Clinical trial NCT03500328: Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial
Official title: A Pragmatic Trial to Evaluate the Intermediate-term Effects of Early, Aggressive Versus Escalation Therapy in People With Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Multiple Sclerosis, Relapsing-Remitting
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
name: National Multiple Sclerosis Society
First posted: 2018-04-18
Enrollment: 900
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to sustained disability progression
timeFrame: From date of randomization until the date of first documented sustained disability progression, up to 99 months
measure: Change in Overall Burden of MS
timeFrame: up to 48 weeks from enrollment into COVID-19 related substudy
Secondary outcomes:
measure: Patient-Determined Disease Steps (PDDS)
timeFrame: up to 99 months
measure: Multiple Sclerosis Functional Composite (MSFC) Composite Score
timeFrame: up to 99 months
measure: Timed 25 Foot Walk Test
timeFrame: up to 99 months
measure: Nine-hole Peg Test
timeFrame: up to 99 months
measure: Paced Auditory Serial Addition Test (PASAT)
timeFrame: up to 99 months
measure: Low contrast visual acuity
timeFrame: up to 99 months
measure: Patient-reported incomplete relapse recovery
timeFrame: up to 99 months
measure: Neurologic exam-based incomplete relapse recovery
timeFrame: up to 99 months
measure: Cognition using Symbol Digit Modality Test (SDMT)
timeFrame: up to 99 months
measure: Multiple Sclerosis Impact Scale (MSIS-29)
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Anxiety Subscale
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Depression Subscale
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Fatigue Subscale
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Upper Extremity Function
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Lower Extremity Function
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Cognitive Function
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Positive Affect/Well-being
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Sleep Disturbance
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Ability to Participate in Social Roles and Activities
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Satisfaction with Social Roles and Activities
timeFrame: up to 99 months
measure: Quality of Life in Neurological Disorders (Neuro-QoL): Stigma
timeFrame: up to 99 months
measure: Employment status
timeFrame: up to 99 months
measure: Marital status
timeFrame: up to 99 months
measure: Serious Adverse Events (SAEs)
timeFrame: up to 99 months
measure: Adverse event resulting in a decision to change disease-modifying therapy
timeFrame: up to 99 months
measure: Severe COVID-19 Infection
timeFrame: up to 48 weeks from enrollment into COVID-19 related substudy
Other outcomes:
measure: Brain Magnetic Resonance Imaging (MRI) evidence of neurodegeneration
timeFrame: From 6 months after starting 1st therapy up to 99 months after randomization
measure: Number of relapses
timeFrame: up to 99 months
measure: Number of new brain lesions on MRI
timeFrame: up to 99 months
measure: Retinal layer thickness by Optical Coherence Tomography (OCT)
timeFrame: up to 99 months
measure: Number of new medications, escalated dosage of medications, and non-pharmacologic interventions for MS-related symptoms
timeFrame: up to 99 months
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mobile
country: United States
facility: The University of South Alabama
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital & Medical Center - Barrow Neurological Institute
state: Arizona
city: Carmichael
country: United States
facility: CommonSpirit Health Research Institute
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Newark
country: United States
facility: Christiana Care Health Services, Inc.
state: Delaware
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida Health
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: The University of Kansas Medical Center (KUMC)
state: Kansas
city: Louisville
country: United States
facility: Norton Neurology MS Services
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Great Falls
country: United States
facility: Advanced Neurology Specialists
state: Montana
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: OhioHealth Research Institute
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Medical Research Foundation
state: Oklahoma
city: Portland
country: United States
facility: Providence Health and Services - Oregon
state: Oregon
city: Danville
country: United States
facility: Geisinger Clinic
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Health Network Research Institute
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Comprehensive MS Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott and White Health
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Burlington
country: United States
facility: The University of Vermont and State Agricultural College
state: Vermont
city: Christiansburg
country: United States
facility: Blacksburg Neurology
state: Virginia
city: Norfolk
country: United States
facility: Neurology Consultants of Tidewater
state: Virginia
city: Seattle
country: United States
facility: Swedish Health Services
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Johns Hopkins University
name: Ellen M. Mowry, MD, MCR
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Scott D. Newsome, DO
role: PRINCIPAL_INVESTIGATOR
References: