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Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. In this randomized, double-blind, sham-controlled study, the investigators will evaluate whether a two-weeks' treatment with cerebellar anodal tDCS and spinal cathodal tDCS can improve symptoms in patients with neurodegenerative cerebellar ataxia and can modulate cerebello-motor connectivity, at short and long term.
Neurodegenerative cerebellar ataxias represent a heterogeneous group of disabling disorders in which progressive ataxia of gait, limb dysmetria, oculomotor deficits, dysarthria and kinetic tremor are the prominent clinical manifestations. Both the hereditary and sporadic forms usually present in young adulthood, and are characterized by atrophy of cerebellar or brainstem structures. Currently, cerebellar ataxia lack effective disease-modifying therapies.
Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present randomized, double-blind, sham-controlled study will investigate whether a two-weeks' treatment with cerebellar anodal tDCS and spinal cathodal tDCS can improve symptoms in patients with neurodegenerative cerebellar ataxia and can modulate cerebello-motor connectivity, at short and long term.
Subjects will be randomized in two groups, one receiving a 10 day (5 days/week for 2 weeks) treatment with anodal cerebellar and cathodal spinal tDCS and the other receiving sham stimulation with identical parameters. After the intervention, patients will be reassessed with a clinical and neurophysiological evaluation at 2 weeks, 1 months and 3 month after treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Real tDCS | Experimental | 10 days anodal cerebellar and cathodal spinal tDCS |
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| Sham tDCS | Sham Comparator | 10 days sham cerebellar and sham spinal tDCS |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anodal cerebellar and cathodal spinal tDCS | Device | 10 sessions of anodal cerebellar and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in the International Cooperative Ataxia Rating Scale (ICARS) Score From Baseline | International Cooperative Ataxia Rating Scale (ICARS): semi-quantitative 100-point scale, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). | Baseline - 2 weeks |
| Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score From Baseline | Scale for the Assessment and Rating of Ataxia (SARA): 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). | Baseline - 2 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the International Cooperative Ataxia Rating Scale (ICARS) Score From Baseline | International Cooperative Ataxia Rating Scale (ICARS): semi-quantitative 100-point scale, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). | Baseline - 2 weeks - 1 month - 3 months |
| Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score From Baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Barbara Borroni, MD | Azienda Ospedaliera Spedali Civili, Brescia | Principal Investigator |
| Alberto Benussi, MD | Università degli Studi di Brescia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AO Spedali Civili | Brescia | BS | 25100 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26274840 | Background | Benussi A, Koch G, Cotelli M, Padovani A, Borroni B. Cerebellar transcranial direct current stimulation in patients with ataxia: A double-blind, randomized, sham-controlled study. Mov Disord. 2015 Oct;30(12):1701-5. doi: 10.1002/mds.26356. Epub 2015 Aug 14. | |
| 27838276 | Background | Benussi A, Dell'Era V, Cotelli MS, Turla M, Casali C, Padovani A, Borroni B. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia. Brain Stimul. 2017 Mar-Apr;10(2):242-250. doi: 10.1016/j.brs.2016.11.001. Epub 2016 Nov 3. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Real tDCS, Then Sham tDCS | Participants first received real tDCS (anodal cerebellar and cathodal spinal tDCS) 5 days/week for 2 weeks. After a washout period of 6 months, they then received sham tDCS (sham cerebellar and sham spinal tDCS) 5 days/week for 2 weeks. |
| FG001 | Sham tDCS, Then Real tDCS |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Intervention (2 Weeks) |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 21, 2016 |
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| Sham cerebellar and sham spinal tDCS | Device | 10 sessions of sham cerebellar and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
|
Scale for the Assessment and Rating of Ataxia (SARA): 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). |
| Baseline - 2 weeks - 1 month - 3 months |
| Change in the 9 Hole Peg Test (9HPT) Score From Baseline | 4 timed trials of the 9 hole peg test (9HPT) were performed and averaged (mean values are reported) for each separate hand (dominant and nondominant). The total time to complete the task is recorded for each trial and for each separate hand (dominant and nondominant). Longer times represent greater impairment. | Baseline - 2 weeks - 1 month - 3 months |
| Change in the 8-Meter Walking Time (8MW) Score From Baseline | 4 timed trials of the 8 meter walking time (8MW) were performed and averaged (mean values are reported). Longer times represent greater impairment. | Baseline - 2 weeks - 1 month - 3 months |
| Change in Cerebellar Brain Inhibition (CBI) Measurements From Baseline | Cerebellar brain inhibition (CBI) is expressed as motor evoked potential amplitude (average of 10 recordings). Lower values reflect higher inhibition and thus reduced impairment. | Baseline - 2 weeks - 1 month - 3 months |
