Clinical Trial to Compare Conventional Multidisciplinary Gait Rehabilitation With the Atalante Self-balancing Walking System in Patients With Multiple Sclerosis
Phase: NA
Conditions: Multiple Sclerosis, Gait Disorders, Neurologic
Sponsor: Multiple Sclerosis Center of Catalonia

1 
 
 
 
Clinical trial to compare conventional 
multidisciplinary gait rehabilitation with 
the Atalante self-balancing walking 
system in patients with Multiple 
Sclerosis 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modification 
Date 
Modification Type 
09.11.2022 
Draft version 1 
16.11.2022 
Comments from IG applied 
18.11.2022 
Comments from GL, CS applied 
18.11.2022 
Comments from CS applied 
31.01.2023 
Version 2 approved by the Ethics Committee 
16.01.2024 
Amendment: Redefinition of outcomes and inclusion of epigenetic 
outcomes. Validation and approval by the Ethics Committee. Final 
version in Spanish without annexes 

2 
 
Index 
1 
JUSTIFICATION .................................................................................................................. 3 
2 
AIMS ....................................................................................................................................... 4 
2.1 
PRIMARY AIM: ..................................................................................................................... 4 
2.2 
SECONDARY AIMS: .............................................................................................................. 4 
3 
MATERIALS AND METHODS .......................................................................................... 5 
3.1 
DESIGN: ................................................................................................................................ 5 
3.2 
INCLUSION AND EXCLUSION CRITERIA.............................................................................. 6 
3.2.1 
INCLUSION CRITERIA ......................................................................................................... 6 
3.2.2 
EXCLUSION CRITERIA ........................................................................................................ 6 
3.3 
ENROLLMENT AND SCREENING.......................................................................................... 7 
3.4 
ASSESSMENTS ...................................................................................................................... 7 
3.4.2 
SCHEDULE .......................................................................................................................... 3 
3.5 
DEVICE ................................................................................................................................. 3 
3.5.1 
DESCRIPTION ..................................................................................................................... 3 
3.5.2 
REGULATORY APPROVAL................................................................................................... 8 
3.6 
INTERVENTION .................................................................................................................... 8 
4 
STATISTICAL CONSIDERATIONS ............................................................................... 13 
5 
REFERENCES .................................................................................................................... 14 
 
 
 

3 
 
1 
Justification 
 
Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central 
nervous system (CNS), affecting more than 2 million people worldwide1. It is a chronic 
and degenerative disease that selectively affects the CNS and represents the leading cause 
of non-traumatic disability in young adults. The age of onset of the disease is usually 
between 20 and 40 years. The prevalence of MS in Spain fluctuates between 40 and 125 
cases per 100,000 inhabitants, with an incidence of 3-4 new cases per 100,000 inhabitants 
and year. 2 
 
Clinically, the disease initially presents in more than 80% of cases in a relapsing-remitting 
form, that is, in the form of outbreaks or exacerbations in one or several locations with 
periods apparently stable between two of these episodes. After a variable period of time, 
a progressive deterioration appears usually associated with important accumulation of 
disability. The symptoms of the people with MS (PwMS)  are very variable and differ 
from one patient to another in topography and intensity. Thus, we can find visual, sensory 
symptoms, loss of strength, sphincter and sexual alterations, coordination problems, 
balance problems, cognitive alterations and fatigue among others. 3  
 
Gait and balance disturbances in MS are already common even in the early stages of the 
disease. Half of the patients refer some alteration in the quality of their gait within the 
first month after diagnosis, reaching 90% at 10 years of evolution.4  5 Furthermore, gait 
is the most valuable body function for MS patients, both for those  with less than 5 years 
of evolution and for those with more than 15 years, as walking restriction hardly affects 
their activity and participation level. 7 
Gait disturbance is caused by multiple factors such as decreased muscle strength, balance, 
coordination, and proprioception, impaired vision, spasticity, fatigue and even cognitive 
impairment.4  
Some impairments arise in the phisical and social context of each patient, limiting 
participation in activities or therapies to improve balance, fatigue, strength and gait 
characteristics such as fatigue, high risk of falls or high disability.7  
 
