Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Discontinuation of disease modifying therapy
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Drug Continuation Arm<br>Participants who remain on their current Disease Modifying Therapies (DMTs) without any changes. DMTs include  14 formulations/doses of drugs approved in the US by the FDA that alter the natural history of the disease. | Drug: Standard of Care<br>* Participants who remain on their current Disease Modifying Therapies (DMTs) without any changes. DMTs include  14 formulations/doses of drugs approved in the US by the FDA that alter the natural history of the disease.<br>|
| Experimental: Drug Discontinuation Arm<br>Participants who will discontinue their Disease Modifying Therapies (DMTs). No other changes to their treatment occur. DMTs include  14 formulations/doses of drugs approved in the US by the FDA that alter the natural history of the disease. | Drug: Discontinuation of disease modifying therapy<br>* Participants who will discontinue their current MS drug. No other changes to their treatment occur.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Developing a New MS Relapse and/or MRI Brain Lesion Over the Course of the Study Duration | The outcome is the proportion of participants in each group developing a new MS relapse and/or MRI brain lesion over the course of the study duration. Count of Participants with either a new MS relapse and/or a new brain MRI lesion is reported. | 18-24 months, based on time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number With Disability Progression Confirmed at 6 Months Using the Expanded Disability Status Scale (EDSS) | The EDSS is a neurological examination performed by a blinded rater. This assessment is collected at each study visit. Increase in the EDSS score shows disease activity or progression, and must be observed six months later to be confirmed. Whether a confirmed change is significant depends on the subject's EDSS at baseline: for those with a baseline EDSS of 5.5 points or fewer, the increase must be at least one point to be significant; for those with a baseline EDSS of 6.0 points or greater, a change of at least 0.5 points is considered significant. We will calculate the percentage in each group of those who had a significant change at anytime during the follow-up period, which was then confirmed at 6 months later. | Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment. | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Upper Extremity Function | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Lower Extremity Function | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Fatigue | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Sleep Disturbance | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- General Concerns | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Executive Function | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Communication | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Anxiety | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Depression | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Positive Affect and Well-Being | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Emotional-Behavioral Dyscontrol | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Satisfaction With Social Roles and Activities | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in Neuro-QoL (Quality of Life) Short Form Scores -- Ability to Participate in Social Roles and Activities | The Neuro-QOL Adult PRO short form measures are collected to evaluate self-reported overall quality of life and functioning in patients with a variety of neurological conditions including MS. The Neuro-Qol short form scales consist of 5-9 single scale item scales. Raw scores are then converted to a standardized score with mean 50 and standard deviation 10. The Neuro-QoL short forms used in this study with higher scores representing better outcomes are: Upper Extremity Function, Lower Extremity Function, Cognitive -- General Concerns, Cognitive -- Executive Function, Communication, Positive Affect and Well-Being, Satisfaction with Social Roles and Activities, and Ability to Participate in Social Roles and Activities. The short forms used with lower scores representing better outcomes are: Fatigue, Sleep Disturbance, Anxiety, Depression, and Emotional-Behavioral Dyscontrol. | Baseline, 18-24 Months, based on time of enrollment | 
| Change in SymptoMScreen Composite Score (SymptoMScreen - Overall Symptom Severity). | SymptoMScreen will be collected to assess overall symptom severity. Participants self-report across multiple neurological domains (mobility, hand function, spasticity, pain, sensory, bladder, fatigue, vision, dizziness, cognition, depression, and anxiety). This scale is a single page, validated measure that allows for quick assessment of multiple symptoms. Single item scores are rated as 0-6 with higher numbers representing increased limitations and symptom severity. Composite score is calculated by summing the single item scores with total score ranges from 0 to 72. | 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. | 
| Change in Patient-Determined Disease Steps (PDDS - Disability). | Patient-Determined Disease Steps will be collected to assess changes in disability from the patient's perspective. This outcome measure is a single question. The scores range from 0 to 8, and a participant with a low score has less perceived disability than a participant with a higher score. | 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. | 
| Change in Symbol Digit Modalities Test (SDMT - Cognition). | The SDMT measures patient attention, concentration, and speed of information processing and has been validated for discriminating patients from controls. Possible scores range from 0 to 110, with higher scores indicating a better outcome. | 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. | 
| Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Physical Impact | The Multiple Sclerosis Impact Scale (MSIS-29) will be collected to assess changes in quality of life from the patient's perspective. The MSIS has 29 questions. Each question asks the participant to rank how impacted they are in a certain aspect of their life. The options are 1 through 4. 1 indicates not at all impacted while 4 indicates extremely impacted. The lower the final score, the less impacted the participant is overall. Scores on the physical impact scale range from 20-80 and from 9-36 on the psychological impact scale. We will compare the proportion in each group who have had a change of 7.5 points or more (considered a clinically meaningful change). | 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. | 
| Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Psychological Impact | The Multiple Sclerosis Impact Scale (MSIS-29) will be collected to assess changes in quality of life from the patient's perspective. The MSIS has 29 questions. Each question asks the participant to rank how impacted they are in a certain aspect of their life. The options are 1 through 4. 1 indicates not at all impacted while 4 indicates extremely impacted. The lower the final score, the less impacted the participant is overall. Scores on the physical impact scale range from 20-80 and from 9-36 on the psychological impact scale. We will compare the proportion in each group who have had a change of 7.5 points or more (considered a clinically meaningful change). | 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. |