Rolipram is a phosphodiesterase (PDE) type 4 inhibitor that has originally been developed by Schering AG, Berlin, Germany, as an antidepressant, before others and our laboratory documented the immunomodulatory properties of the drug. In the current trial, Rolipram will for the first time be tested as a novel immunomodulatory therapy in multiple sclerosis patients. The protocol involves a stage I for finding the highest individually well-tolerated drug dose, before stage II, and 8 months treatment period with this individually well-tolerated dose, will be conducted. The trial shall document the safety, tolerability an efficacy with respect to inhibition of central nervous inflammation in multiple sclerosis patients. Magnetic resonance imaging and clinical examinations will be used to study the above parameters, and immunological studies that will be conducted in parallel to the trial, will address the mechanism of action of Rolipram in MS.
INCLUSION CRITERIA: Inclusion Criteria for Pre-Treatment Screening: Stage I: Between the ages of 18 and 65 years, inclusive. Subjects with clinically definite relapsing-remitting or secondary progressive multiple sclerosis according to pubished criteria. EDSS score between 4.0 and 6.5. Patients have either failed standard treatment (interferon beta, glatiramer acetate) by clinical measures and/or were not eligible for ay of the standard treatments available or opted not to start or to continue with any of these treatments. Stage II: Same as Stage I with exceptiom that EDSS will be between 1.5 and 6.5. Eligibility Criteria For Initiating Therapy: Stage I: Subjects must have an average of up to 2 Gd-enhancing lesions per month over the 3 month pre-treatment baseline period (i.e. over 4 MRI scans). Stage II: Subjects must have an average of at least 0.5 Gd-enhancing lesions per month over the 4 month pre-treatment baseline period. Stage I & II: Subjects must not have a relapse during 30 days before initiation of treatment. If a relapse occurs during the last 30 days of the pre-treatment baseline period and eligibility MRI criteria are fulfilled, beginning of the treatment (day 1) is delayed for at least so many days that treatment starts not earlier than 30 days after the relapse and not earlier than 60 days in case i.v. corticosteroids had been given. Similarly, the baseline needs to be prolonged if corticosteroid treatments become necessary during these three months. EXCLUSION CRITERIA: Patients will be excluded from study entry if any of the following exclusion criteria exist at the time of enrollment. If a washout period of previous treatments becomes necessary, these criteria have to be assessed again at the beginning of the MRI baseline period. An additional assessment of the exclusion criteria follows on day 0 of the 6 months treatment phase. Medical History: Blood tests exceeding any of the limits defined below will lead to exclusion from the study: ALT (SGPT) or AST (SGOT) is greater than three times the upper limit of normal; total white blood cell count is less than 3,000/mm(3), neutrophils less than 2,000; platelet count of less than 85, 000/mm(3); creatinine greater than 1.5 mg/dl; serology indicating HIV infection or active hepatitis A, B, or C infection; postive pregnancy test or breast-feeding female; nausea/vomiting as a frequent complaint; fasting prolactin levels of greater than 20 micrograms/L; history or signs of immunodeficiency; history of galactorrhea and/or history of prolactin-secreting tumors, history of pituitary tumors and adenomas, history of mammary tumors; clinically relevant arrhythmia or other ECG abnormalities. Clinically significant (as determined by the investigator) cardiac, immunological, pulmonary, neurological, renal, and/or other major disease including ECG, echocardiogram, and chest x-ray examinations. Patients with mental impairment that would compromise understanding and judging the consent will be excluded from the study and who are thus not able to give informed consent will be excluded fromthe study. Other neurocognitive deficits or physical disabilities are no exclusion criteria. Treatment History: If prior treatment was recieved, the subject must have been off treatment for the required period prior to enrollment. Miscellaneous: History of alcohol or drug abuse within the 5 years prior to enrollment; female subjects who are not post-menopausal or surgically sterile who are not using an acceptable method of contraception; male subjects not practicing adequate contraception; breastfeeding patients; unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's returing for follow-up visits on schedule; previous participation in this study; and inability to understand/give the informed consent.