0 points, inclusive
* For subjects of reproductive potential (males and females), ability and willingness to use a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during the study, including the safety follow-up period, and for up to 1 year after their last dose of study drug, even if they have discontinued early from the study

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, or mycobacterial infection, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes 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, or syphilis)
* History of cancer, including solid tumors and hematologic malignancies (except fully resolved and resected cutaneous basal cell and squamous cell carcinomas of the skin)
* History of alcohol or drug abuse within 6 months prior to screening
* History of or currently active primary or secondary immunodeficiency
* Presence of significant, uncontrolled disease of the cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal systems
* Diagnosis of secondary progressive, primary progressive, or progressive relapsing MS
* History or presence of vascular disease potentially affecting brain or spinal cord (e.g., stroke, transient ischemic attack, severe 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 CNS 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 encephalopathy or myelopathy (e.g., untreated vitamin B12 deficiency, untreated thyroid deficiency)
* History or presence of infectious causes of encephalopathy or myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 \[HTLV-1\], herpes zoster myelopathy)
* Neuromyelitis optica
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, antiphospholipid antibody syndrome, Sjogren�s syndrome, Behcet disease)
* History or presence of sarcoidosis
* Relapse within 30 days prior to randomization
* Previous treatment with rituximab (MabThera(R)/Rituxan(R))
* Treatment with any investigational agent within 90 days of randomization or five half-lives of the investigational drug (whichever is longer)
* Receipt of a live vaccine within 30 days prior to randomization
* Previous treatment with lymphocyte-depleting therapies (e.g., Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation)
* Treatment with cyclophosphamide or mitoxantrone within 12 months of randomization
* Systemic corticosteroid therapy within 30 days of randomization
* Treatment with IFN-Beta; or Copaxone(R) within 60 days of randomization
* Treatment with IVIG within 60 days of randomization
* Plasmapheresis within 60 days of randomization
* Treatment with non-lymphocyte depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil, cyclosporine) within 90 days prior to randomization
* Statins or hormone replacement therapy started within 30 days of randomization
* Positive pregnancy test
* B-cell count \<1.1% (reported as percent CD19)
* Vitamin B12 below the lower limit of normal with an abnormal methylmalonic acid level
* Positive rapid plasma reagin
* Serum creatinine \>1.4 mg/dL for women or \>1.6 mg/dL for men
* Aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) \>2.5 x the upper limit of normal
* Platelet count \<100,000/mL
* Hemoglobin \<8.5 g/dL
* Neutrophils \<1.5 x 10\^3/mL
* Serum IgG levels below 5.65 mg/mL and serum IgM levels below 0.55 mg/mL
* Findings on brain MRI scan consistent with clinically significant conditions other than MS
* Electrocardiogram (ECG) showing significant abnormality that the treating investigator determines may jeopardize the subject's health (i.e., acute ischemia, left bundle branch, or bifascicular block)
D: Inclusion Criteria:

* Multiple sclerosis (MS) subjects (Mc Donald et al criteria),
* Aged 18 to 65
* Diagnosis of secondary progressive MS ( Lublin and Reingold criteria)
* Progressive deterioration phase of at least 6 months and less than 4 years.
* Reduction of walking capacity and increase EDSS not ascribed to consequence of relapses (at least 0.5 point) in the last 12 months
* EDSS between 4.0 and 6.5 included
* Female participating must use contraceptives while on study drug
* Written informed consent
* Patient protected by French social security system

Exclusion Criteria:

* Others diseases interfering with MS or treatment
* Recent history (within the previous 2 years) of drug or alcohol abuse.
* Patients with psychiatric illnesses who are unable to provide written, informed consent prior to any testing under this protocol
* Hemorrhagic cystitis
* Pregnant or lactating women
* Known allergy at cyclophosphamide, corticoids and in particular methylprednisolone
* Persistent infectious diseases
* Patients with bladder permanent catheterization
* Known history of cardiac arrhythmia after methylprednisolone intravenous treatment
* Abnormal screening/baseline blood tests exceeding any of the limits defined below : Hb \< 9g/dl or Total white blood cell count less than 3 000/mm3 or lymphocytes count less than 900/ mm3 or Platelet count less than 125 000/mm3
* Gastric or duodenal ulcer in evolution
* Gut diverticulosis
* Diabetes mellitus
* Known history of active hepatitis (ASAT \>3 X ULN)
* Known history of renal failure (creatinine level \> 180 µmol/L)
* Psychosis
* Current or past (\< 3 months) participation in another drug trial
* Prior use of cyclophosphamide, lymphoid irradiation, monoclonal antibodies anti CD4 or anti CD52 or anti-VLA-4 therapies, cladribine ou cyclosporine A
* Other clinical types of MS : Secondary progressive phase evolving for more than 4 years ; Remittent type of MS without progression between relapses ; Primary progressive type of MS
* Use of interferon beta, methotrexate or imurel in the month prior to study.
* Treatment with intravenous monthly corticoids in the year prior to study.
* Treatment with corticoids (3 to 5 days) in the 2 month prior to study.

Answer: D