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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03073603

Acronym

DISCOMS

Enrollment

259

Registered

2017-03-08

Start date

2017-04-20

Completion date

2021-08-31

Last updated

2023-08-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Sclerosis

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.

Interventions

DRUGDiscontinuation of disease modifying therapy

Participants who will discontinue their current MS drug. No other changes to their treatment occur.

DRUGStandard of Care

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

55 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Developing a New MS Relapse and/or MRI Brain Lesion Over the Course of the Study Duration	18-24 months, based on time of enrollment	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.

Secondary

Measure	Time frame	Description
Number With Disability Progression Confirmed at 6 Months Using the Expanded Disability Status Scale (EDSS)	Baseline, then every 6 months for up to a maximum of 24 months, based on time of enrollment.	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Upper Extremity Function	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Lower Extremity Function	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Fatigue	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Sleep Disturbance	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- General Concerns	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Executive Function	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Communication	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Anxiety	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Positive Affect and Well-Being	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Emotional-Behavioral Dyscontrol	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Satisfaction With Social Roles and Activities	Baseline, 18-24 Months, based on time of enrollment	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.
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Ability to Participate in Social Roles and Activities	Baseline, 18-24 Months, based on time of enrollment	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.
Change in SymptoMScreen Composite Score (SymptoMScreen - Overall Symptom Severity).	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.	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.
Change in Patient-Determined Disease Steps (PDDS - Disability).	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.	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.
Change in Symbol Digit Modalities Test (SDMT - Cognition).	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.	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.
Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Physical Impact	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.	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).
Evaluation of the Patient's Quality of Life Using the MSIS-29 Scale -- Psychological Impact	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.	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).
Change in Neuro-QoL (Quality of Life) Short Form Scores -- Depression	Baseline, 18-24 Months, based on time of enrollment	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.

Other

Measure	Time frame	Description
Total Number of New T2 Lesions on MRI	Baseline, then every 6 months for 2 years with one exception at 18 months.	MRIs will be reviewed to determine the total number of new T2 lesions that develop for each subject over the course of the study. Lesion counts will be performed by the central MRI facility.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Drug Continuation Arm 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. Standard of Care: 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.	128
Drug Discontinuation Arm 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. Discontinuation of disease modifying therapy: Participants who will discontinue their current MS drug. No other changes to their treatment occur.	131
Total	259

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	5	3
Overall Study	Discontinued DMT	4	0
Overall Study	Financial or insurance-related	8	0
Overall Study	Noncompliance	3	1
Overall Study	Physician Decision	1	2
Overall Study	Required treatment not allowed by protocol	1	0
Overall Study	Restarted DMT	0	1
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Drug Discontinuation Arm	Drug Continuation Arm	Total
Age, Continuous	63.1 years STANDARD_DEVIATION 4.9	63.0 years STANDARD_DEVIATION 5.2	63.0 years STANDARD_DEVIATION 5
MS Phenotype Primary Progressive	6 Participants	2 Participants	8 Participants
MS Phenotype Relapsing-Remitting	108 Participants	108 Participants	216 Participants
MS Phenotype Secondary Progressive	17 Participants	18 Participants	35 Participants
Race/Ethnicity, Customized Black or African American	11 Participants	12 Participants	23 Participants
Race/Ethnicity, Customized Hispanic	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Other	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized White	119 Participants	112 Participants	231 Participants
Region of Enrollment United States	131 Participants	128 Participants	259 Participants
Sex: Female, Male Female	109 Participants	107 Participants	216 Participants
Sex: Female, Male Male	22 Participants	21 Participants	43 Participants
Time since first onset of symptoms related to MS	23.4 years STANDARD_DEVIATION 10.5	20.9 years STANDARD_DEVIATION 10.4	22.2 years STANDARD_DEVIATION 10.5
Time since last documented relapse	14.5 years STANDARD_DEVIATION 7.4	13.2 years STANDARD_DEVIATION 6.2	13.9 years STANDARD_DEVIATION 6.9

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 128	2 / 131
other Total, other adverse events	66 / 128	70 / 131
serious Total, serious adverse events	1 / 128	1 / 131

Outcome results

Primary

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.

Time frame: 18-24 months, based on time of enrollment

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Drug Continuation Arm	Number of Participants Developing a New MS Relapse and/or MRI Brain Lesion Over the Course of the Study Duration	6 Participants
Drug Discontinuation Arm	Number of Participants Developing a New MS Relapse and/or MRI Brain Lesion Over the Course of the Study Duration	16 Participants

Comparison: We tested the null hypothesis of inferiority with the proportion of disease events (i.e., new MS relapse and/or MRI brain lesion) for the drug discontinuation group being 8% greater than the proportion for the drug continuation group under the alternative that the two rates are equal.p-value: 0.52195% CI: [0.0063, 0.15]Exact binomial test

Secondary

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.

Time frame: Baseline, 18-24 Months, based on time of enrollment