| Change in the Short-Form Health Survey 36 (SF36) Score From Baseline | The Italian version of the Short-Form Health Survey 36 (SF-36): consists of 36 scaled score, yielding a total score of 0 (more disability) to 100 (less disability). | Baseline - 2 weeks - 1 month - 3 months |
| 27372845 | Background | Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, Mourdoukoutas AP, Kronberg G, Truong D, Boggio P, Brunoni AR, Charvet L, Fregni F, Fritsch B, Gillick B, Hamilton RH, Hampstead BM, Jankord R, Kirton A, Knotkova H, Liebetanz D, Liu A, Loo C, Nitsche MA, Reis J, Richardson JD, Rotenberg A, Turkeltaub PE, Woods AJ. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016 Sep-Oct;9(5):641-661. doi: 10.1016/j.brs.2016.06.004. Epub 2016 Jun 15. |
| 25797650 | Background | Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015 Jun;126(6):1071-1107. doi: 10.1016/j.clinph.2015.02.001. Epub 2015 Feb 10. |
| 28269725 | Background | Miranda PC, Salvador R, Wenger C, Fernandes SR. Computational models of non-invasive brain and spinal cord stimulation. Annu Int Conf IEEE Eng Med Biol Soc. 2016 Aug;2016:6457-6460. doi: 10.1109/EMBC.2016.7592207. |
| 27866120 | Background | Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29. |
| 27799905 | Background | Fiocchi S, Ravazzani P, Priori A, Parazzini M. Cerebellar and Spinal Direct Current Stimulation in Children: Computational Modeling of the Induced Electric Field. Front Hum Neurosci. 2016 Oct 17;10:522. doi: 10.3389/fnhum.2016.00522. eCollection 2016. |
| 28032321 | Background | van Dun K, Bodranghien F, Manto M, Marien P. Targeting the Cerebellum by Noninvasive Neurostimulation: a Review. Cerebellum. 2017 Jun;16(3):695-741. doi: 10.1007/s12311-016-0840-7. |
| 30135258 | Result | Benussi A, Dell'Era V, Cantoni V, Bonetta E, Grasso R, Manenti R, Cotelli M, Padovani A, Borroni B. Cerebello-spinal tDCS in ataxia: A randomized, double-blind, sham-controlled, crossover trial. Neurology. 2018 Sep 18;91(12):e1090-e1101. doi: 10.1212/WNL.0000000000006210. Epub 2018 Aug 22. |
Participants first received sham tDCS (sham cerebellar and sham spinal tDCS) 5 days/week for 2 weeks. After a washout period of 6 months, they then received real tDCS (anodal cerebellar and cathodal spinal tDCS) 5 days/week for 2 weeks. |
| Received Intervention |
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| COMPLETED |
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| NOT COMPLETED |
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| Washout (6 Months) |
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| Second Intervention (2 Weeks) |
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Baseline analysis are reported for 20 participants who completed the first intervention
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Participants who were randomized to receive either real tDCS or sham tDCS |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Scale for the Assessment and Rating of Ataxia (SARA) score | Scale for the Assessment and Rating of Ataxia (SARA): clinical scale that is based on a semi-quantitative assessment of cerebellar ataxia on an impairment level. It consists of an 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). | Mean | Standard Deviation | units on a scale |
| ||||||||||||||||
| International Cooperative Ataxia Rating Scale (ICARS) score | International Cooperative Ataxia Rating Scale (ICARS): semi-quantitative 100-point scale consisting of 19 items divided into 4 weighted subscores including posture and gait disturbances, limb kinetic function, speech disorder, and oculomotor deficits, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). | Mean | Standard Deviation | units on a scale |
| ||||||||||||||||
| 9 Hole Peg Test (Dominant hand) | 4 timed trials of the 9 hole peg test (9HPT) were performed and averaged (mean values are reported) for each separate hand (dominant and nondominant). The 9HPT is a commonly used test to assess finger dexterity: the patient picks the pegs 1 at time and puts them in 9 holes on a peg board until all holes are filled and then removes them 1 at a time as quickly as possible. The total time to complete the task is recorded for each trial and for each separate hand (dominant and nondominant). Longer times represent greater impairment. | Mean | Standard Deviation | seconds |
| ||||||||||||||||
| 9 Hole Peg Test (non-Dominant hand) | 4 timed trials of the 9 hole peg test (9HPT) were performed and averaged (mean values are reported) for each separate hand (dominant and nondominant). The 9HPT is a commonly used test to assess finger dexterity: the patient picks the pegs 1 at time and puts them in 9 holes on a peg board until all holes are filled and then removes them 1 at a time as quickly as possible. The total time to complete the task is recorded for each trial and for each separate hand (dominant and nondominant). Longer times represent greater impairment. | Mean | Standard Deviation | seconds |
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| 8 Meter Walking Time | 4 timed trials of the 8 meter walking time (8MW) were performed and averaged (mean values are reported). The 8MW is defined as the time needed to walk 8 m as quickly as possible but safely with any device but without the help of another person or wall. Longer times represent greater impairment. | Mean | Standard Deviation | seconds |
| ||||||||||||||||
