Traditional Versus Progressive Robot-assisted Gait Training in People With Multiple Sclerosis and Severe Gait Disability (PROGR-EX)

Traditional Versus Progressive Robot-assisted Gait Training in People With Multiple Sclerosis and Severe Gait Disability: Study Protocol for a the PROGR-EX Randomized-controlled Trial

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease. Qualitative alterations in walking function in MS people involve 75% of subjects with MS and are determined by reduced coordination, mobility, balance, and increased risk of falling. Robot assisted gait training (RAGT) devices seem effective in MS patients with severe motor disabilities, failing to show significant superiority when compared to intensive overground gait rehabilitation (OGT). This study aims to evaluate the effects of a low-intensity RAGT at progressively increasing intensity compared to conventional RAGT and OGT.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Device: Lokomat device (Hocoma AG, Volketswil, Switzerland).; Other: Conventional walking training

Detailed Description

Gait disorders are the most frequent symptoms associated to multiple sclerosis (MS).Robot-assisted gait training (RAGT) in people with MS (PwMS) has been proposed as a possible effective treatment option for severe motor disability. Although RAGT continues to prove effective in increasing patient mobility, no significant superiority was found when compared to intensive overground gait rehabilitation (OGT). In PwMS, RAGT at high-intensity may enhance fatigue and spasticity, compromising the effectiveness and applicability of the intervention.

This study aims to evaluate the effects of a low-intensity RAGT at progressively increasing intensity compared to conventional RAGT and OGT in PwMS and moderate to severe walking impairment.

We will recruit 24 PwMS from the patients afferent to Outpatient Rehabilitation Clinic at University Hospital of Ferrara and we will assign them to one of the three treatment groups: low-intensity RAGT at progressively increasing intensity, conventional RAGT and OGT. All participants will receive 3 weekly treatment sessions of 3 hours each for 4 weeks. In the first 2 hours of treatment, an experienced physiotherapist will propose a programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour, subjects will undergo specific gait training according to the assignment group. Subjects allocated to low-intensity RAGT at progressively increasing intensity group will receive gait rehabilitation on the Lokomat device and a speed initially set at 1.0 km/h, with progressive increments of 0.1 km/h at each training session. The working time consists of bouts of 3 minutes of work alternated by 1 minute of recovery, to be repeated 8 times. Subjects allocated to conventional RAGT will receive gait rehabilitation on the Lokomat device and the machine parameters will be determined based on the patient's characteristics. Subjects allocated to OGT will perform a 40-minute walk on a flat surface supervised by a physiotherapist. Outcomes will be assessed before and after treatment and at 3-month follow-up. The primary outcome is walking speed. Secondary outcomes include mobility and balance, psychological measures, muscle oxygen consumption, electrical and hemodynamic brain activity, urinary biomarkers, usability, and acceptability of robotic devices for motor rehabilitation.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sofia Straudi, PhD; Phone Number: 0532238720; Email: sofia.straudi@unife.it

Study Locations

• Italy
  • Emilia Romagna
    • Ferrara, Emilia Romagna, Italy, 44124
      • Recruiting
      • Department of Neuroscience and Rehabilitation, University Hospital of Ferrara
      • Contact: Sofia Straudi, MD, PhD; Phone Number: 0532236185; Email: s.straudi@ospfe.it
      • Principal Investigator: Sofia Straudi, MD, PhD
      • Sub-Investigator: Andrea Baroni, PhD
      • Sub-Investigator: Nicola Lamberti, PhD
      • Principal Investigator: Fabio Manfredini, MD, PhD
      • Sub-Investigator: Giulia Fregna, MSc
      • Sub-Investigator: Michela Rimondini, PhD
      • Sub-Investigator: Marialuisa Gandolfi, MD, PhD
      • Sub-Investigator: Luigi Zerbinati, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of MS (primary or secondary progressive) without relapses in the preceding 3 months
• Disability rate defined by Expanded Disability Status Scale (EDSS) score from 6 to 7
• Ability to perform the Timed 25-Foot Walk (T25-FW) test
• Mini-Mental Status Examination score ≥ 24/30

