Investigating Mechanism of Action of DAC HYP in the Treatment of High-Inflammatory Multiple Sclerosis (MS)
Investigating Mechanism of Action of DAC HYP in the Treatment of High-Inflammatory Multiple Sclerosis (MS)
Objective:
The primary goal of this study is to investigate the mechanism of action (MOA) of CD25-blocking therapies in high inflammatory multiple sclerosis (HI-MS). The secondary goal of this study is to assess long-term safety and efficacy of CD25-blocking therapies in HI-MS.
Study population:
Two cohorts of patients will be enrolled:
Design:
This is an open label, Phase I trial of 150 mg of daclizumab high yield process (DAC HYP) administered subcutaneously (SC) every 4 weeks for a total of 3 years.
Outcome measures:
Because the main goal of this study is to investigate the MOA of CD25-blocking therapies in MS, the primary outcomes are mechanistic immunological studies performed on clinical samples (peripheral blood mononuclear cells (PBMC), cerebrospinal fluid (CSF) cells and skin biopsies) derived from DAC HYP-treated patients. The secondary outcome measure is long-term safety and tolerability of subcutaneous DAC HYP in HI-MS patients.
Objective:
The primary goal of this study is to investigate the mechanism of action (MOA) of CD25-blocking therapies in high inflammatory multiple sclerosis (HI-MS). The secondary goal of this study is to assess long-term safety and efficacy of CD25-blocking therapies in HI-MS.
Study population:
We will enroll up to 70 patients. We expect to screen up to 40 HI-MS participants to yield 31 patients that will receive study drug. Two cohorts of patients will be enrolled for the treatment part of the protocol: A. Long-term daclizumab therapy cohort: 16 daclizumab-treated patients with relapsing-remitting (RR-MS) or secondary-progressive MS (SP-MS) previously classified as HI-MS based on MRI/clinical criteria, who have been treated with IV daclizumab for a minimum of 1 year and responded to this therapy with significant (>70%) decrease in contrast-enhancing lesions (CEL) or stabilization/improvement of disease activity (>60% decrease in MS relapses and stable or improved EDSS disability score). B. New treatment cohort: 15 HI-MS patients (RR- or SP-MS) with inadequate therapeutic response to first-line, FDA-approved immunomodulatory therapies for MS or who choose not to, for any reason, be treated with first-line, FDAapproved immunomodulatory therapies for MS. Up to 30 subjects with inflammatory MS will be screened to yield 20 controls for immunization and skin biopsy studies (Cohort C: MS controls).
Design:
This is an open label, Phase I trial of 150 mg of daclizumab high yield process (DAC HYP) administered subcutaneously (SC) every 4 weeks for a total of 3 years.
Outcome measures:
Because the main goal of this study is to investigate the MOA of CD25-blocking therapies in MS, the primary outcomes are mechanistic immunological studies performed on clinical samples (peripheral blood mononuclear cells (PBMC), cerebrospinal fluid (CSF) cells and skin biopsies) derived from DAC HYP-treated patients. The secondary outcome measure is long-term safety and tolerability of subcutaneous DAC HYP in HI-MS patients.
A. Long-term daclizumab therapy cohort: Up to 16 patients with HI-MS (both RR-MS and SP-MS) who have been successfully treated with IV daclizumab for a minimum of 1 year.
B. New treatment cohort: Up to 15 patients with HI-MS (both RR-MS and SP-MS) who have not been successfully treated with or have not tolerated standard FDA-approved immunomodulatory therapies, or who, for whatever reason, choose not to be treated with standard FDA approved immunomodulatory therapies.
INCLUSION CRITERIA:
MS as defined by the modified McDonald criteria (Polman, Reingold et al. 2005)
HI-MS (RR-MS or SP-MS) before initiation of daclizumab therapy, defined as:
ADDITIONAL INCLUSION CRITERION FOR THE LONG-TERM DACLIZUMAB THERAPY COHORT ONLY:
-IV daclizumab therapy for at least 1 year with a treatment response consisting of:<TAB>
EXCLUSION CRITERIA (FOR BOTH COHORTS):
PP-MS or low-inflammatory SP-MS
Alternative diagnoses that can explain neurological disability and MRI findings (e.g., ischemia/gliosis, CNS lyme disease, SLE, sarcoidosis, etc.)
History of malignancy, with the following exceptions: excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas, grade 1 endometrial carcinomas treated with total hysterectomy and without evidence for recurrence for greater than or equal to 3 years
Clinically significant medical disorders that, in the judgment of the investigators, could cause CNS tissue damage or limit its repair, expose the patient to undue risk of harm or prevent the patient from completing the study (e.g., immunodeficiency disorders, other autoimmune or immune-mediated disorders or chronic infections). Specific exclusions (based on baseline laboratory evaluation) are:
Abnormal screening/baseline blood tests exceeding any of the limits defined below:
Any of the following treatment history:
Prior treatment with the any of the following:
Prior treatment with any of the following medications or procedures within 1 year prior to initiation of therapy:
Prior treatment with any of the following medications or procedures within 6 months prior to initiation of therapy:
Treatment with any of the following medications within the 30 days prior to initiation of therapy:
For immunizations studies, known history of hypersensitivity or severe allergic reaction to vaccine components (subjects with such history can participate in the trial, but will not be immunized)
For patients in the extension phase: Patients may be excluded if they did not demonstrate an adequate clinical response in the first phase of the trial while receiving DAC HYP.
Inclusion criteria for MS controls for immunization and skin biopsy studies:
Exclusion criteria for MS controls for immunization and skin biopsy studies:
Treatment with immunomodulatory therapies that may have a negative impact on development of antigen-specific responses after immunization, including steroids within the last 60 days before the immunization study
Clinically significant medical disorders that, in the judgment of the investigators, could invalidate the person as appropriate control (e.g., immunodeficiency disorders, other autoimmune or immunemediated disorders or chronic infections). Specific exclusions (based on baseline laboratory evaluation) are:
Abnormal screening/baseline blood tests exceeding any of the limits defined below: