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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation T25W

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 10 clinical trials

Clinical Trials


1 Open-label, Observational, Prospective, 9-month Study to Assess the Efficacy of Ofatumumab on Microglia in Patients With Relapsing Forms of Multiple Sclerosis

We aim to assess the effect of Ofatumumab on microglial activation using [F-18]PBR06 PET in MS patients in relation to changes in serum markers, MRI abnormalities and clinical impairment longitudinally over 9 months. Specific Aims: Specific Aim 1: To determine the effect of Ofatumumab on microglial activation in MS over 9 months. Specific Aim 2: To determine the time course of effect of Ofatumumab on microglial activation and its relationship with peripheral B-cell depletion, serum neurofilament light (sNfL) chain and glial-fibrillary acid protein (GFAP) levels and other serum biomarkers Specific Aim 3: To determine the relationship of PET changes following Ofatumumab initiation with 3T MRI changes and clinical parameters.

NCT04510220
Conditions
  1. Relapsing Multiple Sclerosis
Interventions
  1. Drug: Ofatumumab
  2. Drug: [F-18]PBR06
MeSH:Multiple Sclerosis Sclerosis

Clinical Data: The following non-imaging, clinical data will be obtained: Expanded Disability Status Scale (EDSS), Timed 25-feet walk (T25W), 9-Hole Peg Test (9HPT), Four component MS Functional Composite (MSFC-4), Symbol-Digit Modality test (SDMT), cognitive and symptom questionnaires, vision testing, Levels of serum biomarkers. --- T25W ---

Primary Outcomes

Description: The primary endpoint of the study will be the change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements at early and late time-points (5, 28, 90 and 273 days) as compared to baseline.

Measure: Effect of Ofatumumab on microglial activity

Time: Baseline to 9 months

Secondary Outcomes

Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the peripheral CD19 counts at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and CD19 counts

Time: Baseline to 9 months

Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the serum glial fibrillary acid protein (GFAP) level measurements at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and glial fibrillary acid protein (GFAP)

Time: Baseline to 9 months

Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in the serum neurofilament light chain levels at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and neurofilament light chain

Time: Baseline to 9 months

Description: Association of change in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in MRI -based brain volume (in ml) measurements at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and MRI-based brain atrophy changes

Time: Baseline to 9 months

Description: Association of changes in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in disease severity (measured using expanded disability status scale or EDSS) at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and physical disability

Time: Baseline to 9 months

Description: Association of changes in regional microglial activity in the brain using standardized uptake value ratio (SUVR) measurements with changes in severity of cognitive impairment (measured using symbol digit modality test or SDMT) at 5, 28, 90 and 273 days as compared to baseline. We will calculate the change from day 0 to each of the other time points for each of the measures, and we will estimate the correlation between the changes using Pearson's correlation coefficient.

Measure: Relationship between changes in Microglial activity and cognitive disability

Time: Baseline to 9 months

2 Open-label, Single-center, Single-arm Futility Trial Evaluating Oral Domperidone 10mg QID for Reducing Progression of Disability in Patients With Secondary Progressive Multiple Sclerosis (SPMS)

The purpose of this clinical trial is to determine if Domperidone in a dose of 40 mg daily can prevent worsening of walking ability in people secondary progressive MS. The number of participants in this study will be 62. A maximum of 75 people with secondary progressive MS will be included. Each patient will be followed for 12 months from inclusion. Domperidone is a medication which has been shown to increase levels of the hormone prolactin. The best understood function of prolactin is the stimulation of milk production in women after delivery. However, the increase in prolactin levels seen in patients treated with standard doses of Domperidone (in doses of up to 80mg per day) usually does not lead to clinical symptoms. Prolactin has been shown to improve myelin repair in mice. Domperidone therefore may also improve myelin repair in people with MS. Domperidone is currently approved in Canada to treat slow moving bowels and nausea, for instance in patients with Parkinson's Disease or Diabetes Mellitus, where too slowly moving bowels can cause constipation. Domperidone is available as a tablet that is usually taken four times per day. Doses up to 80mg per day may be used but we estimate that a dose of only 40mg daily will be needed to stimulate myelin repair. Domperidone is usually well tolerated.

NCT02308137
Conditions
  1. Multiple Sclerosis, Secondary Progressive
Interventions
  1. Drug: Domperidone
MeSH:Neoplasm Metastasis Multiple Sclerosis Multiple Sclerosis, Chronic Progressive Sclerosis

Timed 25-Foot Walk (T25W). --- T25W ---

Primary Outcomes

Description: quantitative ambulation performance test

Measure: Timed 25-Foot Walk (T25W)

Time: up to 12 months

Secondary Outcomes

Description: brief, standardized, quantitative test of upper extremity

Measure: 9-Hole Peg Test

Time: administered at baseline, one month, 6 months, and 12 months

Description: measures cognitive processing speed and working memory

Measure: Symbol Digit Modalities Test

Time: administered at baseline, one month, 6 months, and 12 months

Description: EDSS is the standard measure of neurologic impairment that is used to describe disability in MS. The neurological assessment comprises seven functional systems.

