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出境医 / 临床实验 / Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders (HSP-PBP)

Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders (HSP-PBP)

Study Description
Brief Summary:
The aim of this study is to determine the clinical spectrum and natural progression of Hereditary Spastic Paraplegias (HSP) and related disorders in a prospective multicenter natural history study, identify digital, imaging and molecular biomarkers that can assist in diagnosis and therapy development and study the genetic etiology and molecular mechanisms of these diseases.

Condition or disease Intervention/treatment
Hereditary Spastic Paraplegia Other: Clinical rating scale to measure disease severity and progression Diagnostic Test: Next-Gen Sequencing (NGS)

Detailed Description:

The investigators will perform a registry-based standardized prospective Natural History Study (NHS) in HSPs and related disorders. Participants will be seen annually. At study visits a standardized clinical examination will be performed including application of clinical rating scales (selection of rating scales may vary depending on the individual phenotype and specific genotype); data will be entered into a clinical database (HSP Registry; https://www.hsp-registry.net). At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy.

Optionally, additional examinations may be performed including imaging, quantitative movement analysis, neuropsychological examinations, analysis of patient or observer reported outcomes and OMICS analysis to characterize molecular biomarkers.

In participants without a genetic diagnosis, next generation sequencing may be performed.

Study Design
Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 2000 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 20 Years
Official Title: Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
Actual Study Start Date : October 14, 2019
Estimated Primary Completion Date : August 2039
Estimated Study Completion Date : August 2041
Arms and Interventions
Group/Cohort Intervention/treatment
Primary participant:

Participants affected by hereditary spastic paraplegia (HSP) or a phenotypically related disorder Primary participants will be followed at annual intervals. The workup includes clinical, imaging, sensor-based, patient/observer reported and molecular outcome parameters and biosampling.

Participants with unknown genetic diagnosis may receive genetic testing including whole exome or whole genome sequencing and other OMICS techniques.

 Other: Clinical rating scale to measure disease severity and progression
A 13-item scale to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory.
Other Name: Spastic Paraplegia Rating Scale (SPRS)

Diagnostic Test: Next-Gen Sequencing (NGS)
Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Secondary participant/ First or second-degree
First or second degree unaffected family members of primary participants. Secondary participants may undergo the same study procedures as primary participants.
 Diagnostic Test: Next-Gen Sequencing (NGS)
Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Unrelated healthy control
Unrelated healthy controls Healthy controls may undergo the same study procedures as primary participants.
 Diagnostic Test: Next-Gen Sequencing (NGS)
Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Outcome Measures
Primary Outcome Measures :
  1. Change from baseline of Spastic Paraplegia Rating Scale (SPRS) total score at 2 years [ Time Frame: up to 2 years ]
    Disease severity will be assessed by application of the Spastic Paraplegia Rating Scale (SPRS), a clinical rating scale measuring disease severity in Hereditary Spastic Paraplegia (Schüle et al. Neurology 2006). The SPRS contains 13 items, each ranging from 0 to 4 points. The total score is calculated as the sum of all items, yielding a range for the total score between 0 and 52. Hereby, higher SPRS total scores indicate more severe disease.


Biospecimen Retention:   Samples With DNA
optional biosample collection including blood (DNA, serum, plasma, RNA, PBMC), urine, CSF, skin biopsy

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Probands with a clinical or genetic diagnosis of an HSP and related disorders including pre-manifest individuals will be primarily enrolled in this study (primary participants).

Additionally, unaffected family members of primary participants will be enrolled if they are of legal age (>= 18 years) and able to give informed consent (secondary participants).

Unaffected minors will only be enrolled under special circumstances as detailed in paragraph 5.1 (Special Populations - Unaffected minors).

Lastly, healthy unrelated controls will be enrolled; these are necessary to contrast unspecific, gender- or age-related findings to disease specific findings.

Criteria

Inclusion criteria:

  • One of the following:

    1. Primary participant: Clinical or genetic diagnosis of HSP or a related disorder
    2. Secondary participant: Unaffected family member (1st or 2nd degree relative) of primary participant (with the above-mentioned restrictions for special populations) able to give informed consent

    3. Unrelated healthy control able to give informed consent

      AND

  • Written informed consent

AND

- Participants are willing and able to comply with study procedures

Exclusion criteria:

  • Missing informed consent of primary or secondary participant/ healthy control/ legal representatives
  • For controls: evidence of a neurodegenerative disease or movement disorders; inability to give informed consent
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Rebecca Schüle, PD Dr. +49 7071 29 ext 85653 rebecca.schuele-freyer@uni-tuebingen.de
Contact: Ludger Schöls, Prof. Dr. +49 7071 29 ext 85548 ludger.schoels@uni-tuebingen.de

