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Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial (TREAT-MS)

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ClinicalTrials.gov Identifier: NCT03500328
Recruitment Status : Recruiting
First Posted : April 17, 2018
Last Update Posted : October 15, 2018
Sponsor:
Collaborator:
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Other: Early Aggressive Therapy or Traditional Therapy Not Applicable

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pragmatic Trial to Evaluate the Intermediate-term Effects of Early, Aggressive Versus Escalation Therapy in People With Multiple Sclerosis
Actual Study Start Date : May 2, 2018
Estimated Primary Completion Date : October 31, 2022
Estimated Study Completion Date : October 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Time to sustained disability progression [ Time Frame: From date of randomization until the date of first documented sustained disability progression, up to 48 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 > 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.


Secondary Outcome Measures :
  1. Patient-Determined Disease Steps (PDDS) [ Time Frame: up to 54 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).

  2. Multiple Sclerosis Functional Composite (MSFC) Composite Score [ Time Frame: up to 48 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.

  3. Timed 25 Foot Walk Test [ Time Frame: up to 48 months ]
    Time taken to complete the timed 25 foot walk test, measured twice in units of seconds, will be averaged and evaluated.

  4. Nine-hole Peg Test [ Time Frame: up to 48 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.

  5. Paced Auditory Serial Addition Test (PASAT) [ Time Frame: up to 48 months ]
    The paced auditory serial addition test that measures processing speed will be administered once; number and percent correct will be evaluated.

  6. Low contrast visual acuity [ Time Frame: up to 48 months ]
    Low-contrast letter acuity (binocular, 2.5% contrast Sloan charts)

  7. Patient-reported incomplete relapse recovery [ Time Frame: up to 48 months ]
    Among participants identified to have a relapse, relapse recovery will be defined as complete or incomplete based on patient self-report.

  8. Neurologic exam-based incomplete relapse recovery [ Time Frame: up to 48 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).

  9. Cognition using Symbol Digit Modality Test (SDMT) [ Time Frame: up to 48 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.

  10. Multiple Sclerosis Impact Scale (MSIS-29) [ Time Frame: up to 48 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.

  11. Quality of Life in Neurological Disorders (Neuro-QoL): Anxiety Subscale [ Time Frame: up to 48 months ]
    The Anxiety Subscale of Neuro-QoL will be administered as an electronic PRO.

  12. Quality of Life in Neurological Disorders (Neuro-QoL): Depression Subscale [ Time Frame: up to 48 months ]
    The Depression Subscale of Neuro-QoL will be administered as an electronic PRO.

  13. Quality of Life in Neurological Disorders (Neuro-QoL): Fatigue Subscale [ Time Frame: up to 48 months ]
    The Fatigue Subscale of Neuro-QoL will be administered as an electronic PRO.

  14. Quality of Life in Neurological Disorders (Neuro-QoL): Upper Extremity Function [ Time Frame: up to 48 months ]
    The Upper Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.

  15. Quality of Life in Neurological Disorders (Neuro-QoL): Lower Extremity Function [ Time Frame: up to 48 months ]
    The Lower Extremity Function Subscale of Neuro-QoL will be administered as an electronic PRO.

  16. Quality of Life in Neurological Disorders (Neuro-QoL): Cognitive Function [ Time Frame: up to 48 months ]
    The Cognitive Function Subscale of Neuro-QoL will be administered as an electronic PRO.

  17. Quality of Life in Neurological Disorders (Neuro-QoL): Positive Affect/Well-being [ Time Frame: up to 48 months ]
    The Positive Affect/Well-being Subscale of Neuro-QoL will be administered as an electronic PRO.

  18. Quality of Life in Neurological Disorders (Neuro-QoL): Sleep Disturbance [ Time Frame: up to 48 months ]
    The Sleep Disturbance Subscale of Neuro-QoL will be administered as an electronic PRO.

  19. Quality of Life in Neurological Disorders (Neuro-QoL): Ability to Participate in Social Roles and Activities [ Time Frame: up to 48 months ]
    The Ability to Participate in Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.

  20. Quality of Life in Neurological Disorders (Neuro-QoL): Satisfaction with Social Roles and Activities [ Time Frame: up to 48 months ]
    The Satisfaction with Social Roles and Activities Subscale of Neuro-QoL will be administered as an electronic PRO.

  21. Quality of Life in Neurological Disorders (Neuro-QoL): Stigma [ Time Frame: up to 48 months ]
    The Stigma Subscale of Neuro-QoL will be administered as an electronic PRO.

  22. Employment status [ Time Frame: up to 48 months ]
    The incidence of change in employment to "disabled" or "looking for work, unemployed," will be evaluated for all participants through an electronic PRO.