This would support the development and application of rehabilitation strategies for 
mitigating the energetic penalties of gait abnormalities during ambulation. Some of these 
interventions include aerobic, resistance, yoga, and combined exercise training, that have 
shown significant improvements in walking endurance regardless of outcome measures 
(6MWT, 2MWT). 8 
New emerging approaches might involve Robot-assisted gait training In the last 5 years 
a lot of robotic solutions that offer both strategies of support in dialy living and 
rehabilitative devices have appeared. Some studies have shown that people with multiple 
sclerosis and severe gait impairment who participated in Robot-assisted gait training 
(RAGT) achieved significant improvement in lower limb muscle strength and increased 
their walking speed, although the effect was not long-lasting.9 
 
In the last years evidence about robot-based rehabilitation for PwMS has been published, 
and currently, more than 5 devices have been approved for its use in gait 
neurorehabilitation. Yeh et al. concluded that Robotic locomotor training limitedly affects 
motor functions of multiple sclerosis, but improves fatigue and spasticity, it is safe and 
well-tolerated for PwMS and less demanding for physical therapists.10 Bowman et al. 
concluded that Robotic-Assisted Gait therapy (RAGT) improves balance and gait out-

4 
 
comes in a clinically meaningful way in PwMS,  RAGT seems more effective compared 
to conventional  rehabilitation, while it shows similar effects if compared to specific 
balance and gait training in studies with level 2 evidence.11 RAGT has several advantages 
in terms of patient motor assistance, intensity of training, safety, and the possibility to 
combine other therapeutic approaches and should be promoted for PwMS with severe 
disability in a multimodal rehabilitation context as an opportunity to maximize re-
covery.11 In this context is needed a further larger-scale, better-designed RCTs with a 
longer training duration and more studies evaluating the satisfaction, usability and 
effectivity of RAGT.10 12 13 11 
 
The Atalante exoskeleton is composed of an external, powered, motorized orthosis that 
is placed over a person’s limbs to provide self-ambulation functions without the use of 
crutches or other technical aids. The main feature of the exoskeleton is that it is fully 
actuated with 12 actuated degrees of freedom: three at each hip, one at each knee, and 
two at each ankle. 14 15 
 
The molecular bases associated with the functional improvements derived from 
rehabilitation therapies or physical exercise are not yet well defined. However, both 
rehabilitation and exercise have been recognized for their immunomodulatory properties. 
In fact, recent clinical and preclinical findings have established a connection between 
physical activity and rehabilitative interventions with discernible epigenetic alterations in 
immune cells. For example, recent preclinical research has demonstrated how moderate-
intensity training induces lasting changes in chromatin accessibility in macrophages, 
resulting in moderation of their inflammatory responses. However, there is still a lack of 
comprehensive epigenomic studies examining the repercussions of rehabilitation 
therapies in individuals with multiple sclerosis. 
 
2 
 Aims 
 
2.1 
Primary Aim:  
 
- 
To compare the effect of RAGT by use of Atalante self-balance exoskeleton with 
conventional rehabilitation training (cRHB) for improving Walking speed 
measured by the Timed 10-meters walk test (10-MWT), considering a clinically 
relevant change an improvement of 20% of the velocity (m/s) with respect to the 
baseline assessment.16 
 
2.2 
Secondary Aims: 
 
- 
To compare the effect of RAGT by use of the Atalante self-balance exoskeleton 
with conventional Rehabilitation training (cRHB), for improving static balance, 
dynamic balance, mobility, and self-perception of gait impairment measured 
with: 
 
• Static Balance by the Berg Balance Scale (BBS), considering a clinically relevant 
change for improvement in balance as measured by BBS was +3 points, meaning 
that  PwMS are likely to perceive that as a reproducible and clinically important 
change in them balance performance.17 
• Dynamic balance by the Timed Up and Go test (TUG)18 
• Mobility measured by modified Rivermead Mobility Index (mRMI)19  

5 
 
• Self-perception of gait impairment by Multiple Sclerosis Walking Scale-12 
(MSWS-12)20  
• Instrumented gait analysis by the G-walk device (assessing gait cycle duration, 
step length, propulsion index, support phase percentage D/I, oscillation phase 
percentage D/I, double/unique support phase percentage.  
 