Measure: Functional Systems and Expanded Disability Status Scale (EDSS)

Time: administered at baseline, one month, 6 months, and 12 months

Description: structured, self-report questionnaire with 21 itmes concerning how fatigue impacts patient's life

Measure: Modified Fatigue Impact Scale (MFIS)

Time: administered at baseline, one month, 6 months, and 12 months

Description: 54-item multidimensional health-related quality of life measure that combines both generic and MS-specific items

Measure: Multiple Sclerosis Quality of Life Scale 54 item version

Time: administered at baseline, one month, 6 months, and 12 months

3 Project FARMS: Fall Risk Reduction in Multiple Sclerosis

Over half of persons with multiple sclerosis (MS) report falling over a 6-month period and a majority of those who fall require medical attention for injuries. Importantly, balance dysfunction, muscle weakness, and spasticity are modifiable risk factors for falls among community-dwelling older adults and likely persons with MS. Indeed, there is evidence that these physiological risk factors can be minimized with exercise training in persons with MS and this might translate into a decrease in fall risk as documented in community-dwelling older adults. The investigation will examine the effectiveness of a home-based exercise program that is designed to reduce fall risk by targeting specific fall risk factors including balance dysfunction and two of its latent causes, muscle weakness and spasticity in persons with multiple sclerosis. It is predicted that persons who receive home-based exercise program will have a reduction in fall risk.

NCT01837017
Conditions
  1. Multiple Sclerosis
Interventions
  1. Behavioral: Home-based Exercise
MeSH:Multiple Sclerosis Sclerosis

Mobility will be quantified with performance on timed 25 foot walk (T25W), timed up and go (TUG), Six spot step test, 6 minute walk and the MS walking scale-12.. Balance. --- T25W ---

Primary Outcomes

Description: Physiological fall risk will be determined by the physiological profile assessment which assesses physiological function related to fall risk by combining measures of vision, proprioception, lower-limb strength, postural sway, and cognitive function.

Measure: Physiological Fall risk

Time: 3 months

Secondary Outcomes

Description: Mobility will be quantified with performance on timed 25 foot walk (T25W), timed up and go (TUG), Six spot step test, 6 minute walk and the MS walking scale-12.

Measure: Mobility

Time: 3 months

Description: Balance will be quantified with the Berg Balance scale; self-report of balance impairment (ABC); and force platform metrics (sway range and velocity).

Measure: Balance

Time: 3 Months

Description: Spasticity will be assessed with the modified ashworth scale.

Measure: Spasticity

Time: 3 Months

4 Fall Risk Reduction in Multiple Sclerosis: Exercise Versus Behavior

Falls are a serious health concern for persons with multiple sclerosis (MS). Over 50% of persons with MS suffer a fall over a 6-month periodwith the majority of falls resulting in medical attention for injuries (i.e., lacerations, bone fractures, & head injuries). The effects of a fall are often compounded as it can lead to activity curtailment, physiological deconditioning, and institutionalization. Despite the importance of falls in persons with MS, the appropriate prevention strategies (i.e. rehabilitation approaches) are not clear. The purpose of this investigation is to determine whether exercise based or educational based interventions are more suited for fall prevention in older adults with MS.

NCT01956227
Conditions
  1. Multiple Sclerosis
  2. Adult Disease
Interventions
  1. Behavioral: Home-based exercise
  2. Behavioral: Education
  3. Behavioral: Exercise plus Education
MeSH:Multiple Sclerosis Sclerosis

Walking speed was quantified with the Timed 25-Foot Walk (T25W), walking endurance was assessed with the 6-Minute Walk (6MW), and functional mobility was quantified with the Timed Up and Go (TUG) . --- T25W ---

Primary Outcomes

Measure: Fall incidence

Time: 3 months

Secondary Outcomes

Description: Physiological fall risk will be determined by the short form of the Physiological Profile Assessment (PPA)(Lord, 2003). The PPA is a standardized test battery which assesses vision (edge contrast sensitivity), lower limb proprioception, strength (knee extension), postural sway, and cognitive function (simple hand reaction time). The outcome of each test will be combined to generate an overall fall risk score

Measure: Physiological Fall Risk

Time: 3 Months

Description: Specific measures of walking speed, endurance, coordination and self-reported walking function scale will be employed to assess overall mobility of each person. Walking speed was quantified with the Timed 25-Foot Walk (T25W), walking endurance was assessed with the 6-Minute Walk (6MW), and functional mobility was quantified with the Timed Up and Go (TUG) . The Multiple Sclerosis Walking Scale-12 (MSWS-12) will be used as a self-reported measure of walking impairment.

