Multiple Sclerosis
Conditions
Keywords
MRI, OCT, Tysabri, Multiple Sclerosis, cognition
Brief summary
The long-term objective is to further establish the role of Tysabri in preventing neurological degeneration in multiple sclerosis (MS) and to establish powerful and efficient new markers for neurological degeneration in MS. The study intends to correlate cognition with two instruments and their measurements-MRI and OCT (optical coherence tomography).
Detailed description
The specific aims are: 1. To determine the effects of Tysabri on cognition (memory, thought processes, etc.) 2. To determine the effects of Tysabri on specific MRI markers for cognitive dysfunction 3. To determine the effects of Tysabri on retinal nerve fiber layer thickness (RNFL) using optical coherence tomography (OCT), a special instrument used in ophthalmology
Interventions
DRUGTysabri
Infuse TYSABRI® 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP over approximately one hour. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP. Tysabri will be infused every four weeks.
Sponsors
Biogen
University of Chicago
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* 18 through 60 years of age inclusive * Diagnosis of relapsing remitting multiple sclerosis * Prior to treatment phase, have had disease activity with at least 1 documented relapse during the previous year OR 2 documented relapses during the previous 2 years OR one or more new MRI lesions (Gd+ and/or T2 hyperintense) * An Expanded Disability Status Scale (EDSS) score of 0-4.5 inclusive * Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to treatment * Never been treated with Tysabri/natalizumab.
Exclusion criteria
* Another type of MS other than relapsing remitting multiple sclerosis (RRMS) * A history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome/immunocompromised * A history or presence of cancer (except for successfully treated basal or squamous cell carcinoma of skin) * Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively * Have received any live or live attenuated vaccines (including for varicella-zoster virus or Measles) within the last 2 months * Have received total lymphoid irradiation or bone marrow transplantation * Have been treated with: corticosteroids or adrenocorticotropic hormones (ACTH) within the last month, IFN-β or glatiramer acetate within the last 3 months, immunosuppressive medications such as azathioprine or methotrexate within the last 6 months, immunoglobulins and/or monoclonal antibodies (including natalizumab) within the last 6 months, or cladribine, cyclophosphamide or mitoxantrone at any time. * Any medically unstable condition or a progressive neurological disorder, other than MS, which may affect participation in the study * History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or other major disease * Unable to undergo MRI scans, including claustrophobia, have a pacemaker or history of hypersensitivity to gadolinium-DTPA * Have had a relapse within 30 days prior AND/OR not stabilized from a previous relapse * History of severe allergic or anaphylactic reactions or known drug hypersensitivity to natalizumab/Tysabri * A clinically significant infectious disease, such as cellulitis, pneumonia, septicemia * History of progressive multifocal leukoencephalopathy(PML) * Participation in any clinical research study evaluating another investigational drug or therapy within the last 6 months * History of Tysabri therapy * Abnormal screening blood test * Females who are not postmenopausal for at least 1 year, surgically sterile or willing to practice effective contraception during the study * Nursing mothers, pregnant women, and women planning to become pregnant while on study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Function Over Time | Baseline, 48 weeks, 96 weeks | Cognitive function was assessed using the oral version of the Symbol Digit Modalities Test (SDMT). The number of correct responses in 90 seconds was recorded (possible range 0-110). For analysis, SDMT scores were converted to z-scores using published age and education based norms. A negative z-score indicates a SDMT score below the mean based on the age and education based norms, for example a z-score of -2 = 2 standard deviations below the mean; a positive z-score indicating a score above the mean. Higher scores indicate better cognitive function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in Retinal Nerve Fiber Layer Thickness | Baseline, 24, 48, 72, and 96 weeks | Retinal Nerve Fiber Layer (RNFL) thickness was measured using spectral domain OCT scans by a trained technician. Scans were performed without pupil dilation. |
| Change Over Time in Brain Parenchymal Fraction | Baseline, 48 weeks, 96 weeks | Measured based on MRI scan on a 3T Phillips scanner. This is a measure of brain atrophy (i.e., brain volume loss) with lower values indicating greater atrophy (possible range 0-1). |
| Change Over Time in Normalized Thalamic Volume | Baseline, 48 weeks, 96 weeks | Measured on MRI scan |
| Change Over Time in Normalized Hippocampal Volume | Baseline, 48 weeks, 96 weeks | Measured on MRI scan |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tysabri Natalizumab 300 mg IV every 4 weeks | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Development of antibodies to drug | 2 |
| Overall Study | positive anti-JC virus antibody test | 2 |
Baseline characteristics
| Characteristic | Tysabri |
|---|---|
| Age, Continuous | 39 years STANDARD_DEVIATION 9 |
| Race/Ethnicity, Customized African-American | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 8 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Change in Cognitive Function Over Time
Cognitive function was assessed using the oral version of the Symbol Digit Modalities Test (SDMT). The number of correct responses in 90 seconds was recorded (possible range 0-110). For analysis, SDMT scores were converted to z-scores using published age and education based norms. A negative z-score indicates a SDMT score below the mean based on the age and education based norms, for example a z-score of -2 = 2 standard deviations below the mean; a positive z-score indicating a score above the mean. Higher scores indicate better cognitive function.