| Short-Form Health Survey 36 | The Italian version of the Short-Form Health Survey 36 (SF-36), an interview-administered self-reported scale consisting of 36 scaled scores assessing 8 subdomains (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health, communication, psychosocial and energy), was used to assess changes in the patient's quality of life. The scale ranges from 0 (more disability) to 100 (less disability). | Mean | Standard Deviation | units on a scale |
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| Cerebellar Brain Inhibition | Cerebellar brain inhibition (CBI) is evaluated with a transcranial magnetic stimulation (TMS) protocol, using two coils. One placed over the cerebellar hemisphere and the other positioned on the contralateral primary motor cortex, with motor evoked potentials (MEPs) recorded on the first dorsal interosseous muscle. CBI measures the inhibition exerted by cerebellar structures on the motor cortex, and thus on MEPs amplitude, reflecting the integrity of the cerebellar-thalamo-cortical pathway. Lower values reflect higher inhibition and thus reduced impairment. | Mean | Standard Deviation | milli volt |
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| 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 | Change in the International Cooperative Ataxia Rating Scale (ICARS) Score From Baseline | International Cooperative Ataxia Rating Scale (ICARS): semi-quantitative 100-point scale, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks |
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| Primary | Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score From Baseline | Scale for the Assessment and Rating of Ataxia (SARA): 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks |
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| Secondary | Change in the International Cooperative Ataxia Rating Scale (ICARS) Score From Baseline | International Cooperative Ataxia Rating Scale (ICARS): semi-quantitative 100-point scale, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 1 month - 3 months |
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| Secondary | Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score From Baseline | Scale for the Assessment and Rating of Ataxia (SARA): 8-item performance based scale, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 1 month - 3 months |
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| Secondary | Change in the 9 Hole Peg Test (9HPT) Score From Baseline | 4 timed trials of the 9 hole peg test (9HPT) were performed and averaged (mean values are reported) for each separate hand (dominant and nondominant). The total time to complete the task is recorded for each trial and for each separate hand (dominant and nondominant). Longer times represent greater impairment. | Posted | Mean | Standard Deviation | seconds | Baseline - 2 weeks - 1 month - 3 months |
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| Secondary | Change in the 8-Meter Walking Time (8MW) Score From Baseline | 4 timed trials of the 8 meter walking time (8MW) were performed and averaged (mean values are reported). Longer times represent greater impairment. | Posted | Mean | Standard Deviation | seconds | Baseline - 2 weeks - 1 month - 3 months |
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| Secondary | Change in Cerebellar Brain Inhibition (CBI) Measurements From Baseline | Cerebellar brain inhibition (CBI) is expressed as motor evoked potential amplitude (average of 10 recordings). Lower values reflect higher inhibition and thus reduced impairment. | Posted | Mean | Standard Deviation | millivolts | Baseline - 2 weeks - 1 month - 3 months |
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| Secondary | Change in the Short-Form Health Survey 36 (SF36) Score From Baseline | The Italian version of the Short-Form Health Survey 36 (SF-36): consists of 36 scaled score, yielding a total score of 0 (more disability) to 100 (less disability). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 1 month - 3 months |
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9 months
Adverse event has been defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
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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 | Real tDCS, Then Sham tDCS | Participants who were randomized to receive real tDCS first and then sham tDCS | 0 | 10 | 0 | 10 | 0 | 10 |
| EG001 | Sham tDCS, Then Real tDCS | Participants who were randomized to receive sham tDCS first and then real tDCS | 0 | 11 | 0 | 11 | 0 | 11 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Barbara Borroni | University of Brescia | +39 0303995631 | bborroni@inwind.it |
| Dec 22, 2018 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D002524 | Cerebellar Ataxia |
| D020754 | Spinocerebellar Ataxias |
| D017827 | Machado-Joseph Disease |
| D013132 | Spinocerebellar Degenerations |
| D005621 | Friedreich Ataxia |
| C537308 | Spinocerebellar ataxia, autosomal recessive 1 |
| D019578 | Multiple System Atrophy |
| ID | Term |
|---|---|
| D002526 | Cerebellar Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D001259 | Ataxia |
| D020820 | Dyskinesias |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D013118 | Spinal Cord Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D028361 | Mitochondrial Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D001480 | Basal Ganglia Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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