Locations
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Austria
University Innsbruck Recruiting
Innsbruck, Austria, 6020
Contact: Matthias Amprosi    +43 512 504 83686    matthias.amprosi@i-med.ac.at   
Contact: Sylvia Bösch    +43 512 504 83686    sylvia.boesch@i-med.ac.at   
Principal Investigator: Sylvia Bösch, MD         
Sub-Investigator: Matthias Amprosi, MD         
Germany
German Center for Neurodegenerative Diseases (DZNE) Bonn Recruiting
Bonn, Germany, 53127
Contact: Thomas Klockgether    +49 228 28715726    Thomas.Klockgether@dzne.de   
Principal Investigator: Thomas Klockgether, MD         
Sub-Investigator: Xenia Kobeleva, MD         
University of Erlangen Recruiting
Erlangen, Germany, 91054
Contact: Susanne Seifert    +49 9131 85 44751    susanne.seifert@uk-erlangen.de   
Contact: Pia-Marie Pryssok    +49 9131 85 44751    pia-marie.pryssok@uk-erlangen.de   
Principal Investigator: Jürgen Winkler, MD         
Sub-Investigator: Heiko Gassner, Dr. Phil.         
University Medicine Essen Recruiting
Essen, Germany, 45147
Contact: Sylwia Kante    +49 201 - 7236513    sylwia.kante@uk-essen.de   
Principal Investigator: Stephan Klebe, MD         
University Göttingen Recruiting
Göttingen, Germany, 37075
Contact: Anja Schadenberg    +49 551 39 10206    aschadenberg@med.uni-goettingen.de   
Principal Investigator: Michael Sereda, MD         
Sub-Investigator: Sonja Fritzsch, MD         
Sub-Investigator: Knut Brockmann, MD         
Principal Investigator: Anne van Riesen, MD         
University Heidelberg Not yet recruiting
Heidelberg, Germany, 69120
Contact: Heike Jacobi    +49 6221 - 56 - 7510    Heike.Jacobi@med.uni-heidelberg.de   
Principal Investigator: Heike Jacobi, MD         
University of Lübeck Not yet recruiting
Lübeck, Germany, 23562
Contact: Maike Dümcke-Zilian    +49 451 3101 8215    maike.duemcke-zilian@neuro.uni-luebeck.de   
Principal Investigator: Alexander Münchau, MD         
German Center for Neurogedenerative Diseases (DZNE) Magdeburg Recruiting
Magdeburg, Germany, 39120
Contact: Michaela Butryn    +49 391-67-13431    michaela.butryn@med.ovgu.de   
Principal Investigator: Stefan Vielhaber, MD         
Sub-Investigator: Michaela Butryn, MD         
German Center for Neurodegenerative Diseases (DZNE) München Recruiting
München, Germany, 80336
Contact: Jasmina Al-Tamami    +49 89 4400 57425    jasmina.altamami@med.uni-muenchen.de   
Principal Investigator: Thomas Klopstock, MD         
Sub-Investigator: Florentine Radelfahrt, MD         
University of Regensburg Not yet recruiting
Regensburg, Germany, 93053
Contact: Zacharias Kohl    +49 941 941 3074    zacharias.kohl@ukr.de   
Principal Investigator: Zacharias Kohl, MD         
German Center for Neurodegenerative Diseases (DZNE) Rostock Not yet recruiting
Rostock, Germany, 18147
Contact: Christoph Kamm    +49 381 4944763    christoph.kamm@med.uni-rostock.de   
Principal Investigator: Christoph Kamm, MD         
University of Tübingen and German Center for Neurodegenerative Diseases (DZNE) Tübingen Recruiting
Tübingen, Germany, 72076
Contact: Katrin Dillmann    +49 7071 29 85653    katrin.dillmann@med.uni-tuebingen.de   
Principal Investigator: Rebecca Schüle, MD         
Sub-Investigator: Ludger Schöls, MD         
Sub-Investigator: Ingeborg Krägeloh-Mann, MD         
Sub-Investigator: Marion Döbler-Neumann, MD         
Italy
IRCCS Medea Scientific Institute, Conegliano-PIeve di Soligo Research Centre Not yet recruiting
Pieve di Soligo, Italy, 31053
Contact: Andrea Martinuzzi, MD    0438 414337    andrea.martinuzzi@lanostrafamiglia.it   
Principal Investigator: Andrea Martinuzzi, MD         
Sponsors and Collaborators
Dr. Rebecca Schule
German Federal Ministry of Education and Research
German Center for Neurodegenerative Diseases (DZNE)
Investigators
Layout table for investigator information
Principal Investigator: Rebecca Schüle, PD Dr. University Hospital Tübingen
Tracking Information
First Submitted Date June 4, 2019
First Posted Date June 10, 2019
Last Update Posted Date May 19, 2021
Actual Study Start Date October 14, 2019
Estimated Primary Completion Date August 2039   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 7, 2019) 		Change from baseline of Spastic Paraplegia Rating Scale (SPRS) total score at 2 years [ Time Frame: up to 2 years ]
Disease severity will be assessed by application of the Spastic Paraplegia Rating Scale (SPRS), a clinical rating scale measuring disease severity in Hereditary Spastic Paraplegia (Schüle et al. Neurology 2006). The SPRS contains 13 items, each ranging from 0 to 4 points. The total score is calculated as the sum of all items, yielding a range for the total score between 0 and 52. Hereby, higher SPRS total scores indicate more severe disease.
Original Primary Outcome Measures
 (submitted: June 7, 2019) 		Change from baseline of SPRS at 2 years [ Time Frame: up to 2 years ]
Disease severity will be assessed by application of the Spastic Paraplegia Rating Scale (SPRS), a clinical rating scale measuring disease severity in Hereditary Spastic Paraplegia (Schüle et al. Neurology 2006).
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
Official Title Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
Brief Summary The aim of this study is to determine the clinical spectrum and natural progression of Hereditary Spastic Paraplegias (HSP) and related disorders in a prospective multicenter natural history study, identify digital, imaging and molecular biomarkers that can assist in diagnosis and therapy development and study the genetic etiology and molecular mechanisms of these diseases.
Detailed Description

