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.

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.

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, 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