Time frame: Baseline, 48 weeks, 96 weeks
Population: Summary statistics are based on the 15 subjects who completed treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri | Change in Cognitive Function Over Time | Baseline | -1.5 units on a scale | Standard Deviation 0.9 |
| Tysabri | Change in Cognitive Function Over Time | Week 48 | -1.2 units on a scale | Standard Deviation 1 |
| Tysabri | Change in Cognitive Function Over Time | Week 96 | -1.2 units on a scale | Standard Deviation 0.9 |
Comparison: Analysis used all available data from subjects, including those who dropped out early.p-value: 0.17Mixed Models Analysis
Secondary
Change Over Time in Brain Parenchymal Fraction
Measured based on MRI scan on a 3T Phillips scanner. This is a measure of brain atrophy (i.e., brain volume loss) with lower values indicating greater atrophy (possible range 0-1).
Time frame: Baseline, 48 weeks, 96 weeks
Population: Summary statistics are based on subjects completing treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri | Change Over Time in Brain Parenchymal Fraction | Baseline | 0.970 units on a scale | Standard Deviation 0.011 |
| Tysabri | Change Over Time in Brain Parenchymal Fraction | Week 48 | 0.969 units on a scale | Standard Deviation 0.012 |
| Tysabri | Change Over Time in Brain Parenchymal Fraction | Week 96 | 0.971 units on a scale | Standard Deviation 0.014 |
Comparison: Analysis used all available datap-value: 0.3Mixed Models Analysis
Secondary
Change Over Time in Normalized Hippocampal Volume
Measured on MRI scan
Time frame: Baseline, 48 weeks, 96 weeks
Population: Summary statistics are based on subjects completing all treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri | Change Over Time in Normalized Hippocampal Volume | Baseline | 6.8 mL | Standard Deviation 0.8 |
| Tysabri | Change Over Time in Normalized Hippocampal Volume | Week 48 | 6.7 mL | Standard Deviation 1 |
| Tysabri | Change Over Time in Normalized Hippocampal Volume | Week 96 | 6.6 mL | Standard Deviation 0.9 |
Comparison: Analysis used all available datap-value: 0.9Mixed Models Analysis
Secondary
Change Over Time in Normalized Thalamic Volume
Measured on MRI scan
Time frame: Baseline, 48 weeks, 96 weeks
Population: Summary statistics are based on subjects completing all treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri | Change Over Time in Normalized Thalamic Volume | Baseline | 13.9 mL | Standard Deviation 1.9 |
| Tysabri | Change Over Time in Normalized Thalamic Volume | Week 48 | 13.7 mL | Standard Deviation 2 |
| Tysabri | Change Over Time in Normalized Thalamic Volume | Week 96 | 13.7 mL | Standard Deviation 2.1 |
Comparison: Analysis used all available datap-value: 0.02Mixed Models Analysis
Secondary
Change Over Time in Retinal Nerve Fiber Layer Thickness
Retinal Nerve Fiber Layer (RNFL) thickness was measured using spectral domain OCT scans by a trained technician. Scans were performed without pupil dilation.
Time frame: Baseline, 24, 48, 72, and 96 weeks
Population: Summary statistics are provided based on subjects completing all treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tysabri | Change Over Time in Retinal Nerve Fiber Layer Thickness | Baseline | 86 micrometer | Standard Deviation 13 |
| Tysabri | Change Over Time in Retinal Nerve Fiber Layer Thickness | Week 24 | 85 micrometer | Standard Deviation 12 |
| Tysabri | Change Over Time in Retinal Nerve Fiber Layer Thickness | Week 48 | 85 micrometer | Standard Deviation 13 |
| Tysabri | Change Over Time in Retinal Nerve Fiber Layer Thickness | Week 72 | 85 micrometer | Standard Deviation 13 |
| Tysabri | Change Over Time in Retinal Nerve Fiber Layer Thickness | Week 96 | 85 micrometer | Standard Deviation 13 |
Comparison: Analysis used all available datap-value: 0.6Mixed Models Analysis