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The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4

Primary Purpose

Hereditary Spastic Paraplegia, Hereditary, Spastic Paraplegia, Autosomal Dominant

Status
Recruiting
Phase
Not Applicable
Locations
Germany
Study Type
Interventional
Intervention
SPRS Score and clinical signs
Cognition Testing using CANTAB
Lumbar Puncture and blood draw
MRI
Electrophysiology
Testing functional performance
Non motor symptoms
Sponsored by
University Hospital Tuebingen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Hereditary Spastic Paraplegia focused on measuring SPG4, presymptomatic, at risk, mutation carriers, biomarkers, longitudinal progression

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • First degree relatives (parents, offspring, and sibs) of SPG4 patients or symptomatic individuals with known SPAST mutation
  • Age 18 to 70 years
  • Written, informed consent (patient)

Exclusion Criteria:

  • No known SPAST-mutation within the family
  • Manifest spastic gait (subclinical signs like increased deep tendon reflexes, positive Babinski sign are allowed)
  • Participation in interventional trials

Sites / Locations

  • University Hospital Tübingen, Center for NeurologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Mutation carrier

Non-mutation carrier

Known-mutation carriers but presymptomatic

Arm Description

The participants will be tested genetically if they carry a disease causing mutation or not. Depending on their genetic test result they will at the end of the study divided into two groups. The clinician will be blinded throughout the entire study to the genetic results.

The participants will be tested genetically if they carry a disease causing mutation or not. Depending on their genetic test result they will at the end of the study divided into two groups. The clinician will be blinded throughout the entire study to the genetic results.

In a third arm (open arm) we will also include positive predictive tested participants which know that they are carrying a known mutation but are at inclusion into the study asymptomatic (according to the inclusion / exclusion criteria).

Outcomes

Primary Outcome Measures

Identification of a change of recognizable signs or symptoms
Identification of recognizable signs or symptoms and their time course prior to disease-onset defined by the presence of a spastic gait and at least one of three additional features: manifest spasticity in the clinical examination (Ashworth Scale >0) positive Babinski sign pyramidal pattern of muscle weakness (e.g. hip abduction or foot elevation preferentially involved)

Secondary Outcome Measures

Subclinical progression (10m walking time)
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
Subclinical progression (5-stair climbing test time)
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
Subclinical progression (3 minute walking test (3MW))
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
MRI (not obligate) - DTI
To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring diffusion tensor imaging (DTI).
MRI (not obligate) - volumetry
To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring brain volumetry.
Nfl
To compare Nfl levels in serum (and cerebrospinal fluid (CSF) - not obligate) in mutation carriers and non-carriers.
Non-motor symptoms (SPRS inventory V3)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the SPRS inventory V3.
Non-motor symptoms (quality of life)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the EQ-5D.
Non-motor symptoms (fatigue)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the MFI.
Non-motor symptoms (pain)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the Brief Pain Inventory.
Non-motor symptoms (depression)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the Becks Depression Inventory (BDI).
Non-motor symptoms (restless-legs)
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the restless-legs diagnostic criteria questions.
SPRS
To determine the sensitivity of the Spastic Paraplegia Rating Scale (SPRS) to detect the manifestation of disease onset as defined above.
Cognition (CANTAB)
To compare cognitive performance by using the CANTAB battery in mutation and non-mutation carriers
Cognition (MoCA)
To compare cognitive performance by using the Montreal Cognitive Assessment (MoCA) in mutation and non-mutation carriers

Full Information

First Posted
June 21, 2017
Last Updated
August 18, 2022
Sponsor
University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT03206190
Brief Title
The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
Official Title
Studying the Prodromal and Early Phase of Hereditary Spastic Paraplegia Type 4 (SPG4)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2018 (Actual)
Primary Completion Date
December 2029 (Anticipated)
Study Completion Date
December 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Tuebingen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Study goals Prospective longitudinal data on progression in the natural course of SPG4 in presymptomatic mutation carriers prior to clinical disease onset and in early stages of disease Biomarkers providing objective measures of disease activity

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Spastic Paraplegia, Hereditary, Spastic Paraplegia, Autosomal Dominant
Keywords
SPG4, presymptomatic, at risk, mutation carriers, biomarkers, longitudinal progression

