Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial
Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial
FDA-approved multiple sclerosis (MS) disease-modifying therapies (DMTs) target the relapsing
 phase of MS but have minimal impact once the progressive phase has begun. It is unclear if,
 in the relapsing phase, there is an advantage of early aggressive therapy with respect to
 preventing long-term disability. The infectious risks and other complications associated with
 higher-efficacy treatments highlight the need to quantify their effectiveness in preventing
 disability.

 The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic,
 randomized controlled trial that has two primary aims: 1) to evaluate, jointly and
 independently among patients deemed at higher risk vs. lower risk for disability
 accumulation, whether an "early aggressive" therapy approach, versus starting with a
 traditional, first-line therapy, influences the intermediate-term risk of disability, and 2)
 to evaluate if, among patients deemed at lower risk for disability who start on first-line MS
 therapies but experience breakthrough disease, those who switch to a higher-efficacy versus a
 new first-line therapy have different intermediate-term risk of disability.
FDA-approved multiple sclerosis (MS) disease-modifying therapies (DMTs) target the relapsing
 phase of MS but have minimal impact once the progressive phase has begun. It is unclear if,
 in the relapsing phase, there is an advantage of early aggressive therapy with respect to
 preventing long-term disability. The infectious risks and other complications associated with
 higher-efficacy treatments highlight the need to quantify their effectiveness in preventing
 disability.

 The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic,
 randomized controlled trial that has two primary aims: 1) to evaluate, jointly and
 independently among patients deemed at higher risk vs. lower risk for disability
 accumulation, whether an "early aggressive" therapy approach, versus starting with a
 traditional, first-line therapy, influences the intermediate-term risk of disability, and 2)
 to evaluate if, among patients deemed at lower risk for disability who start on first-line MS
 therapies but experience breakthrough disease, those who switch to a higher-efficacy versus a
 new first-line therapy have different intermediate-term risk of disability.

 Hypotheses/Objectives: The main hypothesis is that intermediate-term disability will be
 reduced by earlier use of higher-efficacy medications. Additional objectives include a)
 evaluating the magnitude of the treatment effect in patients deemed to be at higher risk
 versus lower risk of longer-term disability (we hypothesize that the effect size will be
 greater in the former group) and b) evaluating if, among those without indications of a high
 risk of longer-term disability, breakthrough disease can be successfully managed by switching
 to a different first-line therapy or if escalation is required at that time (we hypothesize
 that switching to a higher-efficacy therapy will be more effective in preventing disability
 in this group).

 There is a great unmet need to identify the most appropriate treatment strategy for people
 with MS, especially early in the disease course when it may be possible to maximize an
 individual's chance for preventing long-term disability. There is a paucity of evidence-based
 guidelines to help clinicians, patients, and payers determine which treatment strategy is
 best for an individual with MS. Making treatment decisions is a daunting task, and the
 individualized benefit-risk assessment becomes increasingly difficult as new therapies
 emerge. Without the availability of direct comparative trials, clinicians and patients are
 forced to scrutinize observational studies that only provide basic insights into what may be
 the best treatment path moving forward. It is equally challenging to define what constitutes
 a suboptimal response to a DMT for an individual patient. Clinicians lack guidance on when to
 switch therapies and whether to consider a different first-line or if clinicians should
 escalate immediately to higher-efficacy therapies, so further consensus is needed to
 determine the optimal time to switch therapies and escalate therapy if an individual is on a
 first-line therapy from the start. The TREAT-MS trial will help inform patients and the
 broader health care community on whether patients would most benefit from early, possibly
 more risky aggressive therapy or if starting with a less aggressive (and, often, less risky)
 therapy, followed by a switch if breakthrough disease occurs, is warranted. In addition, this
 study may help identify specific patient populations and/or short-term clinical and
 paraclinical biomarkers that are strongly predictive of long-term disability that can ensue
 from MS.

 Accrual of sustained disability is the most feared complication for people with MS, and the
 patient's own perception of their well-being or ill-being has a profound impact on their
 quality of life. The heterogeneity and unpredictability of MS, along with lack of agreed upon
 treatment guidelines, augments this fear, leading to a significant negative impact on quality
 of life. Even patients who are deemed to have "mild" MS experience a significant negative
 impact on their health-related quality of life that is similar in magnitude to what patients
 with other severe chronic conditions (i.e., congestive heart failure and chronic obstructive
 pulmonary disease) report. An extremely important goal for any intervention is to help
 improve or maintain a high quality of life; therefore, in addition to classic clinical
 endpoints (e.g. slowing disability progression), the TREAT-MS trial will capture several
 important and meaningful PROs that will shed light on what treatment strategies may be the
 best from a patient-centered perspective.

 COVID-19 Related Substudy:

 Since early 2020, the coronavirus disease 2019 (COVID-19) pandemic has caused clinical care
 and research disruptions nationwide, including for patients enrolled in the TREAT-MS trial.
 Many patients with MS, as well as their clinicians, are fearful that MS or the MS therapy
 they are using may increase the risk or severity of COVID-19 infection. Whether a person with
 early MS is more likely to experience more severe COVID-19 if treated with a higher-efficacy
 therapy is not known. Further, whether COVID-19-induced disruptions in therapy or other
 clinical care increase MS disease activity or MS symptoms is not clear but is relevant,
 particularly since greater MS activity in the early therapeutic course is associated in
 observational studies with worse long-term outcomes. Moreover, it is unclear if pre-pandemic
 anxiety and depression, common comorbidities in people with MS, contribute to decisions to
 delay care, overall or differently depending on therapeutic strategy (higher-efficacy vs.
 traditional). TREAT-MS provides an optimal cohort in which to investigate the effect of the
 COVID-19 pandemic on MS outcomes.

 COVID-19 Substudy Aim 1. To evaluate if patients enrolled in TREAT-MS delayed or altered
 their disease-modifying therapy schedule or other MS care, and whether such alterations are
 associated with a greater degree of breakthrough inflammatory disease activity or the
 development of new (or worsening baseline) MS symptoms.

 COVID-19 Substudy Aim 2: To evaluate if patients with MS treated with higher-efficacy, versus
 traditional, therapies differ in the risk of severe COVID-19 infection, defined as requiring
 hospitalization (with or without intubation) or mortality due to COVID-19.
Inclusion Criteria:

 -  Aged 18-60 years

 -  Meets 2017 McDonald criteria for relapsing-remitting MS [patients with clinically
 isolated syndrome (CIS) are not eligible]

 -  Must be EITHER John Cunningham (JC) virus antibody negative or low positive (index
 antibody titer <0.9), OR negative for: Hepatitis B and C, tuberculosis

 -  HIV negative

 -  No chemotherapy in past year; if patient has prior history of chemotherapy or
 malignancy, documentation in chart explaining why potential risks of higher-efficacy
 therapy are justified

 Exclusion Criteria:

 -  Prior treatment with rituximab, ocrelizumab, ofatumumab, alemtuzumab, mitoxantrone or
 cladribine

 -  Prior treatment with any other MS DMT for more than 6 months

 -  Prior treatment with experimental aggressive therapies (e.g., T-cell vaccine, total
 lymphoid radiation, stem cells)

 -  Treatment with teriflunomide within past 2 years (even for ≤ 6 months), unless rapid
 wash out done (i.e., with cholestyramine or activated charcoal)

 -  Treatment in the past 6 months with any MS DMT

 -  Prior treatment with any other investigational immune-modulating /suppressing drug for
 MS not listed above

 -  Pregnant or breast-feeding

 -  Women of child-bearing age who are planning or strongly considering conception during
 the study time frame