Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial
- Conditions
- Multiple Sclerosis, Relapsing-Remitting
- Interventions
- Other: Natalizumab, Alemtuzumab, Ocrelizumab, Rituximab, Cladribine, Ofatumumab, Ublituximab-xiiyOther: Glatiramer acetate, Interferons (intramuscular, subcutaneous, pegylated) Teriflunomide, Fumarates (dimethyl, diroximel, monomethyl) Fingolimod, Siponimod, Ozanimod, Ponesimod
- Registration Number
- NCT03500328
- Lead Sponsor
- Johns Hopkins University
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 900
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Early Aggressive Therapy Natalizumab, Alemtuzumab, Ocrelizumab, Rituximab, Cladribine, Ofatumumab, Ublituximab-xiiy 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 IV every 4 wks * Alemtuzumab (Lemtrada), 12 mg IV daily (QD) for 5 days; 1 year later: 12 mg IV QD for 3 days * Ocrelizumab (Ocrevus), 300 mg IV every 2 wks (for 2 doses) at initiation; then 600 mg IV every 6 mths * Rituximab (Rituxan), 1000 mg IV every 2 wks (for 2 doses); may repeat every 16-24 wks * Cladribine (Mavenclad), 3.5 mg per kg body weight orally divided into 2 yrly treatment courses (1.75 mg per kg body weight each year); each yrly treatment course is divided into 2 treatment cycles; administer cycle dosage as 1 or 2 tablets QD over 4-5 consecutive days * Ofatumumab (Kesimpta), 20 mg SC wkly for wks 0, 1 and 2; 20 mg subcutaneously (SC) monthly starting at wk 4 * Ublituximab-xiiy (Briumvi), 150 mg IV (first dose); 450 mg IV 2 wks after first dose; 450 mg IV q 24 wks Traditional Therapy Glatiramer acetate, Interferons (intramuscular, subcutaneous, pegylated) Teriflunomide, Fumarates (dimethyl, diroximel, monomethyl) Fingolimod, Siponimod, Ozanimod, Ponesimod 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 SC daily, or 40 mg SC 3 times a wk * Intramuscular (IM) interferon (Avonex), 30 mcg IM weekly * SC interferon (Betaseron, Extavia, Rebif), 0.25 mg SC every other day (Betaseron, Extavia); 44 mcg SC 3 times a wk (Rebif) * Pegylated interferon (Plegridy), 125 mcg SC every 14 days * Teriflunomide (Aubagio), 14 mg PO QD * Dimethyl fumarate (Tecfidera and generics), 240 mg PO twice a day (BID) * Diroximel fumarate (Vumerity), 462 mg PO BID * Monomethyl fumarate (Bafiertam), 190 mg PO BID * Fingolimod (Gilenya and generics), 0.5 mg PO QD * Siponimod (Mayzent), 1 mg PO QD or 2 mg PO QD * Ozanimod (Zeposia), 0.92 mg PO QD * Ponesimod (Ponvory), 20 mg PO QD * Fingolimod ODT (Tascenso), 0.25 mg PO QD if \<=40 kg; 0.5 mg PO QD if \> 40 kg
- Primary Outcome Measures
Name Time Method Time to sustained disability progression From date of randomization until the date of first documented sustained disability progression, up to 99 months Time to sustained disability progression is measured by the Expanded Disability Status Scale plus (EDSS+): a composite endpoint that includes EDSS change (change at any 6 month time point of \> or = 1.0 point if baseline EDSS is \< or = 5.5 or of \> or = 0.5 if baseline EDSS is \> or = 6.0, that is sustained 6 months later) OR 20% worsening on either of two specific components of the Multiple Sclerosis Functional Composite (MSFC), the timed 25-foot walk test (T25FWT) and the nine hole peg test (9HPT) that is sustained 6 months later.
Change in Overall Burden of MS up to 48 weeks from enrollment into COVID-19 related substudy The change in overall burden of MS will be defined for the COVID-19 related substudy as the occurrence of breakthrough disease (relapses or new MRI activity) or the development of new (or worsening baseline) MS symptoms, which are (for TREAT-MS) and will continue to be (during the substudy) documented at clinical visits, whether in-person or on tele-visits.
- Secondary Outcome Measures
Name Time Method Patient-Determined Disease Steps (PDDS) up to 99 months PDDS is a self-assessment scale of disability due to MS on a scale from 0 to 8 and will be administered as an electronic patient-reported outcome (PRO).
Multiple Sclerosis Functional Composite (MSFC) Composite Score up to 99 months The MSFC consists of the timed 25 foot walk test, the 9-hole peg test, and the Paced Auditory Serial Addition Test (PASAT) and a composite MSFC z-score will be evaluated.
Timed 25 Foot Walk Test up to 99 months Time taken to complete the timed 25 foot walk test, measured twice in units of seconds, will be averaged and evaluated.
Nine-hole Peg Test up to 99 months Time taken to complete the nine-hole peg test, measured twice for each hand (dominant and non-dominant) in units of seconds, will be averaged for each hand and evaluated.
