A Pragmatic Trial to Evaluate the Intermediate-term Effects of Early, Aggressive Versus Escalation Therapy in People With Multiple Sclerosis

Brief Summary

Detailed Description

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.

Primary Outcomes

Secondary Outcomes

• Patient-Determined Disease Steps (PDDS)(up to 99 months)
• Multiple Sclerosis Functional Composite (MSFC) Composite Score(up to 99 months)
• Timed 25 Foot Walk Test(up to 99 months)
• Nine-hole Peg Test(up to 99 months)
• Paced Auditory Serial Addition Test (PASAT)(up to 99 months)
• Low contrast visual acuity(up to 99 months)
• Patient-reported incomplete relapse recovery(up to 99 months)
• Neurologic exam-based incomplete relapse recovery(up to 99 months)
• Cognition using Symbol Digit Modality Test (SDMT)(up to 99 months)
• Multiple Sclerosis Impact Scale (MSIS-29)(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Anxiety Subscale(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Depression Subscale(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Fatigue Subscale(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Upper Extremity Function(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Lower Extremity Function(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Cognitive Function(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Positive Affect/Well-being(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Sleep Disturbance(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Ability to Participate in Social Roles and Activities(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Satisfaction with Social Roles and Activities(up to 99 months)
• Quality of Life in Neurological Disorders (Neuro-QoL): Stigma(up to 99 months)
• Employment status(up to 99 months)
• Marital status(up to 99 months)
• Serious Adverse Events (SAEs)(up to 99 months)
• Adverse event resulting in a decision to change disease-modifying therapy(up to 99 months)
• Severe COVID-19 Infection(up to 48 weeks from enrollment into COVID-19 related substudy)