Measure: Mobility

Time: 3 months

Description: To assess balance (e.g. postural control), we conducted a clinical assessment To measure balance the Berg Balance Scale (BBS) and self-reports of balance confidence will be used. The BBS is a clinical assessment of balance. Scores on the BBS range from 0-56 with higher scores indicating greater balance. The Activities-Specific Balance Confidence (ABC) scale was used as a measure of balance confidence.

Measure: Balance

Time: 3 Months

5 Effect of Alemtuzumab on Microglial Activation Assessed Using Novel [F-18]-Based Positron Emission Tomography (PET) Ligand in Multiple Sclerosis

Specific Aims The specific aims of the study are: - Primary Objective: To assess the effect of alemtuzumab on microglial activation in MS patients. The hypothesis is that alemtuzumab reduces microglial activation in MS, which may mediate its effect on reducing conversion of RRMS patients to SPMS, and its effects on cognition, including cognitive fatigue. - Secondary Objective: To determine the time course of effect of alemtuzumab on microglial activation. The hypothesis is that alemtuzumab reduces microglial activation at 6 months after initiation of treatment and this effect persists and is accentuated at 18 years, i.e. after administration of the second course

NCT03983252
Conditions
  1. Multiple Sclerosis
Interventions
  1. Drug: [F-18]PBR06
MeSH:Multiple Sclerosis Sclerosis

Non Imaging/Clinical Data The following non-imaging/clinical data will be obtained: Expanded Disability Status Scale (EDSS) Timed 25-feet walk (T25W) MS Functional Composite (MSFC) Minimal Assessment of Cognitive Function Scale in MS (MACFIMS) battery Symbol digit modalities test (SDMT) MSQOL-54 scale (QOL) Modified fatigue Impact Scale (MFIS) Pittsburgh Sleep Quality Index (PSQI) Beck's Depression Inventory (BDI) Center for Epidemiological Studies-Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS) --- T25W ---

Primary Outcomes

Description: PET outcome measure change at 18 months from baseline

Measure: PET Uptake/Standardized uptake value ratio (SUVR) change

Time: baseline and 18 months

Secondary Outcomes

Description: PET outcome measure change at 6 months from baseline

Measure: PET Uptake/Standardized uptake value ratio (SUVR) change

Time: baseline and 6 months

Description: MRI outcome measure change at 18 months from baseline

Measure: T2/FLAIR lesion load change

Time: baseline and 18 months

Description: MRI outcome measure change at 18 months from baseline

Measure: Whole brain/deep gray matter atrophy change

Time: baseline and 18 months

Description: Clinical outcome measure change at 18 months from baseline; Scale Range: 0-10; Higher values represent worse outcomes

Measure: Expanded Disability Status Scale (EDSS) change

Time: baseline and 18 months

Description: Clinical outcome measure change at 18 months from baseline

Measure: Timed 25-foot walk (T25FW) change

Time: baseline and 18 months

Description: Clinical outcome measure change at 18 months from baseline; Physical subscale range: 0-36; Cognitive subscale range: 0-40; Psychosocial subscale range: 0-8; Total MFIS Score scale range (Subscales Summed): 0-84; Higher values represent worse outcomes

Measure: Modified Fatigue Impact Scale (MIFS) change

Time: baseline and 18 months

Description: Clinical outcome measure change at 18 months from baseline

Measure: Minimal Assessment of Cognitive Function in MS (MACFIMS) change

Time: baseline and 18 months

6 A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Satralizumab (SA237) as Monotherapy in Patients With Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorder (NMOSD)

The objectives of this study are to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic and immunogenic profiles of satralizumab in participants with NMO and NMOSD.

NCT02073279
Conditions
  1. Neuromyelitis Optica (NMO)
  2. NMO Spectrum Disorder (NMOSD)
Interventions
  1. Drug: Satralizumab
  2. Drug: Placebo
MeSH:Neuromyelitis Optica

Change From Baseline in Speed of Timed 25-Foot Walk (T25W) at 24 Week Intervals During the DB Period. --- T25W ---

The T25W is an assessment of walking ability. --- T25W ---

Primary Outcomes

Description: TFR was defined as time from randomization to first occurrence of relapse in the DB period. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onset days that were 30 days of one another, they were counted only as 1 relapse), and onset date used in analysis was the date of first relapse.

Measure: Time to First Protocol-Defined Relapse (TFR) During the Double-Blind (DB) Period

Time: Up to Week 216

Secondary Outcomes

Description: The VAS is a subjective measure of pain consisting of a 100 mm line with two endpoints representing 0 = "no pain" and 100 = "pain as bad as it could be". Participants rated their pain by placing a mark on the line corresponding to their current level of pain. The distance along the line from the "no pain" marker was measured with a ruler giving a pain score out of 100. A higher score indicated more pain and lower scores reflected a better health state. A negative change from baseline indicates an improvement. ANCOVA was used for analysis to report the adjusted mean and standard error (SE).

