This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Approximately 90% of patients with multiple sclerosis (MS) have a relapsing-remitting form of the disease (RR-MS). These patients present initially with episodic neurological symptoms/disease activity altering with periods of total or partial clinical remission. The RR phase of the disease typically lasts for 10 to 15 years, with most patients eventually experiencing a subsequent period of gradually increasing disability. Prevention of disability accumulation is the ultimate goad therapy in MS. Over the past 10 years, immunomodulatory agents have become available for the treatment of RR-MS. Although these drugs are proven to be effective for the treatment of RR-MS, some patients continue to have disease activity. There are no established strategies for treating patients with RR-MS who have breakthrough disease activity during treatment with an immunomodualtory agent as monotherapy. Potential options include switching to alternative monotherapy or combination therapy. Research to date has shown that using higher doses and more frequent dosing of interferon-beta (IFN ) does not appear to give much advantage, if any, in controlling disease activity in these breakthrough episodes. Also, the long-term advantage of initiating treatment at higher doses is unproven. Research has also shown that for patients who have breakthrough disease that are already on Avonex, that there may be no advantage to switching to another interferon beta preparation such as Betaseron or Rebif. All IFN preparations have the potential to stimulate the production of neutralizing antibodies (NAb), typically 9 to 15 months after IFN therapy is started. NAb generated in response to treatment with one IFN cross react with other IFN s. In large clinical trials, Avonex had the lowest incidence of NAb response. The presence of Nab is important in the management of patients treated with IFN , because Nab-positive patients have low or undectable serum concentrations of IFN and markedly reduced or absent in vivo biologic response to IFN (ie - relapses and magnetic resonance imaging - MRI). Rather than switching patients with breakthrough disease on Avonex monotherapy to another IFN preparation, a potentially better approach for NAb negative patients may be continuation of Avonex and adding other immunomodulatory agents such as methotrexate (MTX) or intravenous methylprednisolone (IVMP). This study is a randomized, placebo-controlled, 2x2 factorial design, combination therapy study with 24 months of observation. Subjects will be randomized to 1 or 4 treatment groups: Group 1: Avonex weekly and placebo weekly; Group 2: Avonex weekly and MTX weekly; Group 3: Avonex weekly and placebo weekly and IVMP for 3 consecutive days every 2 months; Group 4: Avonex weekly and MTX weekly and IVMP for 3 consecutive days every 2 months. Relapse rates will be assessed by clinical evaluations and disease activity will be monitored by MRI.
Showing the most recent 10 out of 1014 publications
