Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias

Официальное название

Clinical Research Consortium for the Study of Cerebellar Ataxias (CRC-SCA) for the Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias (SCA)

Обзор

Spinocerebellar ataxias (SCA) are genetic neurological diseases that cause imbalance, poor coordination, and speech difficulties. There are different kinds of SCAs and this study will focus on types 1, 2, 3, 6, 7, 8, 10, 27B, and RFC1-ataxia (SCA 1, SCA 2, SCA 3, also known as Machado-Joseph disease, SCA 6, SCA 7, SCA 8, SCA 10, SCA27B, and RFC1-ataxia, also known as CANVAS). The diseases are rare, slowly progressive, cause increasingly severe neurological difficulties, and are variable across and within genotypes. The purpose of this research study is to bring together a group of experts in the field of SCA for the purpose of learning more about the disease. The research questions are: 1. How do these diseases progress over time? 2. What are the best ways to measure the progression? 3. Do some genes, other than the gene that is abnormal in these diseases, have any effect on the way the disease behaves? This is a nationwide study and the investigators expect that 1400 patients will participate all over North America. The participants will remain in the study for an indeterminate period of time, for as long as they are willing to participate. Study visits will be done every 12 months. Within the broader CRC-SCA, there is an Imaging Sub-study aiming to identify magnetic resonance imaging (MRI) markers sensitive to the onset and progression of common SCAs. To accomplish this, participants attend annual visits involving a neurological exam, surveys, a blood draw, and an MRI scan. Participants can attend visits at one of three US locations - Minneapolis, MN; Gainesville, FL; or Dallas, TX and two European locations - Paris, France and Bonn, Germany. Eligible participants must either have SCA1, 2, or 3 or have been a participant of the previous READISCA study (NCT03487367). Gene-positive participants must have a SARA score less than 10; however, there is no SARA limit for participants previously enrolled in READISCA. All participants must be 18 years or older. Gene-negative participants should be 25-65 years old.

Подробное описание

Study participants will have 2 teaspoons (10 milliliters) of blood collected during the first/screening visit in order to extract DNA. The sample will be sent to the University of Chicago Genetics Laboratory for the study of genetic factors that modify the course of the disease.

Participants will be asked to return for visits on an annual basis. As part of this study, whole blood samples will be collected from participants at each visit and deposited into a tissue repository called BioSEND (NINDS biomarker repository housed at Indiana University). Sample submissions to the repository may give scientists valuable research material that can help develop new diagnostic tests, new treatments, and new ways to prevent diseases. Scientists will not use participant samples, or material isolated from it, for commercial products or services.

CSF collection is an optional part of this study for SCA participants aged 18 years or older. If a participant declines the CSF collection, the participant will be allowed to continue with participation in the remainder of the study.

Participant samples will not have the participant's name or other personal information linked to it. Samples may be shared with researchers at other institutions. The only information the researchers will keep with the sample is participant age, disease type, the age at onset of disease, and the duration of the disease. The principal investigator at a participant's study site will be the only person who can link the sample to a participant. Participants can have their samples removed from the bank later by written request to their principal investigator.

At each annual visit, study participants will also be asked to complete several assessments that include questionnaires, motor function tests, a cognitive assessment, a neurological exam, and an MRI scan if enrolled in the MRI Sub-study.

Вмешательства

• Генная терапия Genetic Testing
  About two teaspoons (10 milliliters) of blood will be collected during the first/screening visit to determine SCA type.
• Другое Blood Collection
  Up to 50 milliliters of total blood (whole blood, plasma, serum) may be collected at each visit to measure markers of neurological disease.
• Другое Magnetic Resonance Imaging (MRI) Scan
  Participants in the sub-study will undergo an MRI scan of head and spine lasting up to 90 minutes at 3 Tesla strength.
• Другое Assessments and Questionnaires
  Participants will complete various motor function and cognitive assessments and self-report questionnaires.
• Другое Cerebrospinal Fluid Collection
  (Optional) About 1 1/2 tablespoon (25ml) of CSF collected in adults.

Первичные конечные точки

• Scale for the Assessment and Rating of Ataxia (SARA) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Patient-Reported Outcome Measure of Ataxia (PROM-ataxia) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Pons Volume [Срок оценки: At baseline and then at a 12 month follow-up Visit]
• Timed 25-Foot Walk (T25-FW) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]

Вторичные конечные точки (8)

• The modified Friedreich Ataxia Rating Scale - Part E (mFARS-E) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Friedrich's Ataxia Activities of Daily Living (FA-ADL) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Brief Ataxia Rating Scale (BARS) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Cerebellar Cognitive Affective Syndrome (CCAS) Scale [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Nine-Hole Peg Test (9-HPT) [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• EuroQol 5-Dimension Questionnaire (EQ-5D) Index Score [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Fatigue Severity Scale [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]
• Fall Questionnaire [Срок оценки: At baseline and then at 12 month intervals for Follow-Up Visit]

Критерии участия

Критерии включения

• Affected individuals aged 6 or above with symptoms and/or signs of ataxia with genetic confirmation of SCA 1, 2, 3, 6, 7, 8, 10, 27B, or RFC1-ataxia either in themselves or first degree family member.
• Any individual aged 18 or above with a definite molecular diagnosis of SCA 1, 2, 3, 6, 7, 8, 10, 27B, or RFC1-ataxia.
• Former participants of the READISCA (NCT03487367) study.
• Willingness to participate in the study and ability to give informed consent
• For MRI Sub-Study only: Previous READISCA enrollees; individuals aged 18 or above with a genetic confirmation of SCA1, 2, or 3 and a SARA score <10 at MRI pre-screening; Healthy control participants without neurological condition.