Measure: Change From Baseline to Week 24 in Visual Analogue Scale (VAS) for Pain

Time: Baseline, Week 24

Description: The FACIT Fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the past 7 days. As each of the 13 items of the scale ranges from 0-4, the range of possible scores was computed using FACIT scoring algorithm as 0-52, where 0 is the worst possible score and 52 the best which indicated less fatigue. A positive change from baseline indicates an improvement.

Measure: Change From Baseline to Week 24 in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale

Time: Baseline, Week 24

Description: Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD). Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (i.e., if 2 relapses had onsets within 30 days of one another, they were counted as 1), and onset date used in analysis was the date of first relapse.

Measure: Relapse-Free Rate During the DB Period

Time: Up to Week 216

Description: The ARR is calculated as the total number of participants with adjudicated PDRs experienced divided by the patient-years at risk. Protocol-defined relapse was occurrence of new or worsening neurological symptoms attributable to neurological NMO or NMOSD. Symptoms had to persist for >24 hours and not be attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, adverse reactions to medications). New or worsening neurological symptoms that occurred < 31 days following onset of a protocol-defined relapse were considered part of same relapse (2 relapses with onset days in 30 days of one another was counted as 1 relapse), onset date used in analysis was the date of first relapse.

Measure: Annualized Relapse Rate (ARR) During the DB Period

Time: Up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in Short Form Generic Health Survey (SF-36) Bodily Pain Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 General Health Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Mental Health Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Physical Functioning Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Role-Emotional Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Role-Physical Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Social Role Functioning Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health component summary measures and a preference-based health utility index. The domain scores were transformed to a 0-100 scale, where higher scores indicate better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Vitality Domain Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Mental Component Summary Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The SF-36v2 is a multi-purpose, short form health survey with 36 questions. It has 8 domains (vitality, physical functioning, bodily pain, general health, role-physical, role emotional, social role functioning and mental health) of functional health and well-being scores as well as psychometrically based physical and mental health summary measures and a preference-based health utility index. The component scores were transformed to a 0-100 scale, where higher score indicates better quality of life. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in SF-36 Physical Component Summary Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The EQ-5D is a participant-answered questionnaire measuring 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with 3 possible response categories: 1) no problems; 2) some problems; 3) severe problems. The scores from 5 dimensions are used as input to generate EQ-5D index score using scoring algorithm. The EQ-5D index score is scored on a scale of -0.2 to 1. A higher score reflects a better health state. A positive change from baseline indicates an improvement

Measure: Change From Baseline in EuroQoL-5 Dimensions (EQ-5D) Index Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The T25W is an assessment of walking ability. The time (in seconds) that the participant took to walk 25 feet was measured. Speed is calculated as 1/Timed 25-Foot Walk where time is measured in seconds. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in Speed of Timed 25-Foot Walk (T25W) at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The mRS is a 7-point disability scale that assesses the degree of disability in participants with neurological impairment. Possible scores range from 0 (no symptoms at all) up to 6 (death). Higher scores reflect increased disability. A negative change from baseline indicates an improvement.

Measure: Change From Baseline in Modified Rankin Scale (mRS) Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain caregivers perceive. Responses range from 0 (never) to 4 (nearly always). The overall ZBI score ranges from 0 to 88. The higher the total score, the heavier the perceived burden. A negative change from baseline indicates an improvement.

Measure: Change From Baseline in Zarit Burden Interview (ZBI) Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 120

Description: The EDSS is an ordinal scale with values from 0 points (normal neurological examination) to 10 points (death) increasing in half-point increments once an EDSS of 1.0 has been reached. Higher scores represent increased disability. A negative change from baseline indicates an improvement.

Measure: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: Visual acuity was measured using Snellen 20-foot wall chart and then converted to logMAR visual acuity scoring. Lower values indicate better visual acuity. Data are reported for right eye (OD) and left eye (OS). A negative change from baseline indicates an improvement.

Measure: Change From Baseline in Visual Acuity (Snellen Chart) at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: The LCSLC evaluates the visual function and captures the minimum size at which individuals can perceive letters of a particular contrast level. The change in binocular visual acuity, as assessed by the number of letters read correctly from a distance of 2 meters on 100%, 2.5% and 1.25% contrast level Sloan letter charts, was analyzed. The LCSLC is scored on a scale of 0-60. Higher scores indicate better visual function. A positive change from baseline indicates an improvement.

Measure: Change From Baseline in Visual Function (Low-Contrast Sloan Letter Chart [LCSLC]) Scores at 24 Week Intervals During the DB Period

Time: Baseline up to Week 216

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events.

Measure: Number of Participants With at Least One Adverse Event in the DB Period

Time: Up to Week 216

Description: A serious adverse event is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is medically significant or requires intervention to prevent one or other of the outcomes listed above.

Measure: Number of Participants With at Least One Serious Adverse Event in the DB Period

Time: Up to Week 216

Description: Non-serious adverse events of special interest for this study included: 1) cases of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, 2) suspected transmission of an infectious agent by the study treatment.