- 
To compare the effect of RAGT by use of the Atalante self-balance exoskeleton 
with conventional Rehabilitation training (cRHB) on quality of life, emotional 
status and fatigue measured at pre and post-intervention with: 
 
• Multiple Sclerosis Quality of Life-54 (MSQoL 54 Health Survey Spanish 
version)21   
•  Hospital Anxiety and Depression Scale (HADs) considering a clinically relevant 
change of 1.7 points at HADs22 
• The Modified fatigue scale (MFIS) 23 24 
 
• The patient’ physical effort of each session by means of the scale of perception of 
the effort R.P.E of Borg at the end of each training25 26. 
• To evaluate the epigenetic blueprint of rehabilitation training by comparing the 
genome wide chromatin accessibility of peripheral blood mononuclear cells 
(PBMCs) before and after RAGT or cRHB, by Assay for Transposase-Accessible 
Chromatin sequencing (ATACseq). 
 
• To test the hypothesis that genome wide chromatin accessibility compared to 
clinical measures can be useful for identifying molecular mechanisms underlying 
rehabilitation therapies. 
 
• To compare the changes induced by RAGT versus cRHB on the overall chromatin 
accessibility, and specific genome regions and pathways. 
 
• Use the biological samples to provide additional functional and mechanistic 
information about the rehabilitation effects and subject health, disease or state. 
 
 
3 
Materials And methods 
 
3.1 
Design:  
 
This trial is a prospective, randomized, rater-blinded study (cRHB (N=30) vs RAGT 
(N=30)). 
For the control group, this protocol includes 24 one-hour sessions of cRHB training 
during 8 weeks three times per week, under the supervision of a qualified rehab team. 
For the intervention group (RAGT) this protocol includes 24 one-hour sessions of RAGT 
during 8 weeks three times per week, under the supervision of a qualified rehab team. 
Additionally, peripheral blood (6ml) will be taken from all subjects at three timepoints: 
at baseline (T1), after the 8 weeks of rehabilitation treatment (T2) and, if possible, one 
year after T4. Biological samples will then be given a unique identifier and transferred to 
researchers for analysis. 
 
 

6 
 
   
Informed consent will be obtained from patients prior to inclusion in the study, which 
will be carried out in accordance with the Declaration of Helsinki. 
 
3.2 
Inclusion and exclusion Criteria 
 
Subjects will be evaluated for their eligibility from neurorehabilitation and neurology 
outpatient clinics at the Multiple Sclerosis Center of Catalonia (Cemcat). 
 
3.2.1 Inclusion criteria   
 
• Male or female, between 18 and 75 years of age. 
• Confirmed diagnosis of MS. 
• EDSS from 6.0 to 7.0. 
• Able to maintain the upright position on a daily basis. 
• Stable course of disease-modifying therapy over the past 6 months. 
• Clinical comorbidity asymptomatic (i.e., no underlying cardiovascular disease)  
• Height: between approximately 1.50 m. and 1.90 m. 
• Willingness to visit the Multiple Sclerosis Center of Catalonia (Cemcat) for 
testing and training.  
• Gait disorder conditioned by paresis or hemiparesis associated with ataxia or 
sensory problems. 
• Patient having given written consent. 
Atalante is able to accommodate the following limb lengths: 
• Thigh: 380-460mm. 
• Distance between the ground and the joint space of the knee (to be measured while 
wearing the shoes they intend to wear with Atalante): 
o 457–607mm for patient with an ankle dorsiflexion ≥ 16°  
o 457–577mm for patient with an ankle dorsiflexion between 13° et 16° 
o 457–567mm for patient with an ankle dorsiflexion between 10° et 13° 
o 457–557mm for patient with an ankle dorsiflexion between 0° and 10° 
• Hip with less or equal to 460mm when seated. 
• Maximum weight: 90 kg. 
 