Exclusion Criteria:

• Other (neurological) conditions that may affect motor function
• Medical conditions might interfere with the ability to complete the study protocol safely
• Presence of spasticity with a Modified Ashworth Scale (MAS) score > 3 or retractions limiting the range of motion of the hip, knee or ankle
• MS relapses or medication changes or any other confounding factors during the study period
• Rehabilitation treatment or botulinum toxin injection in the 3 months preceding the start of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-intensity RAGT at progressively increasing intensity; Participants will receive 3 weekly treatment sessions of 3 hours each, for a period of 4 weeks and a total of 12 sessions. In the first two hours of treatment, an experienced physiotherapist will propose a programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour of treatment, subjects allocated to this group will receive gait rehabilitation on the Lokomat device (Hocoma). The device in use will be set at 60% robotic assistance, 50% of load suspension, and a speed initially set at 1.0 km/h, with progressive increments of 0.1 km/h at each training session. The working time consists of bouts of 3 minutes of work alternated by 1 minute of recovery, to be repeated 8 times.	Device: Lokomat device (Hocoma AG, Volketswil, Switzerland).; Robot Assisted Gait Training device
Active Comparator: Conventional RAGT; Participants will receive 3 weekly treatment sessions of 3 hours each, for a period of 4 weeks and a total of 12 sessions. In the first two hours of treatment, an experienced physiotherapist will propose a programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour of treatment, subjects allocated to this group will receive gait rehabilitation on the Lokomat device (Hocoma). . In this case the parameters for setting the machine will be determined by the physiotherapist in charge for treatment administration in relation to the specific characteristics of the patient.	Device: Lokomat device (Hocoma AG, Volketswil, Switzerland).; Robot Assisted Gait Training device
Active Comparator: Over ground training (OGT); Participants will receive 3 weekly treatment sessions of 3 hours each, for a period of 4 weeks and a total of 12 sessions. In the first two hours of treatment, an experienced physiotherapist will propose a programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour of treatment, the subject will perform a 40-minute walk on a flat surface, preceded by a warm-up phase and followed by a 10 minute warm-down phase each. Subjects will walk back and forth over a distance of approximately 30 metres using their walking aid.	Other: Conventional walking training; Self-paced supervised walking training

