This will be a non-randomized, rater-blinded pragmatic trial, which is an extension of the randomized discontinuation trial (RDT), DISCOMS. While RDTs have been done in cancer, and rheumatoid arthritis patients, the original DISCOMS protocol was the first such study in MS. Study sites will be limited to the top 10 recruiting sites from the DISCOMS study due to financial and cost-effectiveness issues. Those sites will have participants who have completed 18-24 months of the primary study. In practice, the vast majority, if not all, will have completed 24 months. The investigators will explicitly include any who have completed, including those who already have exceeded 12 additional months after completion of the primary trial. Individuals who have successfully completed (retained original drug assignment and did not meet the primary endpoint of DISCOMS) the primary DISCOMS trial and are willing to retain their original drug assignment after completion and for an additional 12 months will be offered entry into the extension. The only exception to that will be individuals who continued the original drug assignment during and after the primary trial, up to 24 months, but who then had a relapse, new MRI lesion, or other MS-related reason between months 24 and 36 which resulted in their change of medication assignment. These individuals can and should be included, and counted as "failing" during the extension trial completing the Kaplan-Meier event free survival curve critical to the original hypothesis. A total of up to 100 patients will be consented and enter the extension trial, regardless of assignment, on a first come first serve basis to avoid selection biases to the extent possible. The intent is to take the first 100 who fulfill criteria and agree to participate. The plan is for a 50/50 distribution, but there may not be exactly 50 in each group. As of September 1, 2020, 102 had completed participation of the primary 24-month study, and information as to DMT use after finishing 2-years participation in DISCOMS was available for 46/102, 23 in each group (see Table 1 below). Notably, in the Discontinue group, 87% remained off DMT while only 61% in the Continue group remained on a DMT (13/14 on the same DMT, one switching to an alternative). Overall 74% remained in the primary assignment grouping. If these ratios stay consistent as more finish DISCOMS, discontinuers will account for roughly 59% of the total enrolled in the extension trial. Also, of the 102 completers, 20 have also gone at least an additional 12 months since completion of DISCOMS, and these participants will be offered entry into the extension trial, should these participants otherwise fulfill criteria. There will be no placebo and no sham treatment.

The study procedures will be slightly different for those who are completing Month 24 of the primary trial and simply "rolling over" to extension on the same day, compared to those who already have completed the study. For those rolling over at Month 24, DISCOMS participants will be offered participation in the extension trial. If these participants agree to participate, these participants will do a second study visit at the Month 24 visit, which concurrently will be Time Zero (T0) for the extension. This will consist of obtaining informed consent and going through Inclusion/Exclusion criteria. All the data from Month 24 visit will comprise the baseline data for the extension. Current and past DISCOMS study participants will be identified and screened for eligibility. This may include individuals who already have surpassed a full year since last participation in the trial, so long as these participants continued their original group assignment after the completion of the primary study and for at least for one additional year, or until a relapse or new MRI lesion occurred, as determined in screening. These individuals will explicitly be included, upon verification of the defining event. Patients will be approached at their next study visit or by phone (if these participants already completed the original study) by the PI and/or a study coordinator about participating in the study. The local PI for the study will verify accuracy of meeting inclusion criteria, and screening and consent may take place in person or by electronic means. Participants must agree to have a single SOC, month 36 MRI done by their primary neurologist and have the results and the MRI disk sent to the study site, to be assessed by a blinded central reader as has been done during the primary trial. All research visits will be conducted at the same time as SOC visits when possible, or as separate visits if not possible or the patient receives SOC elsewhere. For those who have exceeded 30 months from onset in the primary trial, the P1 visit (a telephone call) will not occur. All patients will undergo the T1 visit at 36 months, or longer should these participants have already exceed 36 months from onset of their participation in the primary trial.

A thorough discussion of the trial, signing the informed consent form, and confirmation of inclusion/exclusion criteria will be completed during the baseline visit (T0). Consenting may be done in-person on paper or using e-consent. If utilizing e-consent, participants will be presented a consent form ahead of time, and upon signature in the REDCap system, participants will receive a pdf of what was 'signed' electronically via REDCap. A pdf will also be generated for study records. T0 may occur on the same day as T1 if the patient has already completed the main DISCOMS study and is within the window for the Month 36 visit. There will be one phone call (P1), conducted by the study coordinator, at 30 Months post-enrollment in the original DISCO MS trial. On this phone call, the participant will be asked about any new or ongoing adverse events, changes to medications, and any symptoms suggesting a potential relapse. If the participant joins the Extension study after the participant already passed 30 Months post-enrollment in the original DISCO MS trial, the participant will not do P1. Those who have already exceeded 30 months since starting the primary DISCOMS trial will have the equivalent of the phone assessment at the T0 visit. Participants will come in for 1 additional study visit: T1 at 36 Months post-enrollment in the original DISCO MS trial. During T1, patients will undergo a blinded EDSS exam and relapse assessment, vitals, complete an SDMT assessment, and will complete all PROs/comorbidities. All PROs/comorbidities may be completed on paper in person or remotely via the electronic platform within the visit window, based on site and patient needs. Participants will also undergo a standard of care MRI scan of the brain at T1, within 60 days before and 120 days after the study visit. Participants who have already exceeded 12 months from the end of the primary trial will still be recruited and simply do the T1 visit at their earliest convenience. The maximum window will be 30 months after completion of the primary study, or 54 months since starting DISCOMS. Participants should always be brought in as close to 36 months as possible. Some participants' final study visit for the original DISCO MS study will be at 18 Months. For these subjects, the P1 visit will occur 24 Months after enrollment in the original study, and T1 will occur 30 Months after enrollment in the original study.

All participants will undergo the T1 visit, which will include a formal, blinded relapse assessment by the Examining Physician (EDSS rater) in conjunction with the PI (see section E). Prior to enrollment, the enrolling physician will certify, based on their personal review of the prior MRI scans and/or reports which will include data from the 24 month primary DISCOMS trial, that the scans have been stable for a minimum of 4.5 years (review of minimum of two scans, although it could be more, separated by at least 4.5 years). MRI scans at T1, 36+ months after onset of participation in the primary trial, will be performed as per usual SOC, paid for by patient insurance, at whatever site is normally used by the patient (preferably the same scanner each time, and preferably the same scanner as the investigation site), and should be done on a MRI machine with magnet 1.5 Tesla or greater, with and without contrast. Gadolinium may be withheld at the discretion of the PI or request of the patient. The window for T1 MRIs will be 60 day before or 120 days after the T1 study visit, and will be analyzed by a central, board-certified, blinded neuro-radiologist for new activity compared to prior scans. All MRI scans will be read locally for safety and clinical purposes, and PIs will communicate any significant MS or non-MS findings to the primary neurologist (should the investigator not be the primary neurologist). Any new lesion documented on the T1 MRI scan will prompt delivery of a notice within 48 hours, to the PI, that the patient has achieved the endpoint of the study, with a description of relevant findings.

In the event of a suspected relapse, the patient will be instructed to contact their physician and the study coordinator at their local site within 48 hours of new symptoms and come in for an unscheduled visit and relapse evaluation within seven days of symptom onset. Use of corticosteroids will be at the discretion of the patient and the local PI or other physician. Use of systemic steroids to treat MS symptoms will be concluded to be a Protocol-defined relapse. As at scheduled visits, the determination of a relapse at an unscheduled visit will be made by the blinded EDSS examiner, who will perform the EDSS and only then receive information about recent clinical history.