3.2.2 Exclusion criteria   
 
• Pregnancy. 
• Starting or switching from fampridine (Fampyra®) in the last 4 weeks. 
• Height and weight outside the secure standard of safe use, described in the safety 
guides. 
•  Contraindications for Atalante training (eg, bone instability, history of 
osteoporosis or osteoporotic fractures). 
• Subjects under Corticosteroids treatment or relapse. 
• Changes in disease-modifying and symptomatic therapy for MS during the study 
period. 
• Subjects with psychiatric or cognitive comorbidities that may interfere with the 
trial. 
• Whose joint centers cannot be aligned Atalante’s. 
• Ranges of motion below:  
o  Knee: 5° extension, 110° flexion 

7 
 
o Ankle: 0° dorsiflexion, 9° plantar flexion, 18° inversion and eversion 
o Hip: 115° flexion, 15° extension, 17° abduction, 10° adduction, 10° 
o medial rotation, 20° lateral rotation 
• Severe spasticity (greater than Ashworth 3) or uncontrolled clonus. 
• Severe concurrent medical diseases: infections, circulatory, heart or lung, pressure 
sores. 
• Active implantable medical device. 
 
3.3 
Enrollment and Screening 
 
Subjects will be evaluated for their eligibility from neurorehabilitation and neurology 
outpatient clinics at the Multiple Sclerosis Center of Catalonia (Cemcat). 
 
Potential subjects will be referred to the study via Cemcat Physicians. A member of the 
research team will screen the referral and confirm they meet the necessary inclusion and 
exclusion criteria. Following confirmation of criteria, potential subjects will be contacted 
by phone to schedule an initial visit for consent and baseline assessment.  
Additionally, peripheral blood (6ml) will also be taken from all subjects at baseline (T1). 
 
 
Prior to all testing, each of the 60 selected participants will have time to read the consent 
form and ask questions (see Draft Informed Consent). The consent process will take place 
at the Multiple Sclerosis Centre of Catalonia (Cemcat, Vall d’Hebron Barcelona Hospital 
Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona). 
 
3.4 
Assessments 
 
The following information will be collected for all patients: age, sex, weight, height, type 
of MS, years from the diagnosis, Expanded Disability Status Scale (EDSS) and type of 
support device. 
 
To ensure that training sessions are well tolerated, we will assess patients’ blood pressure 
and heart rate weekly. We will also monitor the appearance of pain in any part of the body 
related to the RAGT at end of each training session using a pain registry (type of pain, 
location, intensity)27. 
 
3.4.1.1 To reduce the incidence of any type of muscle injury the physical therapist 
before each RAGT session will assess the level of spasticity using the Numeric 
Rating Scale measure of spasticity (NRS). The 0–10 NRS asks patients to 
indicate their level of spasticity on a scale of 0–10, where 0 is no spasticity and 
10 is the worst possible spasticity. This type of rating tool is widely utilized in 
clinical settings to quickly assess pain.28 
 
A record of any unexpected Serious Adverse Events (SAE) within trial episodes will be 
keep. These are defined as death, a life-threatening adverse event or an event occurring 
as a result of the use of the device that requires medical intervention. 
 
After the 8 weeks of rehabilitation treatment (T2) and, if possible, one year after T4, 
peripheral blood (6ml) will be taken from all subjects to perform the subsequent 
molecular analysis. 

8 
 
 
Molecular analysis 
 
Peripheral blood mononuclear cells (PBMCs) will be purified using the Ficoll-
Hypaque density gradient method according to manufacturer’s instructions. 
Briefly, whole blood will be extracted by venepuncture and collected in CPT 
Vacutainer tubes (Becton Dickinson, BDAM362781) and centrifuged at 2250g 
for 25 min. Supernatant will then be collected, and washed twice with enriched 
saline (0.9% NaCl, 2%FBS). PMBC containing pellet will then be resuspended 
with 1 ml of complete media (RPMI1640 + 2% FBS) and cells will be counted 
and assessed for viability using a Countess 3 automated cell counter (Invitrogene). 
PBMCs will be adjusted to 5 × 106 cells/ml in freezing media media (90% FBS, 
10% DMSO), and frozen at − 80 °C using a Mr. Frosty™ Freezing Container 
(Thermo Scientific™) for 24 h and stored in liquid nitrogen vapor phase. 
 
