Phase IV Study, Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI

We propose to perform a head to head comparison of Interferon beta and Copaxone for treatment of patients with CIS and RR forms of MS using acute changes on MRI as primary outcome. The study will be performed at the two clinical practice sites of the Multiple Sclerosis Center at University of Medicine and Dentistry New Jersey-New Jersey Medical School, One of the two FDA approved preparations of higher dose interferon beta (Betaseron) will be compared at standard dose every other day (QOD) 250 ug subcutaneously(SQ) with Copaxone at 20mg SQ daily (QD) in 70 to 80 patients. Although the current approved plan is to perform monthly MRIs for 1 year followed by another MRI at 2 years, the protocol has been changed to continue performing monthly MRIs during the second year of the study for all patients who complete their first year and up to January 31, 2006 when the study will end. The study uses brain imaging with 3 Tesla MRI with triple dose Gadolinium for primary and secondary outcomes and several clinical and cognitive measures for secondary outcomes. The sample size was estimated to detect a 40-50% difference in the number of active MS lesions by MRI between the two arms at 1 year follow up, consistent with the primary outcome measure. The primary outcome measure is the number of "combined-active" lesions by monthly MRI at the conclusion of the study, which includes contrast enhancing lesions and non-enhancing lesions on long Time repetition (TR) scans that have appeared since the most recent examination. Several secondary MRI outcome measures are studied in addition to the number of enhancing lesions and the number of new lesions on long TR images. We will examine the number of patients who remain "combined-active disease-free" for the duration of the study and the number of "combined-active disease-free" scans. Apart from these traditional methods of analysis by a reader who will be blinded to patient clinical status and therapy, objective volumetric analysis will be carried out. Making use of both automated and manual techniques, we will determine the overall burden of disease (the volume of lesions on long TR scans), the burden of active disease (the volume of brain enhancement) and the burden of chronic disease (the volume of lesions that are markedly hypointense on T1). Another MRI outcome measures will be detection of diffusion anisotropy differences, MR spectroscopy, and magnetization transfer ratio as summarized in Appendix 5. These new techniques have shown promise for detecting disease that cannot be detected with conventional MRI (13, 37).

In addition to MRI, several clinical and cognitive outcome measures will be used for secondary analysis. These include the number and severity of relapses measured by different methods, and change in disability measured by the Expanded Disability Status Scale (EDSS), the Neurological Rating Scale, and the Multiple Sclerosis Functional Composite (MSFC). The cognitive measures will be the subject's neurocognitive function measured by standard neurocognitive examination obtained by a licensed neuropsychologist and the Cognitive Stability Index (CSI), a novel Internet-based test of cognitive function in addition to the Paced Auditory Serial Addition Test (PASAT),which is a component of the MSFC.

Inclusion criteria

Patients must meet all of the following criteria at the time of the baseline visit in order to enter the trial:

• Be Between 18 and 55 years of age, at baseline.
• Be capable of informed consent in English prior to any study related procedures.Spanish speaking patients who do not read English well can give written informed consent if a relative or friend fluent in both English and Spanish has translated the consent and any questions the patient may have.
• Be available and willing to complete all study assessments.
• Presently meet one of the two following forms of multiple sclerosis:

• Relapsing-remitting ms plus evidence of recent disease activity as shown by the development of one or more clinical and/or MRI lesions during the 6 months prior to entry into the study.
• A CIS consistent with central nervous system (CNS) demyelination confirmed on ophthalmologic or neurological examination with onset within 6 months prior to study entry. Also:a- evidence of dissemination in space, there should be two or more brain MRI lesions ≥ 3 mm in size at least one of which should be ovoid and/or periventricular in location; and b- As evidence of dissemination in time, if the CIS is acute (≤1 month) there should be one or more non-enhancing lesion or if the CIS is not acute (older than 1 month) the MRI should show one or more enhancing lesions.

• At baseline, have an EDSS between 0-5.5.
• Females of childbearing potential must agree to practice adequate contraception methods. All females must have negative pregnancy test results at screening and a negative urine pregnancy test at baseline.
• Screening laboratory results that confirm adequate bone marrow, renal, and hepatic function.

Exclusion criteria

Patients were not permitted into the study if they met any of the following criteria:

• Onset of a relapse between screening and Study Day 1.
• Present evidence or history of any conditions that could affect the CNS or interfere with the MRI results or any other evaluation in the study.
• Possess any of the standard metallic devices or foreign bodies that are contraindications for MRI.
• Patient weight and or size unable to fit in the 3T MRI scanner.
• Pregnancy, as denoted by a positive serum pregnancy test at screening visit or a positive urine pregnancy test at the baseline visit. Subjects who are breast-feeding are also excluded.
• Have a known allergy or hypersensitivity to Gadolinium-chelates, human proteins including albumin and interferons, or Glatiramer Acetate or Mannitol.
• Uncontrolled, clinically significant heart diseases, such as dysrhythmias, angina, or uncompensated congestive heart failure. History of or current unstable medical conditions that could be deemed clinically significant.
• Intolerance or any contraindication to acetaminophen, ibuprofen, or steroids.
• Inability, in the opinion of the principal investigator or staff, to be compliant with protocol requirements for the duration of the study.
• Participation in any clinical trial within the past six months
• History or present evidence of addictions.
• Have active peptic ulcer disease.
• Inability to have subcutaneous injections administered.
• Medical, psychiatric or other conditions that compromise the patient's ability to understand the study procedures.
• Claustrophobia.
• Uncontrolled head movements.
• Treatment with any of the following in the indicated time frames: Any of the Interferons for > 6 months· Glatiramer acetate (Copaxone) for > 6 months.No prior use allowed of Total lymphoid irradiation, Anti-lymphocyte monoclonal antibody (e.g.(Campath-1H) .Mitoxantrone,cyclophosphamide, Azathioprine, intravenous immunoglobulin (IVIG), cyclosporine within 6 months before the screening visit·Any investigational drug 21 days before screening visit·Systemic corticosteroids·ACTH from screening visit through Study Day