Meningeal Inflammation on 7T MRI as a Tool for Measuring and Predicting Ocrelizumab Response in Multiple Sclerosis
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology, Neurology, Multiple Sclerosis |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 10/25/2018 |
| Start Date: | September 24, 2018 |
| End Date: | January 2021 |
| Contact: | Kerry Naunton |
| Email: | KNaunton@som.umaryland.edu |
| Phone: | 410-328-1885 |
Multiple Sclerosis (MS) is an autoimmune disorder of the central nervous system. In MS,
inflammation is known to attack areas of the brain, spinal cord, and optic nerves; resulting
in disability. Current MRI technology provides an adequate view of the impact of MS on the
"white matter" of the brain, which contains many of the connections between neurons.
Quantification of lesions in the white matter due to MS are a standard part of clinical
trials and clinical care in MS. However, it has long been known that MS not only can affect
the white matter, but also the "gray matter," which contains the majority of the nerve cells
in the brain and can cause inflammation in the meninges (the protective tissue that surrounds
the brain and spinal cord). Autopsy studies have shown that the inflammation seen in the
meninges is driven by a B-cells, a subset of white blood cells and that meningeal
inflammation may be responsible for damage to the gray matter of the brain.
Ocrelizumab is a new treatment for multiple sclerosis. This medication works by targeting and
destroying circulating B-cells. It is thought that this may reduce the level of meningeal
inflammation in patients with multiple sclerosis. By reducing meningeal inflammation, this
medication may result in less damage to the gray matter and subsequently less disability in
MS patients.
In this study, the investigators will evaluate the use of a method on 7 tesla (7T) MRI to
identify inflammation in the meninges as a potential predictor of response to ocrelizumab
treatment for multiple sclerosis. Further, the investigators will evaluate if this MRI
technique can be used to monitor the long-term effect of the medication on meningeal
inflammation and the development of damage to the gray matter of the brain.
inflammation is known to attack areas of the brain, spinal cord, and optic nerves; resulting
in disability. Current MRI technology provides an adequate view of the impact of MS on the
"white matter" of the brain, which contains many of the connections between neurons.
Quantification of lesions in the white matter due to MS are a standard part of clinical
trials and clinical care in MS. However, it has long been known that MS not only can affect
the white matter, but also the "gray matter," which contains the majority of the nerve cells
in the brain and can cause inflammation in the meninges (the protective tissue that surrounds
the brain and spinal cord). Autopsy studies have shown that the inflammation seen in the
meninges is driven by a B-cells, a subset of white blood cells and that meningeal
inflammation may be responsible for damage to the gray matter of the brain.
Ocrelizumab is a new treatment for multiple sclerosis. This medication works by targeting and
destroying circulating B-cells. It is thought that this may reduce the level of meningeal
inflammation in patients with multiple sclerosis. By reducing meningeal inflammation, this
medication may result in less damage to the gray matter and subsequently less disability in
MS patients.
In this study, the investigators will evaluate the use of a method on 7 tesla (7T) MRI to
identify inflammation in the meninges as a potential predictor of response to ocrelizumab
treatment for multiple sclerosis. Further, the investigators will evaluate if this MRI
technique can be used to monitor the long-term effect of the medication on meningeal
inflammation and the development of damage to the gray matter of the brain.
Twenty-two (22) participants will be recruited from the University of Maryland Center for
Multiple Sclerosis Treatment and Research. Participants will be included if they are aged
18-65, have a diagnosis of relapsing or progressive multiple sclerosis per revised 2010
McDonald Criteria, and are planning to begin ocrelizumab therapy for multiple sclerosis, as
prescribed by their treating physician. Participants will be excluded if they are unable to
undergo an MRI due to metallic implants/devices or claustrophobia, have a history of allergy
to gadolinium contrast, or are unable to provide informed consent.
All participants will undergo a baseline/screening study visit prior to initiation of
ocrelizumab. This will include signing of informed consent, a clinical interview to collect
demographic and clinical data, a physical examination to calculate the EDSS score, and
implementation of the component tests of the Multiple Sclerosis Functional Composite (MSFC).
All participants will then undergo an MRI on a 7T Philips Achieva scanner (housed at the
Kennedy Krieger Institute, Baltimore, MD). This will be a whole brain MRI, including 0.7mm3
resolution magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) and MPFLAIR
images acquired both pre- and post-intravenous infusion of gadolinium contrast.
MP2RAGE images will be processed to create T1 maps and T1-weighted images. All images
(MPFLAIR included) will be co-registered to the pre-contrast MP2RAGE T1 map. Subtraction
images will be created by subtracting the pre-contrast MPFLAIR scan from post-contrast
images. Regions of hyperintensity on the subtraction image will be reviewed on anatomical
images, and marked as regions of leptomeningeal enhancement if they have an amorphous
appearance and are present in the leptomeningeal space.
Participants who are found to have leptomeningeal enhancement on their baseline scan will be
considered as having passed screening and will proceed with further study procedures. Those
that do not have meningeal enhancement on a baseline scan will not return for a follow up
visit.