Measure: Number of Participants With Non-Serious Adverse Events of Special Interest in the DB Period

Time: Up to Week 216

Description: Selected adverse events for this study included: 1) all infections, 2) serious infections, 3) potential opportunistic infections, 4) injection-related reactions (IRRs; an AE which occured within 24 hours after study treatment injection except where the event was not considered an allergic reaction), 5) psychiatric disorders and 6) anaphylaxis (an acute allergic/hypersensitivity reaction).

Measure: Number of Participants With Selected Adverse Events in the DB Period

Time: Up to Week 216

Description: The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool to evaluate suicidal ideation and behavior. Categories have binary responses (yes/no) and include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates suicidal ideation or behavior.

Measure: Number of Participants With Suicidal Behaviors and Ideations Collected by Columbia-Suicide Severity Rating Scale in the DB Period

Time: Baseline and Post-Baseline (up to Week 216)

Measure: Serum Satralizumab Concentration During the DB Period

Time: Baseline, Weeks 2, 4, 5, 6, 8, and every 4 weeks thereafter up to Week 204

Measure: Serum Interleukin-6 (IL-6) Concentration During the DB Period

Time: Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216

Measure: Serum Soluble IL-6 Receptor (sIL-6R) Concentration During the DB Period

Time: Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216

Measure: Serum High Sensitivity C-Reactive Protein (hsCRP) Concentration During the DB Period

Time: Baseline, Weeks 2, 4, and every 4 weeks thereafter up to Week 216

Measure: Blood Anti-Aquaporin-4 (AQP4) Antibody Concentration Over Time

Time: Baseline, Weeks 2, 4, 8, 12, 24, 48, and every 24 weeks thereafter of double-blind period; every 24 weeks for first 48 weeks of open-label extension period (up to approximately 6.75 years)

Measure: Percentage of Blood Plasmablasts Over Time

Time: Baseline, Weeks 2, 4, 8, 12, 24, 48, and every 24 weeks thereafter of double-blind period (up to approximately 38 months)

Description: Reported here is the percentage of participants with at least one positive anti-drug antibody measurement during the DB period.

Measure: Percentage of Participants With Anti-Drug Antibodies to Satralizumab in the DB Period

Time: Up to approximately Week 216

7 Role of Microglial Activation and Norepinephrine Transporter Abnormalities in Pathogenesis of MS-related Fatigue

The overarching aim is to assess the role of microglial activation and norepinephrine transporter binding in pathogenesis of MS-related fatigue, using novel Positron Emission Tomography (PET) radiotracers, [F-18]PBR06 and [C-11]MRB. Specific Aims: Specific Aim 1: To determine the relationship of cerebral microglial activation, as assessed by [F-18]PBR06 PET, with MS-related fatigue. Specific Aim 2: To determine the relationship of norepinephrine transporter (NET) binding, as assessed by [C-11]MRB PET, with MS-related fatigue. Specific Aim 3: To determine the relationship of microglial activation and NET binding, with grey matter pathology (lesion load and brain atrophy) assessed using 7T MRI, and evaluate their independent contribution in development of MS-related fatigue.

NCT04144257
Conditions
  1. Multiple Sclerosis
Interventions
  1. Drug: [F-18]PBR06
  2. Drug: [C-11]Methylreboxetine
MeSH:Multiple Sclerosis Fatigue
HPO:Fatigue

Clinical Data The following non-imaging, clinical data will be obtained: Modified fatigue Impact Scale (MFIS) Fatigue Severity Status Scale (FSSS) Expanded Disability Status Scale (EDSS) Timed 25-feet walk (T25W) MS Functional Composite (MSFC) Symbol digit modalities test (SDMT) MSQOL-54 scale (QOL) Pittsburgh Sleep Quality Index (PSQI) Beck's Depression Inventory (BDI) Center for Epidemiological Studies-Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS) --- T25W ---

Primary Outcomes

Description: PET outcome measure

Measure: Standardized Uptake Value (SUV)/Standardized Uptake Value Ratio (SUVR)

Time: Baseline

Secondary Outcomes

Description: Clinical outcome measure; Physical subscale range: 0-36; Cognitive subscale range: 0-40; Psychosocial subscale range: 0-8; Total MFIS Score scale range (Subscales Summed): 0-84; Higher values represent worse outcomes.

