Effect of Ocrelizumab on Neuroinflammation in Multiple Sclerosis as Measured by 11C-PBR28 MR-PET Imaging of Microglia Activation

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.

Study Overview

• Status: Unknown
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: 11C-PBR28

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Caterina Mainero, MD, PhD; Phone Number: 617-724-7746; Email: cmainero@mgh.harvard.edu
• Study Contact Backup: Name: Ambica Mehndiratta, BSc; Phone Number: 617-724-8823; Email: amehndiratta1@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: 11C-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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroinflammation Changes under Ocrelizumab Therapy	To measure changes in 11C-PBR28 uptake in the brain of multiple sclerosis patients under Ocrelizumab therapy	12 months
To assess whether changes in neuroinflammation under Ocrelizumab treatment relate to changes in structural MR metrics of brain tissue damage	To measure changes in 11C-PBR28 uptake in the brain of multiple sclerosis patients under Ccrelizumab therapy correlate with changes in WM lesion load, cortical atrophy and demyelination in the cortex and in the NAWM as measured by magnetization transfer ratio (MTR)	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To explore whether changes in functional and structural imaging metrics under Ocrelizumab are associated with changes in clinical outcomes measures	To measure whether changes in 11C-PBR28 uptake or in structural imaging metrics correlate with measures of neurological disability and cognition	12 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Caterina Mainero, MD, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 1, 2020
• Primary Completion (ANTICIPATED): January 1, 2022
• Study Completion (ANTICIPATED): July 1, 2022

Study Registration Dates

• First Submitted: January 13, 2020
• First Submitted That Met QC Criteria: January 13, 2020
• First Posted (ACTUAL): January 18, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: 2019P002865

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No