title: The effectiveness of Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressIve MultiplE sclerosis patients (RAGTIME): study protocol for a randomized controlled trial.
abstract: Gait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and (2) to explore changes of clinical and circulating biomarkers of neural plasticity.
  
  
  
  This will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6-7) will be randomly assigned to receive twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed, body weight support) are set during the first session and progressively adjusted during training progression or (2) individual conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The same assessors will perform outcome measurements at four time points: baseline (before the first intervention session); intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after 3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and metabolic parameters).
  
  
  
  The RAGT training is expected to improve mobility compared to the active control intervention in progressive MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes.
  
  
  
  ClinicalTrials.gov, identifier: NCT02421731 . Registered on 19 January 2015 (retrospectively registered).
authors.affiliation: Neuroscience and Rehabilitation Department, Ferrara University Hospital, Via Aldo Moro 8, 44124, Ferrara, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Straudi
authors.affiliation: Neuroscience and Rehabilitation Department, Ferrara University Hospital, Via Aldo Moro 8, 44124, Ferrara, Italy. fabio.manfredini@unife.it.|Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy. fabio.manfredini@unife.it.
authors.forename: Fabio
authors.identifier: 0000-0001-9476-6434
authors.initials: F
authors.lastname: Manfredini
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lamberti
authors.affiliation: Unit of Translational Surgery and Vascular Diseases Center, Ferrara University Hospital, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Zamboni
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bernardi
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marchetti
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bonora
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Tisato
authors.affiliation: Center for Clinical Epidemiology, School of Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volpato
authors.affiliation: Neuroscience and Rehabilitation Department, Ferrara University Hospital, Via Aldo Moro 8, 44124, Ferrara, Italy.
authors.forename: Nino
authors.initials: N
authors.lastname: Basaglia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D002985:Clinical Protocols; D004185:Disability Evaluation; D006233:Persons with Disabilities; D005081:Exercise Therapy / Q000009:adverse effects / Q000379:methods*; D017079:Exercise Tolerance; D005260:Female; D005684:Gait; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D051346:Mobility Limitation; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D018763:Muscle Fatigue; D018482:Muscle, Skeletal / Q000294:innervation*; D009473:Neuronal Plasticity; D004856:Postural Balance; D020127:Recovery of Function; D012107:Research Design; D012371:Robotics; D012720:Severity of Illness Index; D016037:Single-Blind Method; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D016138:Walking; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: Biological markers; Mobility; Motor recovery; Plasticity; Progressive multiple sclerosis; Rehabilitation; Robot-assisted gait training