Measure: Modified Fatigue Impact Scale (MFIS)

Time: Baseline

Description: PET outcome measure

Measure: Binding Potential (BPnd)

Time: Baseline

Description: MRI outcome measure

Measure: MRI grey matter lesional load/brain atrophy

Time: Baseline

Description: PET outcome measure

Measure: Tissue Volume of distribution (Vt)/Distribution Volume Ratios (DVR)

Time: Baseline

Description: MRI outcome measure

Measure: MRI global/regional volumetrics

Time: Baseline

8 A Multicenter, Longitudinal, Open-Label, Single-Arm Study Describing Cognitive Processing Speed Changes in Relapsing Multiple Sclerosis Subjects Treated With Ozanimod (RPC-1063)

This is a multicenter, longitudinal, single-arm, open-label study to describe the change from baseline in cognitive processing speed, measured by the SDMT, in subjects with RMS treated with ozanimod HCl 1 mg at 3 years. All subjects will receive orally administered ozanimod HCl 1 mg. The primary efficacy endpoint is the proportion of subjects with a clinically meaningful increase in raw score of ≥ 4 points or 10% from baseline (improved). The treatment period is 36 months. For subjects who discontinue the study, there will be a 30-day (± 15 days) and a 90-day (± 10 days) Safety Follow-up Visit. There is no planned protocol extension following the end of the study. Approximately 250 subjects with RMS will be recruited for this study. Subjects with RMS will be enrolled in this study if they have received ≤1 DMT, have an EDSS ≤ 3.5, and have been diagnosed with RMS within 5 years of study entry. The Investigator will be responsible for the overall conduct of the study at the site, confirmation of subject eligibility, routine study subject clinical management including for MS relapses, and management of AEs.

NCT04140305
Conditions
  1. Multiple Sclerosis
Interventions
  1. Drug: RPC-1063
MeSH:Multiple Sclerosis Sclerosis

Timed 25-foot Walk (T25W). --- T25W ---

Disability progression assessed by 20% worsening from baseline over 3 years on T25W. --- T25W ---

Primary Outcomes

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with an increase in raw score of ≥ 4 points or 10% from baseline (improved)

Time: Up to approximately 3 years

Secondary Outcomes

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a decrease in raw score of ≥ 4 points or 10% from baseline (worsened)

Time: Up to approximately 3 years

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a raw score change from baseline who do not meet the improved or worsened definition (stable)

Time: Up to approximately 3 years

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with an increase in raw score of ≥ 3 points from baseline

Time: Up to approximately 3 years

Description: Symbol Digit Modalities Test

Measure: Proportion of subjects with a decrease in raw score of ≥ 3 points from baseline

Time: Up to approximately 3 years

Description: The SDMT is a measure of cognitive processing speed

Measure: Change from baseline in Symbol Digit Modalities Test (SMDT)

Time: Up to approximately 3 years

Description: Magnetic resonance imaging (MRI) brain volume

Measure: Percent change from baseline in thalamic, cortical grey matter, whole brain, lateral ventricular, and MOV volumes

Time: Up to approximately 3 years

Description: Magnetic Resonance Imaging

Measure: Proportion of subjects free of gadolinium enhancing (GdE) lesions over 3 years

Time: Up to approximately 3 years

Description: Magnetic Resonance Imaging

Measure: GdE lesion volume over 3 years

Time: Up to approximately 3 years

Description: Magnetic Resonance Imaging

Measure: Number of unique new or enlarging hyperintense T2-weighted lesions and their volume from baseline to Year 3

Time: Up to approximately 3 years

Description: Magnetic Resonance Imaging

Measure: Number of unique new or enlarging hypointense T1 weighted lesions and their volume from baseline to Year 3

Time: Up to approximately 3 years

Description: Change is TSQM score over 3 years

Measure: Treatment Satisfaction Questionnaire for Medication (TSQM v1.4)

Time: Up to approximately 3 years

Description: Change in WPAI score over 3 years

Measure: Work Productivity and Activity Impairment-Multiple Sclerosis (WPAI-MS)

Time: Up to approximately 3 years

Description: The Fatigue Severity Scale (FSS) questionnaire contains nine statements that attempt to explore severity of fatigue symptoms.

Measure: Fatigue Severity Scale (FSS)

Time: Up to approximately 3 years

Description: The MSQOL-54 is a multidimensional health-related QOL measure that combines both generic and MS-specific items into a single instrument

Measure: Multiple Sclerosis Quality of Life-54 (MSQOL-54)

Time: Up to approximately 3 years

Description: The HADS was developed to identify anxiety disorders and depression among subjects in nonpsychiatric hospital clinics

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: Up to approximately 3 years

Description: Change in relapse rate over 3 years

Measure: Annualized relapse rate (ARR)

Time: Up to approximately 3 years

Description: Disability progression assessed by 20% worsening from baseline over 3 years on T25W

Measure: Timed 25-foot Walk (T25W)

Time: Up to approximately 3 years

Description: Change from baseline in the time in seconds needed to complete test activity

Measure: Nine-hole Peg Test (9-HPT)

Time: Up to approximately 3 years

Description: Change from baseline in EDSS score (0-10) yearly and at 3 years

Measure: Expanded Disability Status Scale (EDSS)

Time: Up to approximately 3 years

Description: An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.