Критерии исключения

• Exclusion of SCA 1, 2, 3, 6, 7, 8, 10, 27B, or RFC1-ataxia by previous DNA testing.
• A lack of willingness to participate in the study
• For MRI Sub-study only: Inability to undergo MRI scanning, pregnancy, and other neurological diseases than those of interest.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 16 центров

• University of California Los Angeles — Los Angeles
• University of California San Francisco — San Francisco
• University of Florida — Gainesville
• University of South Florida — Tampa
• Emory University — Atlanta
• Nortwestern University — Chicago
• University of Chicago — Chicago
• John Hopkins University — Baltimore
• … и ещё 8 центров

Канада · 1 центр

• Le Centre hospitalier de l'Université de Montréal — Montreal

Публикации

• Lin Y, Amokrane N, Worley S, Moore LR, Rosen A, Crespo LP, Trace K, Ashizawa T, Billnitzer A, Perlman S, Fisher A, Bushara K, Geschwind MD, Dietiker C, Gomez CM, Padmanaban M, Opal P, Akhtar RS, Paulson H, Srinivasan S, Ferng A, Ferrari F, Onyike CU, Fishman A, Ying S, Paul A, Schmahmann JD, Stephen CD, Gupta A, Lin CC, Subramony SH, Burns M, Wilmot G, Duquette A, Zesiewicz T, Davis MY, Hamedani A PMID 40679685
• Lin CC, Ashizawa T, Kuo SH. Collaborative Efforts for Spinocerebellar Ataxia Research in the United States: CRC-SCA and READISCA. Front Neurol. 2020 Aug 26;11:902. doi: 10.3389/fneur.2020.00902. eCollection 2020. PMID 32982927
• Gan SR, Wang J, Figueroa KP, Pulst SM, Tomishon D, Lee D, Perlman S, Wilmot G, Gomez CM, Schmahmann J, Paulson H, Shakkottai VG, Ying SH, Zesiewicz T, Bushara K, Geschwind MD, Xia G, Subramony SH, Ashizawa T, Kuo SH. Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias. Tremor Other Hyperkinet Mov (N Y). 2017 Oct 9;7:492. doi: 10.7916/D8GM8KRH. eCollection 2017. PMID 29057148
• Kuo PH, Gan SR, Wang J, Lo RY, Figueroa KP, Tomishon D, Pulst SM, Perlman S, Wilmot G, Gomez CM, Schmahmann JD, Paulson H, Shakkottai VG, Ying SH, Zesiewicz T, Bushara K, Geschwind MD, Xia G, Subramony SH, Ashizawa T, Kuo SH. Dystonia and ataxia progression in spinocerebellar ataxias. Parkinsonism Relat Disord. 2017 Dec;45:75-80. doi: 10.1016/j.parkreldis.2017.10.007. Epub 2017 Oct 23. PMID 29089256
• Luo L, Wang J, Lo RY, Figueroa KP, Pulst SM, Kuo PH, Perlman S, Wilmot G, Gomez CM, Schmahmann J, Paulson H, Shakkottai VG, Ying SH, Zesiewicz T, Bushara K, Geschwind M, Xia G, Subramony SH, Ashizawa T, Kuo SH. The Initial Symptom and Motor Progression in Spinocerebellar Ataxias. Cerebellum. 2017 Jun;16(3):615-622. doi: 10.1007/s12311-016-0836-3. PMID 27848087
• Selvadurai LP, Perlman SL, Wilmot GR, Subramony SH, Gomez CM, Ashizawa T, Paulson HL, Onyike CU, Rosenthal LS, Sair HI, Kuo SH, Ratai EM, Zesiewicz TA, Bushara KO, Oz G, Dietiker C, Geschwind MD, Nelson AB, Opal P, Yacoubian TA, Nopoulos PC, Shakkottai VG, Figueroa KP, Pulst SM, Morrison PE, Schmahmann JD. The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Impl PMID 35962273
• Jen JC, Ashizawa T, Griggs RC, Waters MF. Rare neurological channelopathies--networks to study patients, pathogenesis and treatment. Nat Rev Neurol. 2016 Apr;12(4):195-203. doi: 10.1038/nrneurol.2016.18. Epub 2016 Mar 4. PMID 26943780
• Lo RY, Figueroa KP, Pulst SM, Perlman S, Wilmot G, Gomez C, Schmahmann J, Paulson H, Shakkottai VG, Ying S, Zesiewicz T, Bushara K, Geschwind M, Xia G, Yu JT, Lee LE, Ashizawa T, Subramony SH, Kuo SH. Depression and clinical progression in spinocerebellar ataxias. Parkinsonism Relat Disord. 2016 Jan;22:87-92. doi: 10.1016/j.parkreldis.2015.11.021. Epub 2015 Nov 22. PMID 26644294

Идентификаторы

NCT: NCT01060371 · IRB201700740 · 505-2009 · OCR16458

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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