Once all samples are collected, chromatin will be extracted from the frozen 
PBMCs. Briefly, each vial containing 5 × 106 cells will be thawed and centrifuged 
at 300g for 5 min at 4°C. The supernatant will then be removed, and cells will be 
mixed with 100µL of lysis buffer (10 mM NaCl, 3 mM MgCl2, 10 mM Tris–HCl 
pH7.4, 0.1% Tween-20, 0.1% NP40) and lysed on ice for 4 min. Followed by 
2x1ml washes (10 mM NaCl, 3 mM MgCl2, 10 mM Tris–HCl pH7.4, 0.1% 
Tween20) before centrifuging at 500g for 5 min at 4°C.  
Next, ATAC-seq libraries will be generated according to manufacturer guidelines. 
Briefly, transposition mix (Illumina, Cat# 20031198) will be added to the nuclear 
pellets, incubated at 37 °C for 30 min, and DNA purified using the QIAGEN 
MinElute PCR Purification Kit (QIAGEN, Cat#28004). DNA fragments will be 
amplified by PCR for 10 to 11 cycles and resulting libraries purified using the 
QIAGEN MinElute PCR Purification Kit. The libraries will then be sequenced 
with an Illumina Novaseq 6000 S4 flow cell using 150 bp paired-end reads 
(Illumina, Cat# 20027466). FASTQ files will be generated from the NovaSeq 
BCL outputs and used as input to the ENCODE ATAC-seq pipeline 
(https://github.com/ENCODE-DCC/atac-seq-pipeline) using the MACS2 peak-
caller with all default parameters. Differential accessibility will be initially 
calculated between groups using the csaw package. 
To identify differentially open chromatin regions between groups from ATAC-
seq, the R package edgeR will be used to fit a generalized linear model (GLM) to 
test for the effect of rehabilitation between T0 and T1 samples. In addition to time 
group (T0 vs. T1), we will also compare the two different rehabilitation treatments 
(cRHB vs. RAGT at T1). We will also use surrogate variable analysis (SVA) to 
capture unknown sources of variation (e.g., batch effects, age, sex, library 
preparation, etc) statistically independent from time or treatment group 
assignments. SVA decomposes the variation that is not accounted for by known 
factors such as time group or treatment into orthogonal vectors that can then be 
used as additional covariates when fitting a model to test for differential 
accessibility or expression.  
Benjamini-Hochberg P value correction will be used to select differentially open 
peaks at an FDR of 5%.  
Differentially open ATAC-seq peaks will then be annotated with regard to 
functional and positional information. HOMER will be used to annotate peaks 
based on the relative gene position (promoter (±2 kb of known TSS), intergenic, 

9 
 
intronic, among others). For functional annotation of peaks, we will use a 
simplified version of the 18-state ChromHMM-derived chromatin states (such as 
TSSs, enhancers, repressed polycomb, transcriptionally active, or other states 
such as ZNFs or heterochromatin) obtained from Roadmap Epigenomics data for 
PBMC and T cell subsets.  
For gene-based analyses, HOMER will be used used to assign each differentially 
open ATAC-seq peak to the nearest TSS, as measured from the peak center. We 
will then assess enrichment using the hypergeometric test followed by Benjamini-
Hochberg FDR adjustment for P values, as previously mentioned. 
Further functional and ontological enrichment analyses will be performed using 
ClueGO and WikiPathways that will allow us to identify pathways among genes 
associated to differentially open peaks.  
Finally, we will scan the data for transcription factor (TF) footprints using the PIQ 
algorithm which integrates genome-wide TF motifs with chromatin accessibility 
estimates profiled at base pair resolution to generate a list of possible footprint 
matches for a motif. In a nutshell, this will allow the identification of chromatin 
accessibility blueprint generated by the different rehabilitation therapies tested in 
this trial, as well as gather valuable data of its underlying molecular mechanisms 
that in turn might lead to the identification of novel therapeutic targets. 
 