Measure: Adverse Events (AEs)

Time: Up to approximately 3 years

9 Novel Assessment of Synaptic Density in Progressive MS

The investigators propose to use the novel SV2a-PET ligand, [F-18]SDM-8 to assess synaptic density in progressive MS (including primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS)) as compared to relapsing-remitting multiple sclerosis (RRMS) patients and healthy controls, given its improved imaging characteristics and potential for large scale applicability. The specific aims of the study are: Aim 1: To compare the cortical and subcortical grey matter synaptic density in progressive MS patients, patients with relapsing-remitting MS, and healthy subjects, using a novel [F-18] labeled synaptic density PET ligand, [F-18]SDM8, also known as [F-18]SynvesT-1. Aim 2: To compare the relationship of synaptic density PET and standard 3T MRI measures including global and regional brain atrophy and lesion load with clinical measures of physical disability, cognitive impairment, fatigue and depression in MS patients. Aim 3: To assess the relationship of synaptic density PET with serum neurofilament light chain (NfL) and with serum measurements of inflammatory markers, IL-1β, TNF-α, IL-6, MCP-1 (Monocyte Chemoattractant Protein-1) and MIF-1 (Macrophage Migration Inhibitory Factor-1).

NCT04634994
Conditions
  1. Primary Progressive Multiple Sclerosis
  2. Secondary Progressive Multiple Sclerosis
  3. Relapsing Multiple Sclerosis
  4. Multiple Sclerosis
Interventions
  1. Drug: [F-18]SDM-8
MeSH:Multiple Sclerosis Multiple Sclerosis, Chronic Progressive Sclerosis

Non Imaging Data MS subjects Expanded Disability Severity Scale (EDSS) Timed 25-feet walk (T25W) Modified Fatigue impact Scale Hamilton Depression Rating Scale Wechsler Logical Memory paragraph recall Healthy Controls Folstein Mini Mental Status Examination Hamilton Depression Rating Scale Wechsler Logical Memory paragraph recall --- T25W ---

Primary Outcomes

Description: This will be calculated over whole brain, within white matter, within grey matter, and within MRI-visible lesions.

Measure: Tissue volume of Distribution (Vt)

Time: Through study completion, an average of 1 year

Secondary Outcomes

Description: SUV will be calculated based on standard procedures.

Measure: Standardized uptake values (SUV)

Time: Through study completion, an average of 1 year

10 A Phase 1, Two-part, Open-label Dose-escalation and Double-blind, Placebo-controlled Dose-expansion Study With an Open-label Extension to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis

The purpose of this study is to evaluate the safety and tolerability of ATA188 as a monotherapy in Parts 1 and 2, to determine the recommended Part 2 dose (RP2D) of ATA188 as monotherapy in Part 1, and to evaluate the effect of ATA188 treatment on biological markers of disease activity in cerebral spinal fluid in Part 2 in participants with progressive forms of multiple sclerosis (MS) (primary progressive multiple sclerosis [PPMS] and secondary progressive multiple sclerosis [SPMS]).

NCT03283826
Conditions
  1. Primary Progressive Multiple Sclerosis
  2. Secondary Progressive Multiple Sclerosis
Interventions
  1. Biological: ATA188
  2. Drug: Placebo
MeSH:Multiple Sclerosis Multiple Sclerosis, Chronic Progressive Sclerosis

Part 2: Change from baseline in clinical disability as assessed by the EDSS score and/or Timed 25 foot Walk (T25W) and/or 9-hole Peg Test (9HPT). --- T25W ---

Primary Outcomes

Description: Safety and tolerability

Measure: Part 1 and Part 2: Incidence of adverse events

Time: At 12 months after the first dose of study drug

Measure: Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs

Time: At 12 months after the first dose of study drug

Description: Dose assessment

Measure: Part 1: Recommended Part 2 dose of ATA188 monotherapy

Time: Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)

Description: Antibody assessment and quantification

Measure: Part 2: Change from baseline in immunoglobulin G (IgG) index, including quantification of IgG production

Time: At 12 months after the first dose of study drug

Secondary Outcomes

Description: Changes in disability score

Measure: Part 1: Change from baseline in expanded disability status scale (EDSS) score

Time: At 12 months after the first dose of study drug

Description: Changes in disability score

Measure: Part 2: Change from baseline in clinical disability as assessed by the EDSS score and/or Timed 25 foot Walk (T25W) and/or 9-hole Peg Test (9HPT)

Time: At 12 months after the first dose of study drug

Description: Change in MRI activity

Measure: Part 2: Change from baseline in cervical spinal cord volume and whole brain volume on MRI scans

Time: At 12 months after the first dose of study drug

Description: Change in MRI activity

Measure: Part 2: Change from baseline in the number of Gadolinium-enhancing and new or enlarging T2 lesions on brain MRI scans

Time: At 12 months after the first dose of study drug


HPO Nodes


HP:0012378: Fatigue
Genes 399
TLL1 SLC25A26 IGH SERPINA6 MEN1 COL1A1 NPM1 ZBTB16 ABCC2 DDB2 KIT SH2B3 IKZF1 MALT1 SOX3 ATM TCF4 HLA-DPA1 GATA6 TP53 SCNN1G NAB2 ALB DCTN1 PROKR2 TGFBR2 NLRP3 IGH TAZ HBA1 GNAS RARA ALAS2 VAPB SLC26A4 MORC2 TXNRD2 NKX2-5 TRAF3 PIK3CA MYD88 MYH6 TSC1 ATRX HLA-DPB1 KCNN4 SLC40A1 PMS2 DUOXA2 COL9A1 SLC22A4 CBL DLST TNPO3 MEN1 TCF3 DNMT3A HESX1 HESX1 AP2S1 PROP1 STAT5B TARDBP DNAJC6 CTLA4 EPAS1 TET2 MRAP MATR3 ERCC3 COL5A1 KCNE1 CDH23 CD46 CCDC78 BCL2 FOXP1 KRAS GLA CHRND PHKG2 NLRP3 PRPH NKX2-1 KIT SLC12A3 PYGM HNF4A NF1 IL12RB1 SDHAF2 SOX3 SLC25A4 PRKAR1A SLC18A2 CALR AIP FAN1 PRTN3 TET2 MDM4 SDHD SLC4A1 POU1F1 LHX4 ATP13A2 NEFH PDE8B HBA2 PREPL GATA2 ERCC2 STAR IYD BRCA1 DNM1L MET PODXL USP8 KIF1B ARNT2 PAX8 SCNN1A CCNF GPR101 C4A HNF1A MAX CCND1 INSR BTK MSH6 PDGFRA MEFV VCP PALLD TBX20 BCL10 TICAM1 TRNK BCL6 NUMA1 PADI4 GATA4 JAK2 KL MSH2 SDHC EIF2AK4 GBA CITED2 LBR HLA-DRB1 PTPN22 ERBB4 TNFSF15 SLC26A4 DAO SDHA CAV3 NLRP3 STAT6 CDC73 HAVCR2 HMGCL PTPN22 FGFR1 DUOX2 SDHB MMEL1 IL10 LRRC8A IL12A-AS1 EPHA4 CHCHD10 CHMP2B PIEZO1 TSHR NNT DMD KIF23 TSC2 TAF15 ERCC4 TSHB COL9A2 IL18BP TNXB IL12A NKX2-5 CD244 OPTN POLG2 SLC11A1 DBH IRF5 XPC SDHB NLRP3 NABP1 PNPLA8 PTPN22 MC2R CFI NAGS CTNNB1 RPS20 GLE1 ACTC1 OTX2 VHL PIGA UNC13A TBK1 CDH23 MYH7 PFN1 SPIB TRHR SLC2A10 PDE11A GLI2 CDH23 IL12B EPCAM XPA PON2 IL10 TBX19 ATP13A2 PLEC WIPF1 COMP SDHD FOXA2 PTPN3 BCOR LHX3 PROP1 PYGL RRM2B HESX1 FIG4 IL12A TWNK UNC93B1 MPL CDKN2A COL1A2 PMS1 CCND1 BRCA2 PROP1 MLX C9ORF72 SMAD3 IGLL1 MST1 TK2 SRSF2 IGHM CD79A PIK3R1 POMGNT1 OPA1 SDHB CD79B IVNS1ABP CFH CITED2 FTL CFAP410 MLH1 FOXE1 IL23R STAT3 PAX8 COQ2 STEAP3 PRKAR1A PON1 HNRNPA1 AGK SMAD4 GCK IGH TFR2 POLG OTX2 FGF23 ATXN2 NR3C1 HLA-B PIGT PGM1 TLR4 LHX4 ARMC5 SEMA4A SDHA BCR IRF2BP2 PALB2 TET2 ASXL1 WAS DMPK ERCC5 POU1F1 RET C1QBP TET2 ATP7A GLT8D1 KCNQ1 CARMIL2 ARMC5 SCNN1B KRAS JAK2 TSHR STAT4 TWNK SMAD3 TG ACADM TMEM127 RUNX1 SLC18A3 ANG TBX20 ANXA11 CCR1 GCH1 MDH2 UBAC2 HFE BIRC3 AIP EPOR PHKA2 BMPR1A MMADHC FAS CPT1A UBQLN2 NLRC4 PSTPIP1 SOX2 PON3 COL9A3 NR3C1 POU2AF1 ERAP1 PRKACA ALB TLR3 CDC73 SLC3A1 TET2 SLC5A5 PML VHL FIP1L1 MLH3 TBK1 ELANE JAK2 NEK1 TBL1XR1 TREM2 FH KLRC4 HLA-B PPARGC1A SQSTM1 HLA-DRB1 NFKB2 MPL VHL SOD1 TPO TLL1 HELLPAR ABL1 SYNJ1 GPR35 CIITA RUNX1 BLNK SLC25A11 FUS RET COL5A2 DYSF SDHC NFKBIL1 BTNL2 HLA-B
Protein Mutations 3
T25W V158M V18M
SNP 0