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Two Arms are blinded (mutation carriers vs. non mutation carriers) the third arm is an open-arm for presymptomatic tested mutation carriers
Allocation
Non-Randomized
Enrollment
200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Mutation carrier
Arm Type
Experimental
Arm Description
The participants will be tested genetically if they carry a disease causing mutation or not. Depending on their genetic test result they will at the end of the study divided into two groups. The clinician will be blinded throughout the entire study to the genetic results.
Arm Title
Non-mutation carrier
Arm Type
Experimental
Arm Description
The participants will be tested genetically if they carry a disease causing mutation or not. Depending on their genetic test result they will at the end of the study divided into two groups. The clinician will be blinded throughout the entire study to the genetic results.
Arm Title
Known-mutation carriers but presymptomatic
Arm Type
Experimental
Arm Description
In a third arm (open arm) we will also include positive predictive tested participants which know that they are carrying a known mutation but are at inclusion into the study asymptomatic (according to the inclusion / exclusion criteria).
Intervention Type
Other
Intervention Name(s)
SPRS Score and clinical signs
Intervention Description
Patients will clinically characterized by using the SPRS Score and the inventory V3
Intervention Type
Behavioral
Intervention Name(s)
Cognition Testing using CANTAB
Intervention Description
Patients will be tested using the CANTAB
Intervention Type
Diagnostic Test
Intervention Name(s)
Lumbar Puncture and blood draw
Intervention Description
Biomaterial will be collected (not obligate) to compare e.g. Nfl levels in serum and CSF
Intervention Type
Diagnostic Test
Intervention Name(s)
MRI
Intervention Description
MRI will be used to reveal presymptomatic brain morphology changes (not obligate)
Intervention Type
Diagnostic Test
Intervention Name(s)
Electrophysiology
Intervention Description
Electrophysiological tests will be used to characterize patients better.
Intervention Type
Diagnostic Test
Intervention Name(s)
Testing functional performance
Intervention Description
By using the 3 minute walk, 5 stair-climb test, and 10m walking test we will try to identify and measure subclinical progression prior to disease onset
Intervention Type
Diagnostic Test
Intervention Name(s)
Non motor symptoms
Intervention Description
By using a number of different tests we try to identify other non-motor symptoms which might manifest prior to disease onset.
Primary Outcome Measure Information:
Title
Identification of a change of recognizable signs or symptoms
Description
Identification of recognizable signs or symptoms and their time course prior to disease-onset defined by the presence of a spastic gait and at least one of three additional features: manifest spasticity in the clinical examination (Ashworth Scale >0) positive Babinski sign pyramidal pattern of muscle weakness (e.g. hip abduction or foot elevation preferentially involved)
Time Frame
every two years, up to eight years
Secondary Outcome Measure Information:
Title
Subclinical progression (10m walking time)
Description
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
Time Frame
every two years, up to eight years
Title
Subclinical progression (5-stair climbing test time)
Description
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
Time Frame
every two years, up to eight years
Title
Subclinical progression (3 minute walking test (3MW))
Description
To identify measures of subclinical progression of motor symptoms prior to disease onset by comparing functional performance in mutation carriers with that in individuals without mutation.
Time Frame
every two years, up to eight years
Title
MRI (not obligate) - DTI
Description
To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring diffusion tensor imaging (DTI).
Time Frame
every two years, up to eight years
Title
MRI (not obligate) - volumetry
Description
To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring brain volumetry.
Time Frame
every two years, up to eight years
Title
Nfl
Description
To compare Nfl levels in serum (and cerebrospinal fluid (CSF) - not obligate) in mutation carriers and non-carriers.
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (SPRS inventory V3)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the SPRS inventory V3.
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (quality of life)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the EQ-5D.
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (fatigue)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the MFI.
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (pain)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the Brief Pain Inventory.
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (depression)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the Becks Depression Inventory (BDI).
Time Frame
every two years, up to eight years
Title
Non-motor symptoms (restless-legs)
Description
To identify clinical signs (other than spasticity) that are more frequent in mutation carriers than in non-carriers as recorded by the restless-legs diagnostic criteria questions.
Time Frame
every two years, up to eight years
Title
SPRS
Description
To determine the sensitivity of the Spastic Paraplegia Rating Scale (SPRS) to detect the manifestation of disease onset as defined above.
Time Frame
every two years, up to eight years
Title
Cognition (CANTAB)
Description
To compare cognitive performance by using the CANTAB battery in mutation and non-mutation carriers
Time Frame
every two years, up to eight years
Title
Cognition (MoCA)
Description
To compare cognitive performance by using the Montreal Cognitive Assessment (MoCA) in mutation and non-mutation carriers
Time Frame
every two years, up to eight years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: First degree relatives (parents, offspring, and sibs) of SPG4 patients or symptomatic individuals with known SPAST mutation Age 18 to 70 years Written, informed consent (patient) Exclusion Criteria: No known SPAST-mutation within the family Manifest spastic gait (subclinical signs like increased deep tendon reflexes, positive Babinski sign are allowed) Participation in interventional trials
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ludger Schöls, Prof.
Phone
+49 7071 / 29
Ext
82057
Email
ludger.schoels@uni-tuebingen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ludger Schöls, Prof.
Organizational Affiliation
Head of Department
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Tübingen, Center for Neurology
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ludger Schöls, MD
Phone
+49 7071 29 82057
Email
ludger.schoels@uni-tuebingen.de
First Name & Middle Initial & Last Name & Degree
Tim W. Rattay, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35472722
Citation
Rattay TW, Volker M, Rautenberg M, Kessler C, Wurster I, Winter N, Haack TB, Lindig T, Hengel H, Synofzik M, Schule R, Martus P, Schols L. The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study. Brain. 2023 Mar 1;146(3):1093-1102. doi: 10.1093/brain/awac155.
Results Reference
result

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The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4

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