This study will examine the safety of Zenapax (daclizumab) in patients with multiple
sclerosis (MS). MS is thought to be caused by an over-reactive immune response.
T-lymphocytes (cells of the immune system), are thought to damage myelin, a substance that
covers the nerve and parts of the spinal cord and is damaged in patients with MS.
Interleukin-2 is a natural substance in the body that is necessary for the growth of
T-lymphocytes. Zenapax is a genetically engineered antibody that blocks the activity of
interleukin-2 and thus interferes with the growth of lymphocytes. Therefore, Zenapax may
prevent some of the damage to myelin that occurs in multiple sclerosis.
Patients between 18 and 65 years of age with relapsing remitting MS may be eligible for this
study. Patients with secondary-progressive or primary progressive MS may not participate.
Candidates will be screened with a complete neurological and medical evaluation and review
of medical records.
Participants will undergo the following tests and procedures:
- Baseline evaluation: Participants have four magnetic resonance imaging (MRI) scans over
a 3-month period to assess disease activity. For the MRI scans, the patient lies on a
table that slides into the scanner - a narrow metal cylinder with a strong magnetic
field. Scanning time varies from 20 minutes to 3 hours, with most scans lasting between
45 and 90 minutes. Only patients with activity at or above a certain level are eligible
to continue with the treatment phase of the study.
- Zenapax treatment: Patients receive intravenous (through a vein) infusions of Zenapax.
The first two infusions are 2 weeks apart, followed by 13 monthly infusions.
- MRI scans: Patients undergo MRI scanning before every infusion to evaluate disease
activity and identify new brain lesions.
- Blood and urine tests: Blood and urine samples are collected at each clinic visit for
routine laboratory evaluations, immunologic study, and genetic testing to determine a
predisposition for responding to Zenapax treatment.
- Lumbar puncture (spinal tap): This procedure will be done during the last month before
starting treatment and during the seventh month of treatment to examine immune changes
that occur in the cerebrospinal fluid (CSF), which circulates through and surrounds the
brain and spinal cord. A local anesthetic is given and a needle is inserted in the
space between the bones in the lower back where the CSF circulates below the spinal
cord. A small amount of fluid is collected through the needle.
- Skin test: A needle is placed just under the skin is done to assess the patient's
immune status to common antigens such as tetanus, mumps and candida.
- Lymphocytopheresis: Lymphocytes are collected three times - once during the last month
of baseline before starting treatment, once during the fifth month of treatment, and
once during the last month of treatment - for immunologic study. Blood is collected
through a needle in an arm vein in a similar way to donating blood. The blood flows
from the vein through a catheter (plastic tube) into a machine that separates it into
its components by centrifugation (spinning). The lymphocytes are removed and the rest
of the blood (red cells, plasma and platelets) is returned to the body, either through
the same needle or through another needle in the other arm.
Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease leading to
central nervous system (CNS) inflammation, demyelination, axonal loss, and leads to
substantial disability in young adults. Existing approved treatments include interferon
beta, glatiramer acetate and mitoxantrone. These therapies are only moderately effective in
reducing disease activity.
The Neuroimmunology Branch (NIB) has during the last three years tested the tolerability and
safety of monthly intravenously administered daclizumab (Zenapax(Registered Trademark)), a
humanized monoclonal antibody against the IL-2 receptor alpha chain, in patients who receive
interferon-beta, but responded incompletely to therapy with interferon-beta. Daclizumab has
been well tolerated and inhibited inflammatory disease activity by almost 90%. Under an
amendment of this protocol, it was demonstrated that the efficacy of daclizumab is
maintained once interferon-beta therapy is discontinued.
In the current trial, we will test the efficacy of daclizumab alone in relapsing-remitting
MS patients. This trial is a single-centre, open-label, baseline to treatment cross-over
phase II trial. Daclizumab will be administered intravenously at 1mg/kg bodyweight.
Contrast-enhancing MRI lesions will serve as the primary outcome measure in this phase II
trial, and a number of clinical, MRI, and immunological parameters will be measured as
secondary and tertiary outcomes. Daclizumab is a promising new immunomodulatory treatment
for relapsing-remitting MS.
- INCLUSION CRITERIA FOR PRE-TREATMENT SCREENING:
To be eligible for entry into the study, patients must meet the following criteria at the
time of enrollment. Re-assessment of the inclusion criteria will occur on day zero of the
twelve-month treatment phase.
