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

Not Applicable

Recruiting

• Conditions: Hereditary, Spastic Paraplegia, Autosomal Dominant; Hereditary Spastic Paraplegia
• Interventions: Other: SPRS Score and clinical signs; Behavioral: Cognition Testing using CANTAB; Diagnostic Test: Lumbar Puncture and blood draw; Diagnostic Test: MRI; Diagnostic Test: Electrophysiology; Diagnostic Test: Testing functional performance; Diagnostic Test: Non motor symptoms

• Registration Number: NCT03206190
• Lead Sponsor: University Hospital Tuebingen

Brief Summary

Study goals

1. 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

2. Biomarkers providing objective measures of disease activity

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-06-21
• Study First Submitted QC: 2017-06-29
• Study First Posted: 2017-07-02
• Study Start: 2018-07-01
• Status Verified: 2022-08
• Last Update Submitted: 2022-08-18
• Last Update Posted: 2022-08-23
• Primary Completion: 2029-12
• Study Completion: 2031-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mutation carrier	MRI	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.
Mutation carrier	Testing functional performance	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.
Non-mutation carrier	SPRS Score and clinical signs	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.
Non-mutation carrier	Lumbar Puncture and blood draw	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.
Non-mutation carrier	Electrophysiology	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.
Non-mutation carrier	Testing functional performance	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.
Known-mutation carriers but presymptomatic	Lumbar Puncture and blood draw	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).
Known-mutation carriers but presymptomatic	Testing functional performance	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).
Mutation carrier	Cognition Testing using CANTAB	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.
Mutation carrier	Non motor symptoms	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.
Non-mutation carrier	Non motor symptoms	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.
Known-mutation carriers but presymptomatic	SPRS Score and clinical signs	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).
Known-mutation carriers but presymptomatic	MRI	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).
Known-mutation carriers but presymptomatic	Non motor symptoms	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).
Mutation carrier	Lumbar Puncture and blood draw	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.
Mutation carrier	Electrophysiology	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.
Known-mutation carriers but presymptomatic	Cognition Testing using CANTAB	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).
Mutation carrier	SPRS Score and clinical signs	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.
Non-mutation carrier	Cognition Testing using CANTAB	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.
Non-mutation carrier	MRI	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.
Known-mutation carriers but presymptomatic	Electrophysiology	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).

Primary Outcome Measures

Name	Time	Method
Identification of a change of recognizable signs or symptoms	every two years, up to eight years	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: 1. manifest spasticity in the clinical examination (Ashworth Scale \>0); 2. positive Babinski sign; 3. pyramidal pattern of muscle weakness (e.g. hip abduction or foot elevation preferentially involved)

Secondary Outcome Measures

Name	Time	Method
Cognition (MoCA)	every two years, up to eight years	To compare cognitive performance by using the Montreal Cognitive Assessment (MoCA) in mutation and non-mutation carriers
MRI (not obligate) - DTI	every two years, up to eight years	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	every two years, up to eight years	To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring brain volumetry.
Nfl	every two years, up to eight years	To compare Nfl levels in serum (and cerebrospinal fluid (CSF) - not obligate) in mutation carriers and non-carriers.
Subclinical progression (10m walking time)	every two years, up to eight years	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)	every two years, up to eight years	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))	every two years, up to eight years	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.
Non-motor symptoms (quality of life)	every two years, up to eight years	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)	every two years, up to eight years	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)	every two years, up to eight years	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 (restless-legs)	every two years, up to eight years	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.
Cognition (CANTAB)	every two years, up to eight years	To compare cognitive performance by using the CANTAB battery in mutation and non-mutation carriers
Non-motor symptoms (SPRS inventory V3)	every two years, up to eight years	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 (depression)	every two years, up to eight years	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).
SPRS	every two years, up to eight years	To determine the sensitivity of the Spastic Paraplegia Rating Scale (SPRS) to detect the manifestation of disease onset as defined above.

Trial Locations

Locations (1)

University Hospital Tübingen, Center for Neurology; 🇩🇪 Tübingen, Germany