Paced Auditory Serial Addition Test (PASAT) up to 99 months The paced auditory serial addition test that measures processing speed will be administered once; number and percent correct will be evaluated.
Low contrast visual acuity up to 99 months Low-contrast letter acuity (binocular, 2.5% contrast Sloan charts)
Patient-reported incomplete relapse recovery up to 99 months Among participants identified to have a relapse, relapse recovery will be defined as complete or incomplete based on patient self-report.
Neurologic exam-based incomplete relapse recovery up to 99 months Among participants identified to have a relapse, relapse recovery will be defined as complete or incomplete based on neurologic examination (those who have increased Functional System scores, corresponding to the relapse symptoms, of 1.0 point or greater for at least 6 months after the relapse onset, without subsequent accrual of worsening in that same Functional System (e.g. more indicative of progression), will be considered to have incomplete relapse recovery).
Cognition using Symbol Digit Modality Test (SDMT) up to 99 months The SDMT is commonly used in MS to assess processing speed and will be administered orally and used to evaluate changes in cognition throughout the study.
Multiple Sclerosis Impact Scale (MSIS-29) up to 99 months The MSIS-29 will be used to evaluate the impact of MS on the participants and will be administered as an electronic PRO.Multiple Sclerosis Impact Scale (MSIS-29) is an instrument used for measuring the physical (20 items) and psychological (nine items) impact of multiple sclerosis.
Quality of Life in Neurological Disorders (Neuro-QoL): Anxiety Subscale up to 99 months The Anxiety Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Depression Subscale up to 99 months The Depression Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Fatigue Subscale up to 99 months The Fatigue Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Upper Extremity Function up to 99 months The Upper Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Lower Extremity Function up to 99 months The Lower Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Cognitive Function up to 99 months The Cognitive Function Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Positive Affect/Well-being up to 99 months The Positive Affect/Well-being Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Sleep Disturbance up to 99 months The Sleep Disturbance Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Ability to Participate in Social Roles and Activities up to 99 months The Ability to Participate in Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Satisfaction with Social Roles and Activities up to 99 months The Satisfaction with Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.
Quality of Life in Neurological Disorders (Neuro-QoL): Stigma up to 99 months The Stigma Subscale of Neuro-QoL will be administered as an electronic PRO.
Employment status up to 99 months The incidence of change in employment to "disabled" or "looking for work, unemployed," will be evaluated for all participants through an electronic PRO.
Marital status up to 99 months Incident divorce or separation, among those who previously were married or in a domestic partnership, will be evaluated for all participants through an electronic PRO.
Serious Adverse Events (SAEs) up to 99 months SAEs (clinically significant infections, malignancies, or the development of other serious comorbidities, as well as unplanned hospitalizations \[for non-elective issues, excluding MS relapse\] and death)
Adverse event resulting in a decision to change disease-modifying therapy up to 99 months Adverse events meaningful enough to lead to medication discontinuation
Severe COVID-19 Infection up to 48 weeks from enrollment into COVID-19 related substudy Severe COVID-19 infection will be defined as an outcome of "hospitalization or death" due to confirmed or suspected COVID-19 infection
Trial Locations
- Locations (47)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
The University of South Alabama
🇺🇸Mobile, Alabama, United States
St. Joseph's Hospital & Medical Center - Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
CommonSpirit Health Research Institute
🇺🇸Carmichael, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
University of California, San Diego
🇺🇸San Diego, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Christiana Care Health Services, Inc.
🇺🇸Newark, Delaware, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Miami
🇺🇸Miami, Florida, United States
University of South Florida Health
🇺🇸Tampa, Florida, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
The University of Kansas Medical Center (KUMC)
🇺🇸Kansas City, Kansas, United States
Norton Neurology MS Services
🇺🇸Louisville, Kentucky, United States
University of Maryland, Baltimore
🇺🇸Baltimore, Maryland, United States
The Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University of Massachusetts Medical School
🇺🇸Worcester, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Billings Clinic
🇺🇸Billings, Montana, United States
Advanced Neurology Specialists
🇺🇸Great Falls, Montana, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
New York University School of Medicine
🇺🇸New York, New York, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
OhioHealth Research Institute
🇺🇸Columbus, Ohio, United States
Oklahoma Medical Research Foundation
🇺🇸Oklahoma City, Oklahoma, United States
Providence Health and Services - Oregon
🇺🇸Portland, Oregon, United States
Geisinger Clinic
🇺🇸Danville, Pennsylvania, United States
Allegheny Health Network Research Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Vanderbilt Comprehensive MS Center
🇺🇸Nashville, Tennessee, United States
Baylor Scott and White Health
🇺🇸Dallas, Texas, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Central Texas Neurology Consultants
🇺🇸Round Rock, Texas, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
The University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Blacksburg Neurology
🇺🇸Christiansburg, Virginia, United States
Neurology Consultants of Tidewater
🇺🇸Norfolk, Virginia, United States
Swedish Health Services
🇺🇸Seattle, Washington, United States
University of Washington
🇺🇸Seattle, Washington, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States