Purpose

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.

Condition

Eligibility

Eligible Ages
Between 18 Years and 60 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
N/A
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Single (Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Early Aggressive Therapy
Higher efficacy disease-modifying therapy (Early Aggressive Therapy) for treatment of multiple sclerosis Early Aggressive Therapy choices and maximum allowable doses: Natalizumab (Tysabri), 300 mg intravenously (IV) every 4 weeks Alemtuzumab (Lemtrada), 12 mg IV daily for 5 days; 1 year later: 12 mg IV daily for 3 days Ocrelizumab (Ocrevus), 300 mg IV every 2 weeks (for 2 doses) at initiation; subsequently, 600 mg IV every 6 months Rituximab (Rituxan), 1000 mg IV every 2 weeks (for 2 doses); may repeat every 16-24 weeks
  • Other: Early Aggressive Therapy or Traditional Therapy
    Participants will be stratified by whether they are at higher versus lower risk for long-term disability and then randomized 1:1 to a higher-efficacy versus a traditional, first-line disease-modifying therapy (DMT) class.
Active Comparator
Traditional Therapy
First-line disease-modifying therapy (Traditional Therapy) for treatment of multiple sclerosis Traditional Therapy choices and maximum allowable doses: Glatiramer acetate (Copaxone, Glatopa, and other generics), 20 mg subcutaneously (SC) daily, or 40 mg SC three times a week Intramuscular interferon (Avonex), 30 mcg intramuscularly (IM) weekly Subcutaneous interferon (Betaseron, Extavia, Rebif), 0.25 mg SC every other day (Betaseron, Extavia); 44 mcg SC three times a week (Rebif) Pegylated interferon (Plegridy), 125 mcg SC every 14 days Teriflunomide (Aubagio), 14 mg orally (PO) daily Dimethyl fumarate (Tecfidera), 240 mg PO twice a day Fingolimod (Gilenya), 0.5 mg PO daily
  • Other: Early Aggressive Therapy or Traditional Therapy
    Participants will be stratified by whether they are at higher versus lower risk for long-term disability and then randomized 1:1 to a higher-efficacy versus a traditional, first-line disease-modifying therapy (DMT) class.

Recruiting Locations

University of Maryland, Baltimore
Baltimore, Maryland 21201
Contact:
Kerry Naunton, RN, MSCN, CCRC
410-328-1885
knaunton@som.umaryland.edu

More Details

NCT ID
NCT03500328
Status
Recruiting
Sponsor
Johns Hopkins University

Study Contact

Sandra Cassard, ScD
443-287-4353
scassar1@jhmi.edu

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.