Participants who have passed screening (and thus have meningeal enhancement on their baseline
scan) will then undergo initiation of ocrelizumab per clinical trial or commercial drug
protocol as previously planned by their treating neurologists. Participants will then return
for a follow up visit within 1 month after their 12 month ocrelizumab infusion. All of the
above study procedures will be repeated on that date.
Follow up images for each subject will undergo co-registration to the pre-contrast MP2RAGE T1
map. This will allow co-registered review of baseline and 1 year follow up MPFLAIR images
side-by-side for review of the presence or absence of enhancing foci noted at baseline on the
1 year follow up scan. Subtraction images will also be created utilizing the 1 year pre- and
post-contrast MPFLAIR scan for quantification of the number of enhancing foci on the 1 year
follow up scan by the same procedures as above. A semi-automated region growing painting tool
will be used to create masks over areas of contrast enhancement, which will be used to
quantify enhancing focus volume on the baseline and follow up scan. Further, subtraction
mapping will be utilized to highlight regions of hypointensity present in the cortex on
MP2RAGE T1 that were not present on baseline MP2RAGE T1, which would indicate a new cortical
lesion at follow up.
Multiple Sclerosis Treatment and Research. Participants will be included if they are aged
18-65, have a diagnosis of relapsing or progressive multiple sclerosis per revised 2010
McDonald Criteria, and are planning to begin ocrelizumab therapy for multiple sclerosis, as
prescribed by their treating physician. Participants will be excluded if they are unable to
undergo an MRI due to metallic implants/devices or claustrophobia, have a history of allergy
to gadolinium contrast, or are unable to provide informed consent.
All participants will undergo a baseline/screening study visit prior to initiation of
ocrelizumab. This will include signing of informed consent, a clinical interview to collect
demographic and clinical data, a physical examination to calculate the EDSS score, and
implementation of the component tests of the Multiple Sclerosis Functional Composite (MSFC).
All participants will then undergo an MRI on a 7T Philips Achieva scanner (housed at the
Kennedy Krieger Institute, Baltimore, MD). This will be a whole brain MRI, including 0.7mm3
resolution magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) and MPFLAIR
images acquired both pre- and post-intravenous infusion of gadolinium contrast.
MP2RAGE images will be processed to create T1 maps and T1-weighted images. All images
(MPFLAIR included) will be co-registered to the pre-contrast MP2RAGE T1 map. Subtraction
images will be created by subtracting the pre-contrast MPFLAIR scan from post-contrast
images. Regions of hyperintensity on the subtraction image will be reviewed on anatomical
images, and marked as regions of leptomeningeal enhancement if they have an amorphous
appearance and are present in the leptomeningeal space.
Participants who are found to have leptomeningeal enhancement on their baseline scan will be
considered as having passed screening and will proceed with further study procedures. Those
that do not have meningeal enhancement on a baseline scan will not return for a follow up
visit.
Participants who have passed screening (and thus have meningeal enhancement on their baseline
scan) will then undergo initiation of ocrelizumab per clinical trial or commercial drug
protocol as previously planned by their treating neurologists. Participants will then return
for a follow up visit within 1 month after their 12 month ocrelizumab infusion. All of the
above study procedures will be repeated on that date.
Follow up images for each subject will undergo co-registration to the pre-contrast MP2RAGE T1
map. This will allow co-registered review of baseline and 1 year follow up MPFLAIR images
side-by-side for review of the presence or absence of enhancing foci noted at baseline on the
1 year follow up scan. Subtraction images will also be created utilizing the 1 year pre- and
post-contrast MPFLAIR scan for quantification of the number of enhancing foci on the 1 year
follow up scan by the same procedures as above. A semi-automated region growing painting tool
will be used to create masks over areas of contrast enhancement, which will be used to
quantify enhancing focus volume on the baseline and follow up scan. Further, subtraction
mapping will be utilized to highlight regions of hypointensity present in the cortex on
MP2RAGE T1 that were not present on baseline MP2RAGE T1, which would indicate a new cortical
lesion at follow up.
Inclusion Criteria:
- A diagnosis of relapsing or primary progressive multiple sclerosis according to
revised 2010 McDonald Criteria
- Ages 18 to 65, inclusive
- Have been prescribed ocrelizumab by their treating physician for treatment of multiple
sclerosis, with the 1st infusion to occur within 30 days of enrollment
Exclusion Criteria:
- Inability to provide informed consent
- Inability to undergo MRI due to implantable devices or metallic foreign bodies
considered unsafe in the MRI magnet
- Known severe allergic reaction (anaphylaxis) in the past to gadolinium contrast
- A current diagnosis of severe kidney failure and/or use of hemodialysis
- Currently pregnant or lactating
- History of a seizure disorder
We found this trial at
1
site
655 West Baltimore Street
Baltimore, Maryland 21201
Baltimore, Maryland 21201
(410) 706-7410
Principal Investigator: Daniel Harrison, MD
Phone: 410-328-1885
University of Maryland School of Medicine Established in 1807, The School of Medicine is the...
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