This study will examine the safety and effectiveness of Zenapax (a laboratory-manufactured
antibody) in treating multiple sclerosis. Multiple sclerosis may be caused by an abnormal
immune response in which white blood cells called T lymphocytes attack the myelin sheath
that covers nerves and parts of the spinal cord. Zenapax binds to protein receptors on
lymphocytes, keeping them from interacting with interleukin-2, a substance necessary for
Patients with multiple sclerosis who have had at least one relapse within 18 months of the
start of the study and in whom interferon-beta treatment has not been successful may be
considered for this study. There are two study phases: baseline and treatment. During the
baseline phase, patients will have three magnetic resonance imaging (MRI) scans over 2
months to evaluate their disease activity. During treatment, patients will receive seven
intravenous (I.V.) infusions of Zenapax in the clinic. The first two infusions will be
given 2 weeks apart; the next five will be given once a month.
Patients will have MRI scans before each infusion. The MRIs will be done using the standard
procedure and again using a contrast agent, gadolinium, injected into a vein. Gadolinium
helps identify new multiple sclerosis lesions in the brain. Blood and urine samples will be
taken during each clinic visit. In addition, patients will have skin tests, similar to a
tuberculin test, to evaluate immune status, and will be asked to undergo two lumbar
punctures (spinal tap; these will be optional)-one before the treatment phase begins, and
another when treatment is completed. Lymphocytes will also be collected from patients
before, during and after treatment. The lymphocytes are obtained by a procedure called
apheresis: about a pint of whole blood is drawn through a needle in the arm, the lymphocytes
are separated out and removed by a machine, and the rest of the blood is returned through a
needle in the other arm. These studies will hopefully allow conclusions about the safety of
Zenapax in MS, but also address its effectiveness with respect to modifying the inflammatory
activity in the brain of MS patients and inhibit autoimmune T lymphocytes that are involved
in the disease process.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous
system (CNS) that preferentially affects young adults. While its etiology is unknown,
current concepts assume that CD4+ helper T cells with specificity for components of the
myelin sheath initiate the pathogenetic process. The activation and expansion of such
autoreactive T cells involves the secretion of autocrine growth factors, particularly
interleukin-2 (IL-2), and the concomitant expression of its receptor, IL-2R, on the surface
of T cells. Since only activated T lymphocytes can migrate through the blood brain barrier
into the CNS and induce the inflammatory process, blocking the IL-2R should have an impact
on disease activity in MS.
In this trial , a humanized antibody against the IL-2Ra subunit (Zenapax(Registered
Trademark)) will be used to inhibit T cell activation in MS patients who have failed
conventional therapy by interferon-b. We will focus on the latter group of patients, since
a substantial number of patients on conventional therapy respond only partially or
completely fail treatment after longer periods of time. Up to 10 patients fulfilling these
criteria will be enrolled in this baseline-to-treatment, cross-over, MRI-controlled
single-center phase I/II trial to assess the safety of Zenapax(Registered Trademark)
treatment and, at the same time, examine the clinical course and particularly the
inflammatory activity in the CNS by monthly magnetic resonance imaging (MRI). Furthermore,
immunological studies will be performed in parallel to the trial in order to a) identify the
impact of Zenapax(Registered Trademark) treatment on immune parameters that should be
affected by the blocking of the IL-2R, and b) to improve our understanding of the relevance
of activated autoreactive T lymphocytes in MS.
- INCLUSION CRITERIA
Between the ages of 18 and 65 years, inclusive.
Subjects with relapsing-remitting or secondary progressive Multiple Sclerosis who have had
more than 1 relapse within 18 months preceding study enrollment.
EDSS score between 1 - 6.5, inclusive.
Give written informed consent prior to any testing under this protocol, including
screening/pre-treatment tests and evaluations that are not considered part of the
subject's routine care.
Patients who have failed standard IFN-beta therapy.
To be eligible to proceed to the treatment phase of the study, subjects must have at least
2 Gd-enhancing lesions or greater in the 3 pre-treatment MRI scans (an average of at least
0.67 Gd-enhancing lesions per scan).
In patients with high inflammatory activity and high relapse rates it has been our
experience that the requirement of steroid therapy for the treatment of relapses may
prolong the baseline phase. In patients with high disease activity who require steroid
therapy and quickly afterwards demonstrate disease activity again, the investigator
retains the option to enroll patients with less than the stipulated baseline months in
order to initiate daclizumab therapy as quickly as possible. Since treatment escalation
would otherwise require therapy with mitoxantrone or cyclophosphamide, which both have
substantial toxicity, this step is in the best interest of the patient.
Diagnosis of primary progressive MS, defined as gradual progression of disability from the
onset without relapses.
Abnormal screening/pre-treatment blood tests exceeding any of the limits defined below:
Alanine transaminase (ALT) or aspartate transaminase (AST) greater than two times the
upper limit of normal;
Total white blood cell count less than 3,000/mm(3);
CD4+ count less than 320/mm(3);
Platelet count less than 80,000/mm(3);
Creatinine greater than 2.0 mg/dL.
Concurrent, clinically significant (as determined by the investigator) cardiac,
immunologic, pulmonary, neurologic, renal, and/or other major disease.
Any contraindication to monoclonal antibody therapies.
Patients who are HIV+ since the effects of anti-Tac are not defined in these patients.
If prior treatment was received, the subject must have been off treatment for the required
period prior to enrollment.
Prior treatment with any other investigational drug or procedure for MS.
History of alcohol or drug abuse within the 5 years prior to enrollment.
Male and female subjects not practicing adequate contraception.
Female subjects who are not post-menopausal or surgically sterile must be using an
acceptable method of contraception. Acceptability of various methods of contraception
will be at the discretion of the investigator. Written documentation that the subject is
post-menopausal or surgically sterile must be available prior to study start.
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 returning for follow-up visits on schedule.
Previous participation in this study.