  23. Marital status [ Time Frame: up to 48 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.

  24. Serious Adverse Events (SAEs) [ Time Frame: up to 48 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)

  25. Adverse event resulting in a decision to change disease-modifying therapy [ Time Frame: up to 48 months ]
    Adverse events meaningful enough to lead to medication discontinuation


Other Outcome Measures:
  1. Brain Magnetic Resonance Imaging (MRI) evidence of neurodegeneration [ Time Frame: From 6 months after starting 1st therapy up to 48 months after randomization ]
    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.

  2. Number of relapses [ Time Frame: up to 48 months ]
    The number of relapses (new or worsening neurologic symptoms lasting for 24 hours or more in the absence of fever).

  3. Number of new brain lesions on MRI [ Time Frame: up to 48 months ]
    The number of new/enlarging T2-weighted hyperintense lesions and T1-weighted hypointense lesions will be quantified on each MRI scan

  4. Retinal layer thickness by Optical Coherence Tomography (OCT) [ Time Frame: up to 48 months ]
    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

  5. Number of new medications, escalated dosage of medications, and non-pharmacologic interventions for MS-related symptoms [ Time Frame: up to 48 months ]
    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.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03500328


Contacts
Contact: Sandra Cassard, ScD 443-287-4353 scassar1@jhmi.edu
Contact: Madiha Qutab, MS 410-614-9201 mqutab1@jhmi.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
Contact: Christie Lowe    205-996-2980    christielowe@uabmc.edu   
Contact: Kerry Howard, RN, MSCN    205-934-1885    kdhoward@uabmc.edu   
Principal Investigator: William Meador, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Nisha R Revirajan, CCRC    415-502-7220    NishaRaj.Revirajan@ucsf.edu   
Principal Investigator: Emmanuelle L Waubant, MD, PhD         
United States, Delaware
Christiana Care Health Services, Inc. Recruiting
Newark, Delaware, United States, 19713
Contact: Kathleen Greenbaum, MSN, RN, CCRC, CDE    302-623-3844    kgreenbaum@christianacare.org   
Principal Investigator: Jason Silversteen, DO         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Contact: Victoria Hope    352-294-8948    Victoria.Hope@neurology.ufl.edu   
Contact: Jennifer Steshyn    352-273-9022    Jennifer.Steshyn@neurology.ufl.edu   
Principal Investigator: Tirisham Gyang, MD         
United States, Kansas
The University of Kansas Medical Center (KUMC) Recruiting
Kansas City, Kansas, United States, 66160
Contact: Lisa Schmidt, LPN    913-588-3968    LSCHMIDT@kumc.edu   
Principal Investigator: Sharon Lynch, MD         
United States, Kentucky
Norton Neurology MS Services Recruiting
Louisville, Kentucky, United States, 40207
Contact: Deborah Lockridge, RN, BSN, MSCN, CCRC    502-899-6417    Deborah.Lockridge@nortonhealthcare.org   
Principal Investigator: Geeta A Ganesh, MD, MPH         
United States, Maryland
The Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21287
Contact: Research coordinator       TREATMS@jhmi.edu   
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Jessica Sagen, MA    507-538-3761    Sagen.Jessica@mayo.edu   
Principal Investigator: W. Oliver Tobin, MB, BCh, BAO, PhD         
United States, Montana
Advanced Neurology Specialists Recruiting
Great Falls, Montana, United States, 59405
Contact: Laura Armstrong, LPN    406-455-2583    laurafarmstrong@ansresearch.com   
Principal Investigator: Dennis Dietrich, MD         
United States, New York
New York University School of Medicine Recruiting
New York, New York, United States, 10016
Contact: April Jacob, MS    929-455-5086    April.Jacob@nyumc.org   
Principal Investigator: Lana Zhovtis Ryerson, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Kaho Onomichi    212-305-9155    ko2418@cumc.columbia.edu   
Principal Investigator: Claire Riley, MD         
University of Rochester Medical Center Recruiting
Rochester, New York, United States, 14642
Contact: Paul DeRitis, RN    585-273-3688    Paul_DeRitis@URMC.Rochester.edu   
Principal Investigator: Andrew Goodman, MD         
United States, Vermont
The University of Vermont and State Agricultural College Recruiting
Burlington, Vermont, United States, 05405
Contact: Jane Low, MPA, CCRC    802-847-0983    Jane.Low@uvmhealth.org   
Principal Investigator: Andrew Solomon, MD         
United States, Washington
Swedish Health Services Recruiting
Seattle, Washington, United States, 98122
Contact: Yuriko Courtney, CCRC    206-320-2647    Yuriko.Courtney@swedish.org   
Principal Investigator: Peiqing Qian, MD         
Sponsors and Collaborators
Johns Hopkins University
Patient-Centered Outcomes Research Institute
Investigators
Principal Investigator: Ellen M. Mowry, MD, MCR Johns Hopkins University
Principal Investigator: Scott D. Newsome, DO Johns Hopkins University

Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT03500328     History of Changes
Other Study ID Numbers: IRB00143534
First Posted: April 17, 2018    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases