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| Name | Class |
|---|---|
| Biogen | INDUSTRY |
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The purpose of this investigation is to systematically study the efficacy of Tecfidera in those individuals who possess incidental white matter anomalies within the brain following a MRI study that is performed for a reason other than for the evaluation of MS (multiple sclerosis).
This is a multi-center, randomized, double-blinded study in which approximately 90 RIS (radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo for 2 years (1:1 randomization). Study participants, along with the treating and examining physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S.
Following informed consent and verification of entry criteria by the core units, study participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or immediately following clinical exacerbations. During clinical visits, comprehensive medical history data will be obtained by the treating physician. All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to re-evaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made. In addition to the face-to-face visits described above, study participants will be contacted over the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties and for study medication compliance. Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain and/or spinal cord performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the cervical spinal cord with and without contrast will be recommended to study participants at week 96 as medical standard of care.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tecfidera | Active Comparator | Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) |
|
| Placebo | Placebo Comparator | Placebo by mouth twice daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tecfidera | Drug | Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
| Measure | Description | Time Frame |
|---|---|---|
| The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial. | 96 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Lesion Volume on T2-weighted MRI | Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | Baseline, 96 weeks |
| Number of Newly Enlarging T2 Lesions |
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Inclusion criteria
Males and females meeting 2009 RIS criteria
Identified RIS cases with the initial MRI demonstrating anomalies suggestive of demyelinating disease dated > 2009
Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI resulting from an evaluation of a process other than MS
CNS white matter anomalies meeting the following MRI criteria:
MRI anomalies do not account for clinically apparent neurological impairments in patients
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Darin T Okuda, MD | University of Texas Southwestern Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Keck School of Medicine - USC - Department of Neurology | Los Angeles | California | 90089 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16283615 | Background | Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec;58(6):840-6. doi: 10.1002/ana.20703. | |
| 21387374 |
| Label | URL |
|---|---|
| Tecfidera USPI | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tecfidera | Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) Tecfidera: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 5, 2018 | Mar 10, 2022 |
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|
| Placebo | Drug | Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
|
Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
| 96 weeks |
| Number of New T2 Lesions | Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks |
| Newly Enlarging T2 Lesions and New T2 Lesions Combined | Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks |
| Number of Contrast Enhancing Lesions | Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks |
| Change in the Number of Participants With Brain Atrophy | Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | Baseline, 96 weeks |
| Johns Hopkins University - Neurology |
| Baltimore |
| Maryland |
| 21287 |
| United States |
| Mayo Clinic Department of Neurology | Rochester | Minnesota | 55905 | United States |
| Washington University Department of Neurology | St Louis | Missouri | 63110 | United States |
| Cleveland Clinic - Lou Ruvo Center for Brain Health | Las Vegas | Nevada | 89106 | United States |
| MS Clinical Care and Research Center, Dept of Neurology, Columbia University | New York | New York | 10032 | United States |
| Oklahoma Medical Research Foundation, MS Center of Excellence | Oklahoma City | Oklahoma | 73104 | United States |
| MS Treatment Center of Dallas | Dallas | Texas | 75246 | United States |
| UT Southwestern Medical Center | Dallas | Texas | 75390-8806 | United States |
| Swedish Medical Center | Seattle | Washington | 98122 | United States |
| MultiCare Institute for Research and Innovation | Tacoma | Washington | 98405 | United States |
| Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366. |
| 18202208 | Background | Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P, Brassat D, Labauge P, Roullet E; CFSEP. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):195-8. doi: 10.1136/jnnp.2006.108274. |
| 19667020 | Background | Siva A, Saip S, Altintas A, Jacob A, Keegan BM, Kantarci OH. Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease. Mult Scler. 2009 Aug;15(8):918-27. doi: 10.1177/1352458509106214. |
| 20610492 | Background | Lebrun C, Blanc F, Brassat D, Zephir H, de Seze J; CFSEP. Cognitive function in radiologically isolated syndrome. Mult Scler. 2010 Aug;16(8):919-25. doi: 10.1177/1352458510375707. Epub 2010 Jul 7. |
| 21559385 | Background | De Stefano N, Stromillo ML, Rossi F, Battaglini M, Giorgio A, Portaccio E, Hakiki B, Malentacchi G, Gasperini C, Santangelo M, Bartolozzi ML, Sormani MP, Federico A, Amato MP. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One. 2011 Apr 29;6(4):e19452. doi: 10.1371/journal.pone.0019452. |
| 22740024 | Background | Gabelic T, Radmilovic M, Posavec V, Skvorc A, Boskovic M, Adamec I, Milivojevic I, Barun B, Habek M. Differences in oligoclonal bands and visual evoked potentials in patients with radiologically and clinically isolated syndrome. Acta Neurol Belg. 2013 Mar;113(1):13-7. doi: 10.1007/s13760-012-0106-1. Epub 2012 Jun 28. |
| 22076541 | Background | Giorgio A, Stromillo ML, Rossi F, Battaglini M, Hakiki B, Portaccio E, Federico A, Amato MP, De Stefano N. Cortical lesions in radiologically isolated syndrome. Neurology. 2011 Nov 22;77(21):1896-9. doi: 10.1212/WNL.0b013e318238ee9b. Epub 2011 Nov 9. |
| 22300971 | Background | Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, Okuda DT; Club Francophone de Sclerose en Plaques (CFSEP); Radiologically Isolated Syndrome Consortium (RISC) Group. Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler. 2012 Sep;18(9):1297-302. doi: 10.1177/1352458511435931. Epub 2012 Feb 2. |
| 21270417 | Background | Okuda DT, Mowry EM, Cree BA, Crabtree EC, Goodin DS, Waubant E, Pelletier D. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 2011 Feb 22;76(8):686-92. doi: 10.1212/WNL.0b013e31820d8b1d. Epub 2011 Jan 26. |
| 19073949 | Result | Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, Hauser SL, Pelletier D. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009 Mar 3;72(9):800-5. doi: 10.1212/01.wnl.0000335764.14513.1a. Epub 2008 Dec 10. |
| 36401339 | Derived | Okuda DT, Kantarci O, Lebrun-Frenay C, Sormani MP, Azevedo CJ, Bovis F, Hua LH, Amezcua L, Mowry EM, Hotermans C, Mendoza J, Walsh JS, von Hehn C, Vargas WS, Donlon S, Naismith RT, Okai A, Pardo G, Repovic P, Stuve O, Siva A, Pelletier D. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Ann Neurol. 2023 Mar;93(3):604-614. doi: 10.1002/ana.26555. Epub 2022 Dec 10. |
| FG001 |
| Placebo |
Placebo by mouth twice daily. Placebo: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
| COMPLETED |
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| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Tecfidera | Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) Tecfidera: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
| BG001 | Placebo | Placebo by mouth twice daily. Placebo: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Expanded Disability Status Scale (EDSS) | The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. | Median | Full Range | units on a scale |
| ||||||||||||||
| Multiple Sclerosis (MS) family history | Count of Participants | Participants |
| ||||||||||||||||
| Presence of gadolinium enhancing lesions | 11 missing data | Count of Participants | Participants |
| |||||||||||||||
| T2-weighted hyperintense lesion volume | 4 missing data | Mean | Standard Deviation | mm^3 |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial. | Posted | Mean | Standard Deviation | weeks | 96 weeks |
|
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| |||||||||||||||||||||||||||||
| Secondary | Change in Lesion Volume on T2-weighted MRI | Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed. 3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed. | Posted | Mean | Standard Deviation | mm³ | Baseline, 96 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | Number of Newly Enlarging T2 Lesions | Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed. 3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed. | Posted | Mean | Standard Deviation | T2 lesions | 96 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | Number of New T2 Lesions | Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed. 3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed. | Posted | Mean | Standard Deviation | T2 lesions | 96 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | Newly Enlarging T2 Lesions and New T2 Lesions Combined | Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed. 3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed. | Posted | Mean | Standard Deviation | T2 lesions | 96 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | Number of Contrast Enhancing Lesions | Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed. 3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed. | Posted | Mean | Standard Deviation | contrast enhancing lesions | 96 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | Change in the Number of Participants With Brain Atrophy | Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | Data were not collected. | Posted | Baseline, 96 weeks |
|
|
2 years
Adverse Events (AE) occurred during 2 years of follow up. AEs were routinely determined through regular investigator assessment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tecfidera | Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) Tecfidera: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. | 0 | 44 | 4 | 44 | 44 | 44 |
| EG001 | Placebo | Placebo by mouth twice daily. Placebo: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. | 0 | 43 | 4 | 43 | 43 | 43 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Procedural headache | Injury, poisoning and procedural complications | MedDRA | Non-systematic Assessment |
| |
| Spondylolysis | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
| |
| Breast cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Non-systematic Assessment |
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| Invasive ductal breast carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
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| Prostate cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Non-systematic Assessment |
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| Renal cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Non-systematic Assessment |
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| Migraine | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Spontaneous cerebrospinal fluid leak syndrome | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vision blurred | Eye disorders | MedDRA | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
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| Chest discomfort | General disorders | MedDRA | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA | Non-systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA | Non-systematic Assessment |
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| Blood glucose increased | Investigations | MedDRA | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Hypoaesthesia | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Urticaria | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
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| Flushing | Vascular disorders | MedDRA | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Darin T. Okuda, M.D. | UT Southwestern Medical Center | 214-645-8800 | darin.okuda@utsouthwestern.edu |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 9, 2021 | Mar 15, 2022 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 5, 2018 | Mar 17, 2022 | ICF_002.pdf |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000069462 | Dimethyl Fumarate |
| ID | Term |
|---|---|
| D005650 | Fumarates |
| D003998 | Dicarboxylic Acids |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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