Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

— TREAT-MS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03500328
• Other study ID #: IRB00143534
• Status: Recruiting
• Phase: N/A
• Start date: May 2, 2018
• Est. completion date: August 1, 2025

Study information

• Verified date: February 2024
• Source: Johns Hopkins University
• Contact: Sandra Cassard, ScD
• Phone: 443-287-4353
• Email: scassar1[@]jhmi.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 900
• Est. completion date: August 1, 2025
• Est. primary completion date: August 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Other:
• Natalizumab, Alemtuzumab, Ocrelizumab, Rituximab, Cladribine, Ofatumumab, Ublituximab-xiiy
Early Aggressive Therapy
• Glatiramer acetate, Interferons (intramuscular, subcutaneous, pegylated) Teriflunomide, Fumarates (dimethyl, diroximel, monomethyl) Fingolimod, Siponimod, Ozanimod, Ponesimod
Traditional Therapy

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland, Baltimore	Baltimore	Maryland
United States	Billings Clinic	Billings	Montana
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The University of Vermont and State Agricultural College	Burlington	Vermont
United States	CommonSpirit Health Research Institute	Carmichael	California
United States	Novant Health Neurology and Sleep	Charlotte	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Blacksburg Neurology	Christiansburg	Virginia
United States	University of Cincinnati	Cincinnati	Ohio
United States	OhioHealth Research Institute	Columbus	Ohio
United States	Baylor Scott and White Health	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Geisinger Clinic	Danville	Pennsylvania
United States	Wayne State University	Detroit	Michigan
United States	University of Florida	Gainesville	Florida
United States	Advanced Neurology Specialists	Great Falls	Montana
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	The University of Kansas Medical Center (KUMC)	Kansas City	Kansas
United States	RWJBarnabas Health Multiple Sclerosis Comprehensive Care Center	Livingston	New Jersey
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of California, Los Angeles	Los Angeles	California
United States	Norton Neurology MS Services	Louisville	Kentucky
United States	University of Louisville	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	The University of South Alabama	Mobile	Alabama
United States	Vanderbilt Comprehensive MS Center	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York University School of Medicine	New York	New York
United States	Christiana Care Health Services, Inc.	Newark	Delaware
United States	Neurology Consultants of Tidewater	Norfolk	Virginia
United States	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	St. Joseph's Hospital & Medical Center - Barrow Neurological Institute	Phoenix	Arizona
United States	Allegheny Health Network Research Institute	Pittsburgh	Pennsylvania
United States	Providence Health and Services - Oregon	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Central Texas Neurology Consultants	Round Rock	Texas
United States	University of Utah	Salt Lake City	Utah
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	Swedish Health Services	Seattle	Washington
United States	University of Washington	Seattle	Washington
United States	Stony Brook University	Stony Brook	New York
United States	University of South Florida Health	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Johns Hopkins University	National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Brain Magnetic Resonance Imaging (MRI) evidence of neurodegeneration	Changes in brain MRI measures of neurodegeneration, including whole brain and normalized gray matter volumes, cortical thickness, subcortical gray matter compartment volumes, and measures of T2 lesion burden.	From 6 months after starting 1st therapy up to 87 months after randomization
Other	Number of relapses	The number of relapses (new or worsening neurologic symptoms lasting for 24 hours or more in the absence of fever).	up to 87 months
Other	Number of new brain lesions on MRI	The number of new/enlarging T2-weighted hyperintense lesions and T1-weighted hypointense lesions will be quantified on each MRI scan	up to 87 months
Other	Retinal layer thickness by Optical Coherence Tomography (OCT)	Retinal nerve fiber layer and ganglion cell/inner plexiform thickness will be evaluated among patients at centers and offices with access to OCT as standard of care	up to 87 months
Other	Number of new medications, escalated dosage of medications, and non-pharmacologic interventions for MS-related symptoms	As an exploratory outcome, the number of newly-prescribed or dose-escalated medications used for treating MS symptoms (including pain, weakness, numbness/tingling, trouble walking, cognitive problems, fatigue, depression, anxiety, visual dysfunction, spasticity, vertigo, or bladder/bowel/sexual dysfunction) during the trial will be evaluated using the electronic health record. In addition, non-pharmacologic interventions (and referrals to other healthcare providers) for symptom management will also be captured.	up to 87 months
Primary	Time to sustained disability progression	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 > 1.0 point if baseline EDSS is < 5.5 or of > 0.5 if baseline EDSS is > 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.	From date of randomization until the date of first documented sustained disability progression, up to 75 months
Primary	Change in Overall Burden of MS	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.	up to 48 weeks from enrollment into COVID-19 related substudy
Secondary	Patient-Determined Disease Steps (PDDS)	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).	up to 87 months
Secondary	Multiple Sclerosis Functional Composite (MSFC) Composite Score	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.	up to 87 months
Secondary	Timed 25 Foot Walk Test	Time taken to complete the timed 25 foot walk test, measured twice in units of seconds, will be averaged and evaluated.	up to 87 months
Secondary	Nine-hole Peg Test	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.	up to 87 months
Secondary	Paced Auditory Serial Addition Test (PASAT)	The paced auditory serial addition test that measures processing speed will be administered once; number and percent correct will be evaluated.	up to 87 months
Secondary	Low contrast visual acuity	Low-contrast letter acuity (binocular, 2.5% contrast Sloan charts)	up to 87 months
Secondary	Patient-reported incomplete relapse recovery	Among participants identified to have a relapse, relapse recovery will be defined as complete or incomplete based on patient self-report.	up to 87 months
Secondary	Neurologic exam-based incomplete relapse recovery	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).	up to 87 months
Secondary	Cognition using Symbol Digit Modality Test (SDMT)	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.	up to 87 months
Secondary	Multiple Sclerosis Impact Scale (MSIS-29)	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.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Anxiety Subscale	The Anxiety Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Depression Subscale	The Depression Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Fatigue Subscale	The Fatigue Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Upper Extremity Function	The Upper Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Lower Extremity Function	The Lower Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Cognitive Function	The Cognitive Function Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Positive Affect/Well-being	The Positive Affect/Well-being Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Sleep Disturbance	The Sleep Disturbance Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Ability to Participate in Social Roles and Activities	The Ability to Participate in Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Satisfaction with Social Roles and Activities	The Satisfaction with Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Quality of Life in Neurological Disorders (Neuro-QoL): Stigma	The Stigma Subscale of Neuro-QoL will be administered as an electronic PRO.	up to 87 months
Secondary	Employment status	The incidence of change in employment to "disabled" or "looking for work, unemployed," will be evaluated for all participants through an electronic PRO.	up to 87 months
Secondary	Marital status	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.	up to 87 months
Secondary	Serious Adverse Events (SAEs)	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)	up to 87 months
Secondary	Adverse event resulting in a decision to change disease-modifying therapy	Adverse events meaningful enough to lead to medication discontinuation	up to 87 months
Secondary	Severe COVID-19 Infection	Severe COVID-19 infection will be defined as an outcome of "hospitalization or death" due to confirmed or suspected COVID-19 infection	up to 48 weeks from enrollment into COVID-19 related substudy