The primary outcome measure is PIRA (progression independent of relapse activity), based primarily on clinical assessment, dichotomized as present or not.

For Aim 1, the cohort, patient-derived disability status (PDDS) score, and ambulation score (self-reported) will be the primary endpoints of interest.

For Aim 2, the clinical trial, PIRA will be measured pre-GLP-1 start and at study end (week 72). A composite score of disability, similar to the ORATORIO13 trial will be constructed including EDSS score, 25-foot timed walk, 9-hole peg test, and SDMT score.

STUDY PROCEDURES:

Aim 1 will allow fully remote participation, drawing from geographically diverse settings throughout the USA. Participants in Aim 1 do not need to visit the study site in person or be independently mobile but must be continuously available during the study timeframe remotely for PROMS and study surveys and calls.

Participants will be enrolled for an estimated 72 weeks: Measurements will be requested every four weeks (i.e. q28 days) on a specifically designed survey instrument for MS participants. Participants will be asked to report medication dosing, adherence to medicine, tolerability, weight, height, and exercise activities. Self-reported scales will be administered to the participants as well (measuring disability, fatigue, mood, and quality of life).

Participants must be currently on Ocrelizumab (last dose within the past <6 months) and currently taking a GLP-1 medication.

Participants will be contacted and interviewed via Zoom every 6 months to ensure study procedures are going as planned, verify data reported on medication and MS disease history, and ensure study procedures are operating smoothly. Participants who do not complete the surveys within 7 days of the scheduled timing will be contacted by a study coordinator by phone up to 3 times. Participants will also be asked to report any medication changes, dose changes, or discontinuations if they occur at any point between study visits.

Participants will be enrolled until a total of 40 individual participants are reached. Study procedures for each group are listed in Tables 1 and 2. All scheduled events will be part of the study and not part of routine clinical care.

Allocation and Blinding

All participants will be treated with the two drugs of interest: Ocrelizumab and the GLP-1 agonist. The participants will be blinded to the study outcome of interest, i.e. progression or PIRA. The investigators will not be blinded to the study outcome. The participants will not have access to their prior PDDS scores on file, earlier in the study. The EDSS raters will not have access to the prior EDSS scores on file, earlier in the study. The statisticians will not be blinded to the study outcome.

Criteria for Study Drug Discontinuation in a Single Participant

Reasons for GLP-1 agonist drug discontinuation will be at the discretion of the treating prescriber include: (1) laboratory test abnormalities (e.g. transaminitis) whether related to the drugs or not; (2) intercurrent illness; (3) severe intolerance to the GLP-1 agonist; (4) lack of access to the GLP-1 drug within an affordable range; (5) patient preference; (6) achieved weight target earlier than anticipated; or (7) any other reason as determined by the prescribing physician or study principal investigator.

Criteria for Study Withdrawal of a Participant

Participants who discontinue GLP-1 agonist drugs for any reason, including tolerability, cost, desired weight loss outcome, etc., will continue to be observed until the end of the study period. It is possible that participants will have periods of discontinuation and then resume GLP-1 agonist treatment. The participant will be observed until (a) week 72 visit (i.e. end of study period), (b) participant withdrawal with no consent to continue monitoring, or (c) investigator-decided withdrawal of a participant from the study (e.g. severe medical illness preventing study completion, departure far from study site, etc.).

There is no anticipated drug development or future product anticipated in this study. A study participant will not have any right to compensation or ownership interest related to such development.

Inclusion Criteria:

• Diagnosis of MS (2019 revised McDonald criteria) of any type (PPMS, RRMS, SPMS) by a neurologist,
• Adult age 18-70 years,
• BMI >=24.0 kg/m2,
• Taken at least one dose of Ocrelizumab prior to study entry,
• EDSS <7.0,
• Able to provide individual informed consent,
• MRI available to confirm the diagnosis of MS.

Exclusion Criteria:

• Prior exposure to Mavenclad, Lemtrada, Cyclophosphamide, stem cell transplant or related bone marrow suppressive treatment,
• Current clinical trial participant,
• Unable to speak a language for which translation can be found in the hospital system,
• Unclear documentation of MS diagnosis or prior or current MS treatment,
• Relapse within the past 3 months,
• Recent major surgical procedure in the past 6 months,
• Exposure to steroids (systemic) within the past 3 months,
• Not on Ocrelizumab in the past >9 months,
• Moribund status,
• Underweight or experiencing protein malnutrition,
• Unable to provide consent voluntarily due to reasons of capacity or other reasons (e.g. incarcerated, dementia, etc.),
• Unable to complete the study activities for any reason as deemed by the study investigator.

Additional Inclusion Criteria Aim 1:

• Exposed to GLP-1 agonist treatment in the last 3 years or less, or starting on a GLP-1 agonist in the coming <3 months,
• Willing to report monthly patient-reported outcomes remotely or in-person.

Additional Inclusion Criteria Aim 2:

• Able to present for baseline and follow up in person,
• Unexposed to a GLP-1 agonist in the past year,
• Starting on a GLP-1 agonist in the next <6 months,
• Plan to be exposed to GLP-1 agonist for a minimum of 72 weeks following enrollment.

Individuals with multiple sclerosis already treated with both Ocrelizumab and are either currently on a GLP-1 agonist or who are soon starting a GLP-1 agonist.