Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial

NCT03500328 | Active Not Recruiting DMC

• 1 other identifier: IRB00143534
• Study Type: interventional
• Target: 900
• Locations: 1 country
• Sites: 47

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Outcome Measures

Primary Outcomes (2)

• 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 \> 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.

  From date of randomization until the date of first documented sustained disability progression, up to 99 months

• 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 Outcomes (26)

• 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

Other Outcomes (5)

• Brain Magnetic Resonance Imaging (MRI) evidence of neurodegeneration

  From 6 months after starting 1st therapy up to 99 months after randomization

• Number of relapses

  up to 99 months

• Number of new brain lesions on MRI

  up to 99 months

Study Arms (2)

Early Aggressive Therapy

ACTIVE COMPARATOR

Early Aggressive Therapy choices and maximum allowable doses: * Natalizumab/natalizumab-sztn (Tysabri/Tyruko), 300 mg IV q 4 wks * Alemtuzumab (Lemtrada), 12 mg IV daily (QD) for 5 days; 1 yr later: 12 mg IV QD for 3 days * Ocrelizumab (Ocrevus), 300 mg IV every 2 wks (for 2 doses) at initiation; 600 mg IV q 6 mths * Rituximab/rituximab biosimilars (Rituxan/Riabni/Truxima/Ruxience), 1000 mg IV every 2 wks (for 2 doses); may repeat q 16-24 wks * Cladribine (Mavenclad), 3.5 mg per kg body wt orally divided into 2 yrly tmt courses (1.75 mg per kg body wt each yr); yrly tmt course divided into 2 tmt cycles; administer cycle dose as 1-2 tablets QD over 4-5 days * Ofatumumab (Kesimpta), 20 mg SC wkly for wks 0, 1 and 2; 20 mg subcutaneously (SC) mthly starting at wk 4 * Ublituximab-xiiy (Briumvi), 150 mg IV (1st dose); 450 mg IV 2 wks after first dose; 450 mg IV q 24 wks * Ocrelizumab and hyaluronidase-ocsq (Ocrevus Zunovo), 920 mg ocrelizumab and 23,000 U hyaluronidase SC q 6 months

Other: Natalizumab/natalizumab-sztn, Alemtuzumab, Ocrelizumab, Rituximab/rituximab-arrx/rituximab-abbs/rituximab-pvvr, Cladribine, Ofatumumab, Ublituximab-xiiy, Ocrelizumab and hyaluronidase-ocsq

Traditional Therapy

ACTIVE COMPARATOR

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

Other: Glatiramer acetate, Interferons (intramuscular, subcutaneous, pegylated) Teriflunomide, Fumarates (dimethyl, diroximel, monomethyl) Fingolimod, Siponimod, Ozanimod, Ponesimod

Interventions

Natalizumab/natalizumab-sztn, Alemtuzumab, Ocrelizumab, Rituximab/rituximab-arrx/rituximab-abbs/rituximab-pvvr, Cladribine, Ofatumumab, Ublituximab-xiiy, Ocrelizumab and hyaluronidase-ocsq OTHER

Early Aggressive Therapy

Also known as: Tysabri, Lemtrada, Ocrevus, Rituxan/Riabni/Truxima/Ruxience, Mavenclad, Kesimpta, Briumvi, Ocrevus Zunovo

Early Aggressive Therapy

Glatiramer acetate, Interferons (intramuscular, subcutaneous, pegylated) Teriflunomide, Fumarates (dimethyl, diroximel, monomethyl) Fingolimod, Siponimod, Ozanimod, Ponesimod OTHER

Traditional Therapy

Also known as: Copaxone, Glatopa, Avonex, Betaseron, Extavia, Rebif, Plegridy, Aubagio, Tecfidera, Vumerity, Bafiertam, Gilenya, Mayzent, Zeposia, Ponvory, Tascenso

Traditional Therapy

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• Patient-Centered Outcomes Research Institute: collaborator
• National Multiple Sclerosis Society: collaborator

Study Sites (47)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

The University of South Alabama

Mobile, Alabama, 36604, United States

Location

St. Joseph's Hospital & Medical Center - Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

CommonSpirit Health Research Institute

Carmichael, California, 95608, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

University of California, San Diego

San Diego, California, 92037, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

Christiana Care Health Services, Inc.

Newark, Delaware, 19713, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

University of South Florida Health

Tampa, Florida, 33612, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

The University of Kansas Medical Center (KUMC)

Kansas City, Kansas, 66160, United States

Location

Norton Neurology MS Services

Louisville, Kentucky, 40207, United States

Location

University of Maryland, Baltimore

Baltimore, Maryland, 21201, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Massachusetts Medical School

Worcester, Massachusetts, 01655, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Billings Clinic

Billings, Montana, 59101, United States

Location

Advanced Neurology Specialists

Great Falls, Montana, 59405, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45219, United States

Location

OhioHealth Research Institute

Columbus, Ohio, 43214, United States

Location

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, 73104, United States

Location

Providence Health and Services - Oregon

Portland, Oregon, 97225, United States

Location

Geisinger Clinic

Danville, Pennsylvania, 17822, United States

Location

Allegheny Health Network Research Institute

Pittsburgh, Pennsylvania, 15212, United States

Location

Vanderbilt Comprehensive MS Center

Nashville, Tennessee, 37215, United States

Location

Baylor Scott and White Health

Dallas, Texas, 75246, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-8806, United States

Location

Central Texas Neurology Consultants

Round Rock, Texas, 78681, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

The University of Vermont and State Agricultural College

Burlington, Vermont, 05405, United States

Location

Blacksburg Neurology

Christiansburg, Virginia, 24073, United States

Location

Neurology Consultants of Tidewater

Norfolk, Virginia, 23502, United States

Location

Swedish Health Services

Seattle, Washington, 98122, United States

Location

University of Washington

Seattle, Washington, 98133, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Kwon S, Sillau S, Corboy JR, Nair KV, Carlson AM. Shifting patterns of multiple sclerosis treatment in a highly prevalent United States population. Ann Clin Transl Neurol. 2024 Jun;11(6):1526-1534. doi: 10.1002/acn3.52069. Epub 2024 Apr 23.

  PMID: 38654416 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Natalizumab; Alemtuzumab; ocrelizumab; Cladribine; ofatumumab; Rituximab; Glatiramer Acetate; Interferons; Injections, Intramuscular; Injections, Subcutaneous; teriflunomide; Fumarates; Fingolimod Hydrochloride; siponimod; ozanimod; ponesimod; Coat Protein Complex I; Interferon beta-1a; Interferon beta-1b; peginterferon beta-1a; Dimethyl Fumarate; diroximel fumarate; monomethyl fumarate

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Murine-Derived; Peptides; Cytokines; Intercellular Signaling Peptides and Proteins; Biological Factors; Injections; Drug Administration Routes; Drug Therapy; Therapeutics; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Sphingosine; Amino Alcohols; Alcohols; Propylene Glycols; Glycols; Amines; Vesicular Transport Proteins; Membrane Proteins; Interferon-beta; Interferon Type I

Study Officials

• Ellen M. Mowry, MD, MCR

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Scott D. Newsome, DO

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2018
• First Posted: April 18, 2018
• Study Start: May 2, 2018
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: October 14, 2025

Record last verified: 2025-10

Locations

US (47)