Multiple Sclerosis
Conditions
Brief summary
Using magnetic resonance-PET (MR-PET) imaging with \[11C\]PBR28, a second-generation 18kDa translocator protein (TSPO) radiotracer, we have previously demonstrated abnormally high TSPO expression, indicative of microglia activation, across different brain tissue compartments of multiple sclerosis (MS) patients1. In this study, we propose to study the efficacy of ocrelizumab, a humanized monoclonal antibody that has been shown to decrease neuroinflammation in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (MS) patients. We will test these effects by studying a cohort of 24 MS patients (12 RRMS, 12 progressive MS). Participants will be studied before (within 3 months prior to initiating treatment) and after treatment with ocrelizumab (\ 12 month follow up), a therapeutic drug that will be part of their standard medical care. We will use \[11C\]PBR28 to help determine changes in neuroinflammation. The purpose of this study is to determine the effects of ocrelizumab treatment on neuroinflammation by analyzing the uptake and distribution of \[11C\]PBR28 in individuals with multiple sclerosis. The specific aims of the current study are: 1. To assess whether treatment with ocrelizumab in subjects with either relapsing-remitting MS or progressive MS is associated with decreased \[11C\]PBR28 binding in the cortex and white matter (lesions and normal appearing white matter), suggesting reduced neuroinflammation. 2. To assess whether changes in neuroinflammation under ocrelizumab treatment, as measured by \[11C\]PBR28 uptake at 12-month follow up relative to baseline, are associated with changes in structural MR metrics of brain tissue damage including white matter lesion load, cortical atrophy, and demyelination in the cortex and in the normal-appearing white matter as measured by magnetization transfer ratio (MTR). 3. To explore whether changes in functional and structural imaging metrics under ocrelizumab are associated with changes in clinical outcome measures.
Interventions
DRUG11C-PBR28
This study will evaluate, serially, functional and structural tissue changes in the cortex and WM of subjects with RRMS and progressive disease under Ocrelizumab using 11C-PBR28 MR-PET imaging at baseline and at approximately 12-month follow up.
Sponsors
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
24 multiple sclerosis patients
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent 2. RRMS and/or PMS subtype 3. EDSS between 0 and 7.0 4. Express at least one high-affinity (Ala147) allele of the TSPO receptor for PBR28 5. Initiating Ocrelizumab treatment within the next 3 months
Exclusion criteria
1. Hypersensitivity to trial medications 2. History of life-threatening reaction to Ocrelizumab 3. Acute or uncontrolled chronic medical condition 4. Impaired hearing 5. Claustrophobia 6. 300 lbs of greater (weight limit of MRI table) 7. Pregnancy or breastfeeding 8. Sensitivity to imaging agents 9. Contraindications to MRI 10. Use of benzodiazepines, topiramate, doxycycline, mynocicline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | Baseline to 12 month | The primary endpoint is change in mean 11C-PBR28 SUVR in multiple sclerosis patients after 1-year of ocrelizumab therapy in different brain regions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Magnetization Transfer Ratio (MTR) | Baseline to 12-month | Secondary endpoint is changes in mean magnetization transfer ratio (MTR) in cortex and normal appearing white matter (NAWM) of multiple sclerosis patients after 1-year of ocrelizumab therapy. MTR is defined as: S0 - S\_MT/S0; where S0 is the signal intensity without the magnetization transfer (MT) pulse and S\_MT is the signal intensity with the MT pulse. It is dimensionless because it is defined as a ratio of two signals with the same physical units, so the units cancel out. Larger MTR indicate stronger interaction between free water protons and macromolecular-bound protons. |
| Cortical Thickness | Baseline to 12-month | Secondary endpoint is changes in cortical thickness after 1-year ocrelizumab treatment in patients with multiple sclerosis. |
| White Matter (WM) Lesion Volume | Baseline to 12 months | Secondary endpoint is changes in WM lesion load after 1-year of ocrelizumab therapy in patients with MS. |
Countries
United States
Participant flow
Recruitment details
22 patients signed the consent form.
Pre-assignment details
Out of the 22 patients that signed the consent form, 2 patients became later ineligible to continue with the baseline study procedures.
Participants by arm
| Arm | Count |
|---|---|
| Multiple Sclerosis Patients Multiple sclerosis patients will be evaluated with 11C-PBR28 MR-PET at baseline before and at 12 month follow up after Ocrelizumab therapy.
This study will evaluate, serially, functional and structural tissue changes in the cortex and brain white matter (lesions and normal appearing white matter) of subjects with RRMS and progressive disease under Ocrelizumab using 11C-PBR28 MR-PET imaging at baseline and at approximately 12-month follow up. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Multiple Sclerosis Patients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 43.15 years STANDARD_DEVIATION 12.7 |
| Race/Ethnicity, Customized Black/African American | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants |
| Race/Ethnicity, Customized White | 18 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 18 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 | 12 / 20 |
| serious Total, serious adverse events | 1 / 20 |
Outcome results
Primary
11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR)
The primary endpoint is change in mean 11C-PBR28 SUVR in multiple sclerosis patients after 1-year of ocrelizumab therapy in different brain regions.