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Walking function	The walking function will be assessed by the T25-FW test	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mobility	Timed Up and Go (TUG) test	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Walking endurance	6-Minute Walk Test (6MWT)	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Balance	Berg Balance Scale (BBS), a 5-point ordinal scale used to assess the ability to maintain balance statically and while performing functional movements. BBS comprises 14 tasks; the total score is calculated by summing the scores of each item (0-4). The maximum total score is 56. Higher totals reflect more balance impairment.	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Spasticity	Modified Ashworth Scale (MAS), a 6-point measure of spasticity. The assessor will rate the perceived amount of resistance or tone at the flexor and extensor muscles of the hip, knee, and ankle. Higher scores reflect more spasticity	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Perceived quality of life	Multiple Sclerosis Impact Scale-29 (MSIS-29), a questionnaire that evaluates the impact of MS on physical and psychological functioning. It comprises 29 items, with 20 items assessing physical activity and 9 assessing psychological state. Each item can be rated from 0 to 5; the total score is the sum of all items. Higher score reflect higher impact of MS on quality of life.	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Perceived walking ability	Multiple Sclerosis Walking Scale-12 (MSWS-12), a questionnaire used to evaluate the impact of MS on walking ability. It comprises 12 items that inquire about the patient's perception of gait speed, running, confidence in ascending/descending stairs, balance, and fatigue. The total score is calculated by summing the scores of each item (0-5) and then converting it into a value ranging from 0 to 100. Higher score reflect higher impact of MS on walking ability.	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Fatigue	Fatigue Severity Scale (FSS), a short questionnaire that requires the subject to rate their level of fatigue from 1 to 7 in different activities. Higher score reflect higher impact of fatigue	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Anxiety	Beck Anxiety Inventory (BAI), a questionnaire used to measure anxiety levels, consisting of 21 items. Respondents indicate how severely each symptom affected them using a 4-point Likert scale, ranging from 0 (not at all) to 3 (severely). The sum of all responses provides an overall score, with higher totals reflecting more intense anxiety symptoms	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Depression	Beck Depression Inventory - II (BDI-II), a questionnaire comprised of 21 multiple-choice questions. Respondents assign a score ranging from 0 to 3 to each answer, where higher cumulative scores signal a greater severity of depressive symptoms	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Kinesiophobia	Tampa Scale of Kinesiophobia (TSK), a 17-item self-evaluation checklist on a 4-point Likert scale to assess the fear of movement or potential re-injury. The scoring yields a total raw score that can range from 17 to 68 and higher cumulative scores reflect higher fear of movement.	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Adaptation to medical condition	Psychosocial Adjustment to Illness Scale-Self Report (PAIS-SR), a 46-item self-report tool designed to evaluate a patient's adaptation to either a current medical condition or the aftermath of a past illness. Each question within the PAIS-SR is scored on a scale from 0 to 3, where a higher score reflects a lower level of adjustment	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Coping strategies	Brief COPE, a self-report questionnaire used to evaluate coping strategies in facing stressful, unpredictable, and damaging events. It comprises 28 items grouped in 14 faced-scales which represent 14 different coping reactions. Respondents rate each item on a 4-point Likert scale, ranging from 1 (I haven't been doing this at all) to 4 (I've been doing this a lot). Total scores on each scale range from 2 (minimum) to 8 (maximum). Higher scores indicate increased utilization of that specific coping strategy.	Score changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Muscle oxygen consumption	The Near-infrared spectroscopy (NIRS) technology will evaluate muscle oxygen consumption. The patient, lying supine, will be fitted with a pair of NIRS sensors (transmitter and receiver) at the medial belly of the gastrocnemius to monitor changes in oxygenated and deoxygenated hemoglobin.	Data changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Hemodynamic cortical activation	Hemodynamic cortical activation recorded during reaching and grasping activities performed with the most impaired (or not dominant) upper limb. Each patient will be equipped with a Near-infrared spectroscopy (NIRS) system composed of 16 sources and 16 detectors emitting two wavelengths of near-infrared light (760 and 850 nm). Hemodynamic signals will be recorded at a sampling rate of 3.81 Hz. A standard cap will be placed over each participant's scalp, and sources and detectors were positioned on the measuring cap according to the 10-20 international system with standard interoptode distances of approximately 3 cm. Optodes were placed over both hemispheres, resulting in 48 channels covering the regions of the primary motor and sensorimotor cortices. Data will be analyzed assessing the variations in oxygenated and deoxygenated hemoglobin	Data changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
Electrical brain activity	EEG recording during action observation task. Stimuli will consist in videos, filmed in the first person, in which a hand will show reaching for and grasping a can. The EEG will be recorded during the 20 minutes of the session: 3 minutes with open eyes, 3 minutes with closed eyes, and 14 minutes of video observation.	Data changes before (T0) and after (T1) the twelve sessions of treatment and at 3-months follow-up (T2).
miRNA expression	Urinary lab examination	Data changes before (T0) and after (T1) the twelve sessions of treatment.
Acceptability of robot intervention	Ad-hoc questionnaire with closed 1-10 Likert-scale and open-ended questions to assess patients' experience with the robot intervention. The questionnaire will specifically explore the usability, acceptability, perceived pleasantness, and safety of the intervention. Higher scores reflects higher satisfaction of the treatment.	Scores registered after (T1) the twelve sessions of robotic treatment.

Collaborators and Investigators

• Sponsor: University Hospital of Ferrara
• Collaborators: Universita di Verona; Università degli Studi di Ferrara
• Investigators: Principal Investigator: Fabio Manfredini, PhD, Ferrara University

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2023
• Primary Completion (Estimated): November 30, 2024
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: April 2, 2024
• First Submitted That Met QC Criteria: April 18, 2024
• First Posted (Actual): April 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Biomarkers; Mobility; Robot Assisted Gait Training
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: PROGR-EX_MNESYS

Drug and device information, study documents

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