Clinical trial NCT03073603: Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS)
Official title: Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Multiple Sclerosis
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
name: National Multiple Sclerosis Society
name: University of Alabama at Birmingham
First posted: 2017-03-08
Enrollment: 259
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Natural history research in Multiple Sclerosis (MS) suggests that risk of relapses and new Magnetic Resonance Imaging (MRI) changes diminish significantly as people age, especially in MS patients 55 or older. Thus, the need to continue MS medicines that reduce relapses and new MRI lesions may also decrease as people age, especially in those who have not had relapses or MRI scan changes for prolonged times. This study plans to learn more about the safety of stopping MS medication in this population, as compared to continuing on the medication.

Detailed description: Participants will be randomized (1:1) to one of two groups. One group will stay on their current MS medication (Continue group), and one group will discontinue their medication (Discontinue group). They will also have some extra assessments done at their regular routine MS clinic appointment and every 6 months for the next 18-24 months. The following items will be done in addition to any assessments or procedures they are already having done as part of their clinical care:

* Questionnaires about the participant's quality of life including questions about health, mood, thinking, and social life
* Questionnaires about the participant's MS symptoms
* Test of the participant's attention, concentration, and thinking
* Test of the participant's physical symptoms
* In addition to any MRIs the participants may get as part of their routine care, they will also have an MRI 6 months from their enrollment into the study.

Eligibility criteria: Inclusion Criteria:

* Patients with either Relapsing-remitting MS (RRMS), Secondary progressive MS (SPMS), or Primary progressive MS (PPMS) by McDonald 2010 criteria.
* Patients defined by subtype based on 2013 updated phenotypic criteria.
* Progression of MS defined by the local PI either:

  * prospectively with an EDSS change of at least 1.0 points over the last two years, or
  * retrospectively, with any significant change in motor function over at least one year, unrelated to relapse.
* 55 years of age or older at time of randomization;
* No evidence of recent new inflammatory disease activity (inactive by the Lublin criteria16) with no new relapse for at least five years and no new MRI lesion for at least three years
* Using any of the FDA-approved MS DMTs (to include:

  * interferon β-1a,
  * interferon β-1b,
  * glatiramer acetate,
  * natalizumab,
  * fingolimod,
  * dimethyl fumarate,
  * ocrelizumab, or
  * teriflunomide; continuously for no less than 5 years.
* Taking most recent DMT continuously\* for no less than two years.
* Willing to be randomized per this protocol; each patient will be questioned as to their willingness to stay in the trial regardless of the group to which group they are randomized.
* Willing to follow the protocol
* Able to undergo a brain MRI without anesthesia

  * Continuously will be defined as no less than 75% of all prescribed doses, with no time of greater than four weeks from last intended dose to have missed a dose (8 weeks for natalizumab, i.e. one missed dose).

Exclusion Criteria:

* Any MS relapse in the last five years, as determined at the screen visit by the PI
* Any new or definitely enlarging T2/FLAIR lesion or new gadolinium-enhancing lesion within the past three years (at least two scans separated by at least three years must be reviewed) on brain or spine MRI scan. Lesions must be 3mm or larger to be exclusionary.
* Significant (as defined by the PI) intolerance of presently-used DMT
* More than two courses of acute, systemic (IV or oral) steroids in the last 5 years or any use within the last year. Course is defined as three or more days continuously, and not to exceed 14 days. No use of chronic, systemic steroids, defined as 15 or more days, in the last 5 years. Any use of steroids to treat MS relapse, possible relapse, or pseudo-relapse in the last 5 years.

  * Use of inhaled or topical steroids are not an exclusion criteria.
  * Use of oral steroids for no greater than 14 days given for a non-MS condition is not exclusionary.
* Prior use of the following in the past 5 years:

  * alemtuzumab,
  * mitoxantrone,
  * cyclophosphamide,
  * methotrexate,
  * cyclosporine,
  * rituximab,
  * siponimod, or
  * cladribine
* Prior use of any experimental agent used as a DMT for MS in the last five years
* Other significant medical or psychiatric illness, if uncontrolled. Examples:

  * uncontrolled hypertension,
  * uncontrolled diabetes,
  * uncontrolled asthma, or
  * uncontrolled depression
* Cancers other than basal cell skin cancers within the last 5 years
* Unable to give informed consent or follow the protocol
* Unable to undergo brain MRI
* Unwilling to be randomized per this protocol
* History of other chronic neurological illnesses that might mimic MS with chronic or intermittent symptoms (i.e. ALS, myasthenia gravis, chronic neuropathy, etc.)

Primary outcomes:
measure: Number of Participants Developing a New MS Relapse and/or MRI Brain Lesion Over the Course of the Study Duration
timeFrame: 18-24 months, based on time of enrollment
Secondary outcomes:
measure: Number With Disability Progression Confirmed at 6 Months Using the Expanded Disability Status Scale (EDSS)
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment.
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Upper Extremity Function
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Lower Extremity Function
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Fatigue
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Sleep Disturbance
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- General Concerns
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Executive Function
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Communication
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Anxiety
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Depression
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Positive Affect and Well-Being
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Emotional-Behavioral Dyscontrol
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Satisfaction With Social Roles and Activities
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in Neuro-QoL (Quality of Life) Short Form Scores -- Ability to Participate in Social Roles and Activities
timeFrame: Baseline, 18-24 Months, based on time of enrollment
measure: Change in SymptoMScreen Composite Score (SymptoMScreen - Overall Symptom Severity).
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. The change between baseline and Month 18-24 is reported.
measure: Change in Patient-Determined Disease Steps (PDDS - Disability).
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. The change between baseline and Month 18-24 is reported.
measure: Change in Symbol Digit Modalities Test (SDMT - Cognition).
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. The change between baseline and Month 18-24 is reported.
measure: Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Physical Impact
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. The change between baseline and Month 18-24 is reported.
measure: Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Psychological Impact
timeFrame: Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. The change between baseline and Month 18-24 is reported.
Other outcomes:
measure: Total Number of New T2 Lesions on MRI
timeFrame: Baseline, then every 6 months for 2 years with one exception at 18 months.
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Aurora
country: United States
facility: University of Colorado Denver - Anschutz Medical Campus
state: Colorado
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Mt. Sinai University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Health Services
state: Washington
Study officials:
affiliation: University of Colorado, Denver
name: John Corboy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hartung HP, Meuth SG, Miller DM, Comi G. Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis. Curr Opin Neurol. 2021 Aug 1;34(4):598-603. doi: 10.1097/WCO.0000000000000960.
citation: McGinley MP, Cola PA, Fox RJ, Cohen JA, Corboy JJ, Miller D. Perspectives of individuals with multiple sclerosis on discontinuation of disease-modifying therapies. Mult Scler. 2020 Oct;26(12):1581-1589. doi: 10.1177/1352458519867314. Epub 2019 Aug 1.