Time frame: Baseline to 12 month
Population: Fifteen MS patients completed the follow-up MR-PET study, which was performed at an average interval of 19.8 days (SD=22.6) after receiving the 1-year ocrelizumab dose. A patient was excluded from the PET analysis after it was discovered that they were using a medication not allowed by the study protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | Baseline SUVR in perilesional white matter | 0.9 SUVR | Standard Deviation 0.19 |
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | Baseline SUVR in white matter lesions | 0.9 SUVR | Standard Deviation 0.21 |
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | Baseline SUVR in thalamus | 1.31 SUVR | Standard Deviation 0.26 |
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | 12-month SUVR in perilesional white matter | 0.84 SUVR | Standard Deviation 0.19 |
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | 12-month SUVR in white matter lesions | 0.83 SUVR | Standard Deviation 0.2 |
| Multiple sclerosis patients | 11C-PBR28 Uptake as Measured by Standardized Uptake Values Normalized by a Pseudoreference Region (SUVR) | 12-month SUVR in thalamus | 1.23 SUVR | Standard Deviation 0.25 |
p-value: 0.011t-test, 2 sided
Comparison: Paired-t test baseline vs follow-up SUVR in perilesional white matter multiple sclerosis patients.p-value: 0.018t-test, 2 sided
Comparison: Paired-t test baseline vs follow-up SUVR in the thalamus of multiple sclerosis patients.p-value: 0.047t-test, 2 sided
Secondary
Cortical Thickness
Secondary endpoint is changes in cortical thickness after 1-year ocrelizumab treatment in patients with multiple sclerosis.
Time frame: Baseline to 12-month
Population: A patient was excluded from the study analysis after it was discovered that they were using a medication not allowed by the study protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multiple sclerosis patients | Cortical Thickness | Baseline cortical thickness | 2.35 mm2 | Standard Deviation 0.09 |
| Multiple sclerosis patients | Cortical Thickness | 12-month cortical thickness | 2.35 mm2 | Standard Deviation 0.07 |
Comparison: Changes in cortical thickness after 1-year ocrelizumab treatment in patients with multiple sclerosisp-value: 0.69t-test, 2 sided
Secondary
Magnetization Transfer Ratio (MTR)
Secondary endpoint is changes in mean magnetization transfer ratio (MTR) in cortex and normal appearing white matter (NAWM) of multiple sclerosis patients after 1-year of ocrelizumab therapy. MTR is defined as: S0 - S\_MT/S0; where S0 is the signal intensity without the magnetization transfer (MT) pulse and S\_MT is the signal intensity with the MT pulse. It is dimensionless because it is defined as a ratio of two signals with the same physical units, so the units cancel out. Larger MTR indicate stronger interaction between free water protons and macromolecular-bound protons.
Time frame: Baseline to 12-month
Population: Longitudinal MTR scans were acquired in 15 patients; in one subject, however, the MT\_off acquisition was not completed due to early scan termination as the subject was unable to tolerate the scan duration. MTR maps from another subject were excluded from the group analysis due to severe motion artifacts.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multiple sclerosis patients | Magnetization Transfer Ratio (MTR) | Baseline NAWM MTR | 27.9 % of MTR | Standard Deviation 1.4 |
| Multiple sclerosis patients | Magnetization Transfer Ratio (MTR) | Baseline cortical MTR | 17.3 % of MTR | Standard Deviation 0.9 |
| Multiple sclerosis patients | Magnetization Transfer Ratio (MTR) | 12-month NAWM MTR | 27.0 % of MTR | Standard Deviation 1.9 |
| Multiple sclerosis patients | Magnetization Transfer Ratio (MTR) | 12-month cortical MTR | 16.8 % of MTR | Standard Deviation 1.1 |
Comparison: Baseline vs follow-up MTR in NAWMp-value: 0.07t-test, 2 sided
Comparison: Baseline vs follow-up MTR in cortexp-value: 0.024t-test, 2 sided
Secondary
White Matter (WM) Lesion Volume
Secondary endpoint is changes in WM lesion load after 1-year of ocrelizumab therapy in patients with MS.
Time frame: Baseline to 12 months
Population: A patient was excluded from the study analysis after it was discovered that they were using a medication not allowed by the study protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Multiple sclerosis patients | White Matter (WM) Lesion Volume | Baseline white matter lesion volume | 6248 mm cubic | Standard Deviation 7314 |
| Multiple sclerosis patients | White Matter (WM) Lesion Volume | 12-month white matter lesion volume | 6021 mm cubic | Standard Deviation 6821 |
Comparison: Wilcoxon related samples test comparing baseline vs follow-up changes in white matter lesion volume of multiple sclerosis patients.p-value: 0.64Wilcoxon (Mann-Whitney)