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

Studying the Prodromal and Early Phase of Hereditary Spastic Paraplegia Type 4 (SPG4)

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

Study Overview

• Status: Recruiting
• Conditions: Hereditary Spastic Paraplegia; Hereditary, Spastic Paraplegia, Autosomal Dominant
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ludger Schöls, Prof.; Phone Number: 82057 +49 7071 / 29; Email: ludger.schoels@uni-tuebingen.de

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • Recruiting
    • University Hospital Tübingen, Center for Neurology
    • Contact: Ludger Schöls, MD; Phone Number: +49 7071 29 82057; Email: ludger.schoels@uni-tuebingen.de
    • Principal Investigator: Tim W. Rattay, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mutation carrier; 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.	Other: SPRS Score and clinical signs; Patients will clinically characterized by using the SPRS Score and the inventory V3; Behavioral: Cognition Testing using CANTAB; Patients will be tested using the CANTAB; Diagnostic test: Lumbar Puncture and blood draw; Biomaterial will be collected (not obligate) to compare e.g. Nfl levels in serum and CSF; Diagnostic test: MRI; MRI will be used to reveal presymptomatic brain morphology changes (not obligate); Diagnostic test: Electrophysiology; Electrophysiological tests will be used to characterize patients better.; Diagnostic test: Testing functional performance; 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; Diagnostic test: Non motor symptoms; By using a number of different tests we try to identify other non-motor symptoms which might manifest prior to disease onset.
Experimental: Non-mutation carrier; 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.	Other: SPRS Score and clinical signs; Patients will clinically characterized by using the SPRS Score and the inventory V3; Behavioral: Cognition Testing using CANTAB; Patients will be tested using the CANTAB; Diagnostic test: Lumbar Puncture and blood draw; Biomaterial will be collected (not obligate) to compare e.g. Nfl levels in serum and CSF; Diagnostic test: MRI; MRI will be used to reveal presymptomatic brain morphology changes (not obligate); Diagnostic test: Electrophysiology; Electrophysiological tests will be used to characterize patients better.; Diagnostic test: Testing functional performance; 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; Diagnostic test: Non motor symptoms; By using a number of different tests we try to identify other non-motor symptoms which might manifest prior to disease onset.
Experimental: Known-mutation carriers but presymptomatic; 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).	Other: SPRS Score and clinical signs; Patients will clinically characterized by using the SPRS Score and the inventory V3; Behavioral: Cognition Testing using CANTAB; Patients will be tested using the CANTAB; Diagnostic test: Lumbar Puncture and blood draw; Biomaterial will be collected (not obligate) to compare e.g. Nfl levels in serum and CSF; Diagnostic test: MRI; MRI will be used to reveal presymptomatic brain morphology changes (not obligate); Diagnostic test: Electrophysiology; Electrophysiological tests will be used to characterize patients better.; Diagnostic test: Testing functional performance; 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; Diagnostic test: Non motor symptoms; By using a number of different tests we try to identify other non-motor symptoms which might manifest prior to disease onset.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	every two years, up to eight years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	every two years, up to eight years
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.	every two years, up to eight years
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.	every two years, up to eight years
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).	every two years, up to eight years
MRI (not obligate) - volumetry	To reveal alterations in brain morphology with magnetic resonance im-aging (MRI) in presymptomatic mutation carriers by measuring brain volumetry.	every two years, up to eight years
Nfl	To compare Nfl levels in serum (and cerebrospinal fluid (CSF) - not obligate) in mutation carriers and non-carriers.	every two years, up to eight years
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.	every two years, up to eight years
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.	every two years, up to eight years
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.	every two years, up to eight years
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.	every two years, up to eight years
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).	every two years, up to eight years
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.	every two years, up to eight years
SPRS	To determine the sensitivity of the Spastic Paraplegia Rating Scale (SPRS) to detect the manifestation of disease onset as defined above.	every two years, up to eight years
Cognition (CANTAB)	To compare cognitive performance by using the CANTAB battery in mutation and non-mutation carriers	every two years, up to eight years
Cognition (MoCA)	To compare cognitive performance by using the Montreal Cognitive Assessment (MoCA) in mutation and non-mutation carriers	every two years, up to eight years

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Investigators: Principal Investigator: Ludger Schöls, Prof., Head of Department

Publications and helpful links

General Publications

• 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. 2022 Apr 26:awac155. doi: 10.1093/brain/awac155. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Anticipated): December 1, 2029
• Study Completion (Anticipated): December 1, 2031

Study Registration Dates

• First Submitted: June 21, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: biomarkers; at risk; presymptomatic; SPG4; mutation carriers; longitudinal progression
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Manifestations; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Paralysis; Muscle Hypertonia; Polyneuropathies; Hereditary Sensory and Motor Neuropathy; Muscle Spasticity; Paraplegia; Spastic Paraplegia, Hereditary
• Other Study ID Numbers: preSPG4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No