Between the ages of 18 and 65 years, inclusive.
Patients with relapsing-remitting MS according to published criteria.
EDSS score between 1.0 and 5.5.
Patients have either failed standard therapies (interferon-beta, glatiramer acetate) by
clinical measures, or are not eligible for standard therapies, or opted not to start or
continue with any of the standard therapies.
Patients are able to provide written, informed consent prior to any testing under this
protocol, including screening and baseline investigations that are not considered part of
routine patient care.
Age criteria for inclusion in this study follow those of published diagnostic criteria for
multiple sclerosis. Due to the uncommon occurrence of MS in individuals under the age of
18 and the requirement to study a large MS cohort to include these rarely occurring
patients, this is an appropriate lower age range.
Patient decision not to start, or not to continue with standard immunomodulatory therapy,
has to be made by the patient after discussing conventional treatment options to ensure
the patient has made an informed decision. Additionally, the consent document provided to
the patient will explicitly state the currently approved therapies and their potential
ELIGIBILITY CRITERIA FOR INITIATING THERAPY:
To be eligible to proceed to the treatment phase of the study, patients must have at least
two new gadolinium-enhancing lesions or greater in the four sequential baseline MRI scans
(average of greater than or equal to 0.5 gadolinium-enhancing lesions or more).
Patients can not have a relapse during 30 days before initiation of treatment. If a
relapse occurs during this period and eligibility criteria are otherwise fulfilled,
treatment (day one) will be delayed while corticosteroids are administered. If
corticosteroids are administered, the MRI during that period will not be considered. An
additional MRI will be added at 4 weeks following the completion of corticosteroids, to
maintain a total of four MRI's that are analyzed in the baseline period. In the event of
relapse, the baseline period will be prolonged, as necessary, to meet these criteria.
EXCLUSION CRITERIA FOR PRE-TREATMENT SCREENING:
Patients will be excluded from the study if any of the exclusion criteria exist at the
time of enrollment. Re-assessment of the exclusion criteria will occur on day zero of the
twelve month treatment phase.
Diagnosis of secondary-progressive or primary-progressive MS, as defined by published
Abnormal screening/baseline blood tests exceeding any of the limits defined below:
- Serum alanine transaminase or aspartate transaminase levels which are greater than
three times the upper limit of normal values.
- Total white blood cell count less than 3000/mm(3)
- Platelet count less than 85000/mm(3)
- Serum creatinine level greater than 2.0 mg/dl
- Serological evidence of HIV or active hepatitis A, B or C infection since the effects
of daclizumab are not defined in these patients
- Positive pregnancy test
Pregnant or breast-feeding female.
History or signs of immunodeficiency.
Concurrent clinically significant (as determined by the investigators) cardiac,
immunological, pulmonary, neurological, renal or other major disease.
Any contraindication to monoclonal antibody therapy. Contraindication to monoclonal
antibody therapy includes prior history of serum-sickness or similar hypersensitivity
reaction to receipt of monoclonal antibody or intravenous immunoglobulin therapies.
Patients with cognitive impairments who are unable to provide written, informed consent
prior to any testing under this protocol, including screening and baseline investigations
that are not considered part of routine patient care.
If prior treatments were administered, the patient must be off the following treatment
agents for the required period prior to enrollment:
- Glatiramer acetate, interferon-beta - 24 weeks
- IVIg, azathioprine, methotrexate, cyclophosphamide, mitoxantrone, plasma exchange,
cyclosporine, oral myelin, cladribine and other immunosuppressive treatments - 24
- Corticosteroids - 6 weeks
Prior treatment with other investigational drugs or procedures will be evaluated
individually by the investigators.
History of alcohol or drug abuse within the 5 years prior to enrollment.
Female patients who are not post-menopausal or surgically sterile who are not using an
acceptable method of contraception. Acceptability of various methods of contraception will
be at the discretion of the investigator. Documentation that the patient is
post-menopausal or surgically sterile must be available prior to enrollment.
Male patients who are not surgically sterile and not practicing adequate contraception.
Acceptability of various methods of contraception will be at the discretion of the
investigator. Documentation that the patient is surgically sterile must be available prior
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
patient returning for follow-up visits on schedule.
Previous participation in this study.