This study will evaluate the safety, tolerability, and effect of the drug Rolipram on
multiple sclerosis (MS). It will examine whether Rolipram can dampen the part of the immune
response believed to lead to MS and reduce disease activity.
Patient with multiple sclerosis who are between the ages of 18 and 65 may be eligible for
this study. Candidates will be screened with a complete neurological and medical
evaluation. Participants will complete three study phases-baseline, treatment and
follow-up, as follows:
Baseline (3 months) - Approximately four magnetic resonance imaging (MRI) scans will be
obtained to assess MS activity. Participants with MS activity above a certain level will
continue with the treatment phase.
Treatment (8 months) - Patients will take Rolipram tablets in increasing doses every 2 to 3
days for the first month of this phase until their individual maximum tolerated dose is
established. Dosing will continue at that level for the rest of the treatment phase.
Dosing is in the morning, midday and evening. Patients will be seen monthly in the clinic
for examination and MRI scans.
Follow-up - Participants will have monthly exams and MRIs for 3 months following the
treatment phase, after which their participation in the study ends.
Patients' monthly visits during treatment and follow-up include a neurological examination
to assess disease status; MRI to assess brain changes; and blood and urine collection to
monitor liver, kidney and other functions. In addition, a lumbar puncture (spinal tap) is
done during the last month of the baseline phase and one month after treatment ends to study
changes in the spinal fluid surrounding the brain and spinal cord, and leukapheresis is done
once during the last month of the baseline phase and once during the last month of treatment
to collect white blood cells for study. These procedures involve the following:
MRI uses a strong magnetic field and radio waves instead of X-rays to produce images showing
structural and chemical changes in tissues. The patient lies on a table in a narrow
cylinder (the scanner) containing a magnetic field and images are taken. A contrast agent
called gadolinium is injected into a vein during the last set of images to help identify new
lesions. Magnetic resonance spectroscopy, which is similar to MRI, is also done once during
the baseline phase, at 4 months and at 8 months to measure brain chemicals. For the spinal
tap, a local anesthetic is given and a needle is inserted in the space between the bones
(vertebrae) in the lower back. About 2 tablespoons of fluid is collected through the
needle. For leukapheresis, whole blood is collected through a needle placed in an arm vein.
The blood circulates through a machine that separates it into its components. The white
cells are removed and the red cells, platelets and plasma are returned to the body through a
second needle placed in the other arm.
Patients may also have studies to measure levels of Rolipram in the blood. These are done
on study days 1 and 29 and at months 2, 4, and 6. For days 1 and 29, a catheter is placed
in an arm vein and 4 ml. of blood is drawn immediately before the morning dose and at
several intervals from 20 minutes to 6 hours after the dose. For the other tests, a single
4-ml sample is collected before the noon dose.
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 for Pre-Treatment Screening:
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.
Same as Stage I with exceptiom that EDSS will be between 1.5 and 6.5.
Eligibility Criteria For Initiating Therapy:
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).
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
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
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.