The investigators will perform a registry-based standardized prospective Natural History Study (NHS) in HSPs and related disorders. Participants will be seen annually. At study visits a standardized clinical examination will be performed including application of clinical rating scales (selection of rating scales may vary depending on the individual phenotype and specific genotype); data will be entered into a clinical database (HSP Registry; https://www.hsp-registry.net). At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy.

Optionally, additional examinations may be performed including imaging, quantitative movement analysis, neuropsychological examinations, analysis of patient or observer reported outcomes and OMICS analysis to characterize molecular biomarkers.

In participants without a genetic diagnosis, next generation sequencing may be performed.
Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration 20 Years
Biospecimen Retention:   Samples With DNA
Description:
optional biosample collection including blood (DNA, serum, plasma, RNA, PBMC), urine, CSF, skin biopsy
Sampling Method Non-Probability Sample
Study Population

Probands with a clinical or genetic diagnosis of an HSP and related disorders including pre-manifest individuals will be primarily enrolled in this study (primary participants).

Additionally, unaffected family members of primary participants will be enrolled if they are of legal age (>= 18 years) and able to give informed consent (secondary participants).

Unaffected minors will only be enrolled under special circumstances as detailed in paragraph 5.1 (Special Populations - Unaffected minors).

Lastly, healthy unrelated controls will be enrolled; these are necessary to contrast unspecific, gender- or age-related findings to disease specific findings.
Condition Hereditary Spastic Paraplegia
Intervention
  • Other: Clinical rating scale to measure disease severity and progression
    A 13-item scale to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory.
    Other Name: Spastic Paraplegia Rating Scale (SPRS)
  • Diagnostic Test: Next-Gen Sequencing (NGS)
    Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Study Groups/Cohorts
  • Primary participant:

    Participants affected by hereditary spastic paraplegia (HSP) or a phenotypically related disorder Primary participants will be followed at annual intervals. The workup includes clinical, imaging, sensor-based, patient/observer reported and molecular outcome parameters and biosampling.

    Participants with unknown genetic diagnosis may receive genetic testing including whole exome or whole genome sequencing and other OMICS techniques.

    Interventions:
    • Other: Clinical rating scale to measure disease severity and progression
    • Diagnostic Test: Next-Gen Sequencing (NGS)
  • Secondary participant/ First or second-degree
    First or second degree unaffected family members of primary participants. Secondary participants may undergo the same study procedures as primary participants.
    Intervention: Diagnostic Test: Next-Gen Sequencing (NGS)
  • Unrelated healthy control
    Unrelated healthy controls Healthy controls may undergo the same study procedures as primary participants.
    Intervention: Diagnostic Test: Next-Gen Sequencing (NGS)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: June 7, 2019) 		2000
Original Estimated Enrollment Same as current
Estimated Study Completion Date August 2041
Estimated Primary Completion Date August 2039   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion criteria:

  • One of the following:

    1. Primary participant: Clinical or genetic diagnosis of HSP or a related disorder
    2. Secondary participant: Unaffected family member (1st or 2nd degree relative) of primary participant (with the above-mentioned restrictions for special populations) able to give informed consent

    3. Unrelated healthy control able to give informed consent

      AND

  • Written informed consent

AND

- Participants are willing and able to comply with study procedures

Exclusion criteria:

  • Missing informed consent of primary or secondary participant/ healthy control/ legal representatives
  • For controls: evidence of a neurodegenerative disease or movement disorders; inability to give informed consent
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers Yes
Contacts
Contact: Rebecca Schüle, PD Dr. +49 7071 29 ext 85653 rebecca.schuele-freyer@uni-tuebingen.de
Contact: Ludger Schöls, Prof. Dr. +49 7071 29 ext 85548 ludger.schoels@uni-tuebingen.de
Listed Location Countries Austria,   Germany,   Italy
Removed Location Countries  
 
Administrative Information
NCT Number NCT03981276
Other Study ID Numbers HSP-PBP
01GM1905 ( Other Grant/Funding Number: Bundesministerium für Bildung und Forschung (BMBF) )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Dr. Rebecca Schule, University Hospital Tuebingen
Study Sponsor Dr. Rebecca Schule
Collaborators
  • German Federal Ministry of Education and Research
  • German Center for Neurodegenerative Diseases (DZNE)
Investigators
Principal Investigator: Rebecca Schüle, PD Dr. University Hospital Tübingen
PRS Account University Hospital Tuebingen
Verification Date May 2021

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