3-1 
 
 
Type 
outcome 
Test 
Baseline (T1) 
RAG 
Session 
1-24 
(S1-S24) 
end of training (T2) 
Follow up at 2 months 
(T3) 
Follow up at 1 year 
(T4) 
CRO PROMs Blood 
sample CRO PROMs Blood 
sample CRO PROMs Blood 
sample CRO PROMs Blood 
sample CRO PROMs Blood 
sample 
Pain 
1 
Pain registry 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
Physiologic 
indicators 
2 
Heart rate 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
3 
Arterial pressure 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Effort 
4 
Rating 
perception 
exertion 
The 
Borg 
R.P.E scale 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Fatigue: 
5 
Modified fatigue scale 
(MFIS) 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Depression 6 
Hospital Anxiety and 
Depression 
Scale 
(HADs) 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Health-
related 
quality 
of 
life 
7 
MSQoL 
54 
Health 
Survey 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Mobility 
8 
Modified Rivermead 
Mobility Index 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
Disability 
9 
Expanded 
Disability 
Status Scale (EDSS) 
de Kurtzke 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
Balance 
10 Berg scale test and 
Timed Up and Go test x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
Gait 
11 Timed 10-meters walk 
test 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
12 
self-report 
12-Item 
Multiple 
Sclerosis 
Walking Scale 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
13 
G-walk Assess (gait 
cycle duration, step 
length, 
propulsion 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
 

3-2 
 
Table 1Assessments
index, support phase 
percentage 
D/I, 
oscillation 
phase 
percentage D/I, double 
support 
phase 
percentage, 
unique 
support 
Phase 
Percentage 
Spasticity 
14 NRS 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
 
 
 
User 
Satisfaction 15 Gagnon scale 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Factors  
epigenetics 16 Homer Gene Based 
analyses 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
IC, Informed consent; Patient-Reported Outcome Measures (PROMs), Clinic report, CRO; 

3 
 
3.4.2 Schedule 
 
Following completion of day 1 assessments and randomization, all subjects will be scheduled for the 
intervention phase of the study. Each participant will receive 24 sessions of RAGT or cRHB scheduled 
for three times a week for 8 weeks. If a subject cancels a treatment session, it will be counted as missed 
session. If a subject misses three consecutive treatment sessions, they will be dropped from the study due 
to inconsistency in treatment carryover. Cancellations and changes in patient scheduling represent a true 
clinical environment and represents normal clinical patient management.  
At the end of the intervention phase, a new exploration will be carried out.  
 
 
Figure 1 schedule 
 
3.5 
Device 
3.5.1 Description 
 
Atalante is the first exoskeleton designed and developed by Wandercraft. Atalante is intended to perform 
ambulatory functions, mobility exercises and adapted physical exercises, hands-free for individuals 
having lower limb and trunk disability in rehabilitation centers, city cabinets or adapted physical exercise 
centers under the supervision of a trained operator.   
 
The device is available with one unique model and allows for length mechanical adjustment of specific 
parts so that patients with different physical characteristics can undergo care sessions with the same unit 
of Atalante - after it has been adjusted to their own set of measurements. 
 
Figure 2 shows the main parts of the device. 
 

4 
 
 
Figure 2: Atalante main parts 
 
Atalante is an exoskeleton composed of: 
• Two operated legs made up of articulated parts: thigh, leg, and foot. These parts can move thanks 
to 12 actuators comprised each of an electric motor, a position sensor (encoder), and a motor 
controller board to process related data. Figure 3 shows the location of each of the actuators. In 
addition, the thighs and legs are adjustable in length to allow adaptation to different patient 
morphologies. The lower structure is made of aluminium alloy, parts of which are covered by 
plastic shells. 
• A back, made of composite material, which links the lower limbs together and supports the upper 
body of the patient. 
• A vest, made of fabric, and equipped with an inertial sensor (IMU) to detect the intention of the 
patient inside the exoskeleton based on the motion of his chest. The vest is available in two sizes: 
small (S) and large (L). 
• Five additional inertial sensors located in the back, legs and feet for orientation estimation of 
different parts of the exoskeleton. 
• Force sensors placed in the feet for contact state estimation. 
• An embedded computing system (Wanderbrain and Wanderneuron software) to retrieve data 
from all sensors and boards, and coordinate motion - determining commands for the actuator 
blocks. 
• A set of plastic wedges to adapt to the patient morphology. The wedges compensate for a less 
than 16° dorsal flexion of the ankle and/or increase the distance between the patient’s knee and 
Atalante’s foot. They exist in 8 different sizes in terms of inclination (between 0 and 16°) and 
height and they are placed on Atalante’s feet, if needed. 
• A battery system consisting of two pluggable and rechargeable packs of Lithium-Ion cells 
enclosed in plastic casings and located each on the thighs. 
 

5 
 
 
Figure 3: Atalante joints 
 
The ranges of motion of the 12 joints are constrained by mechanical stops and supplemented by software 
stops to protect the patient’s joints from exceeding motion limits. Atalante is attached to the patient in 3 
locations per leg (thigh, leg, foot) plus at the abdomen level thanks to the vest’s belt. These interfaces are 
made of rigid shells covered with foams and equipped with adjustable straps that maintain the patient 
and facilitate transmission of the system movements to the patient, all while ensuring their comfort. The 
rigid shells are located at the back of the patient’s thigh and at the front of the leg. 
Atalante is controlled (Figure 4) by its user thanks to: 
• Sensors, especially a motion sensor (i.e., the IMU) placed on the back of the vest which triggers 
the movement. 
• Two keyboards, one for the operator (physio controller) leading the care session and one remote 
intended for either the operator or optionally the patient. 
 
 
 
Figure 4: Control interface of Atalante 
 

6 
 
As Atalante is destined to be used in healthcare facilities, city cabinets or adapted physical exercise 
centers with several patients in a day, the angular amplitudes of each articulation have been designed to 
allow a broad range of patients to be included into the exoskeleton. 
Furthermore, the device is equipped with mechanical adjustments allowing the length of the legs and the 
thighs to be regulated in the range 40-49 cm and 38-46 cm respectively, according to the dimensional 
measurements of the patients. The angular amplitudes of the 12 motorized articulations and the 
mechanical adjustment ranges are shown in the figure below. 
 
 
Figure 5: Angular amplitudes and mechanical adjustments of the V5 exoskeleton 
 
Atalante exoskeleton is part of a system (Figure 6) composed of: 
• DataGen: a dynamic adaptation of the algorithms is performed by a computation software 
running on a server called DataGen. It takes as input the patient measurements and computes a 
model of Atalante and the patient, as well as patient-specific trajectories for standing, sitting, 
walking, repositioning, and turning. All these outputs are transmitted to the exoskeleton. 
• AGUI (commercial name WanderTouch): an application running on a portable device, called 
AGUI, offers a way to communicate with the exoskeleton using Bluetooth communication, as 
well as with DataGen using Wi-Fi. Data flows from AGUI to DataGen (patient measurements) 
and back from DataGen to AGUI to Atalante exoskeleton (algorithm outputs). AGUI also allows 
for real-time configuration and monitoring of a session, by fine tuning the gait pattern, and by 
selecting the level of assistance (ActiveGait) provided by Atalante to the patient while performing 
walking steps. Gait can be resistive (ActiveGait up to -25%), fully supported by the patient 
(ActiveGait 0%), assisted by Atalante at a chosen level per leg (ActiveGait up to 100%), or fully 
passive where Atalante provides all the necessary effort to perform the gait. Additional indicators 
are collected and available on AGUI per session and per patient. 
• Bluetooth dongle: plugged in the back of Atalante and used to establish the communication 
between the AGUI and the exoskeleton. 
• Battery charger for the removable battery packs that power the exoskeleton. 
• Dynamometric screwdriver to adjust the thighs and legs. 

7 
 
 
Figure 6: Atalante system 
 
In addition, the Atalante system is used in combination with 
- 
a seat with the following characteristics: 
o A minimal depth of 40 cm, 
o A minimal width of 65 cm, 
o A height in the range 40-55 cm, 
o Able to support at least 200 kg, 
o Be covered with a cushion. 
- 
an electrical safety rail having the following characteristics:  
o Legally marketed medical device intended to support or lift people (compliance with ISO 
10535 “Hoists for the Transfer of Disabled Persons - Requirements and Test Methods” 
standard or equivalent). 
o Stable and installed in accordance with the manufacturer instructions. 
o Able to support at least 200 kg. 
 
The electrical safety rail and the seat are not distributed by Wandercraft. Only the swivel to link the safety 
rail to Atalante is provided with its protection. An example of safety rail without the protection is shown 
in Figure 6 below. 
 
Figure 7: Atalante fixation to a safety rail without the protection 
 
The exoskeleton is handled by the remote control, the “operator” interface located on the right-hand side 
of Atalante’s back and the sensor and an installation button located on Atalante's thighs at knee level at 
each side. The patient or the healthcare or the adapted physical activity professional select a mode or 
transition by pressing the relevant button. Then, the patient moves the bust; the sensor placed on the 
patient’s back detects the patient’s intention and trigger the movement. 
  
The various modes and transitions are listed below: 
- 
SITTING position: stable and comfortable sitting position. 
- 
STANDING position: stable and comfortable standing position. The STANDING button also 
allows to switch to "exercise" mode, to stand up and to stop the motion.  
- 
SITTING DOWN transition allows the patient to switch from standing up to sitting down. 
- 
WALKING mode allows the patient to walk with Atalante. 
- 
ROTATION mode allows the patient to turn with Atalante to the left or right. 

8 
 
- 
REPOSITION mode allows the patient to perform side and back steps with Atalante. 
- 
INSTALLATION mode allows the patient to be transferred from his/her wheelchair to Atalante, 
or vice versa.  
 
 
3.5.2 Regulatory approval 
 
The Atalante system including its parts and accessories is considered as a Class IIa medical device 
following Rule 9, according to the annex VIII, according to the regulation (EU) 2017/745 and is covered 
by a EU certificate N° MDR 727 876 R000 issued by BSI on May 26th, 2021. 
 
3.6 
Intervention 
 
The intervention will be delivered through the Neurorehabilitation Cemcat team. 
 
Traditional Gait Rehabilitation training (tRHB): 
 
Participants randomize to receive a tRHB, will be trained 3 times per week, with an intensity of 40 to 60 
minutes, and duration over 8-weeks. Progression will occur by increasing the session intensity weekly. 
 
A standardized protocol based on the usual clinical practice of physiotherapy in people with multiple 
sclerosis will be follow, according to patient characteristics, to design the sessions based on the patient 
objectives to be achieved, choosing the type of specific exercises to be performed based on the patient's 
condition and with the possibility of adapting them to their evolution during the twenty-four sessions. 
 
PHYSIOTHERAPY TREATMENT PROTOCOL 
Goa
l 
To re-educate the balance 
(sitting and standing).  
To normalize upper limbs 
muscle tone  
To improve the upper limbs 
muscular balance (MB) 
Intervention 
 Trunk work on stable surface: 
anterior-flexion, lateralization 
and turns to make appear the 
straightening 
reactions 
(5 
minutes)  
Local 
cryotherapy 
application to the most 
affected muscles using cold-
packs (15 minutes) 
If BM = 1: isometrical exercises 
of deltoid, bicep, triceps, carpal 
extensors and carpal flexors (3 
sets of 5 repetitions for each 
muscular group) 
Trunk work on instable surface 
(air cushion): anterior flexion, 
lateralization and turns to make 
appear 
the 
straightening 
reactions (5 minutes) 
Inhibitory postural treatment 
in flexion, abduction and 
external rotation of humeral-
scapula 
for 
the 
flexor 
patterns during cryotherapy 
application    
If MB = 2: Weight-bearing 
and/or active-assisted exercises 
for deltoids, biceps, triceps, 
carpal extensors and carpal 
flexors (3 sets of 5 repetitions for 
each muscle group) 
Balance work with Bobath ball 
(5 minutes)  
Passive mobilizations and 
myotendinous stretching of 
spastic 
musculature 
(5 
minutes) 
If MB= 3 : active-resisted 
exercises  with ½ kg of deltoid, 
bicep, triceps, carpal extensors 
and carpal flexors (3 sets of 5 
repetitions  for each muscular 
group) 
Balance standing exercises at 
bars: 
antero-posterior 
and 
lateral load transfer, different 
support bases, and changing 
props and surfaces (10 minutes)  
Pectoral and brachial biceps 
kneading and lats stretching 
(5 minutes) 
If MB = 4: active-resisted 
exercises with 1 kg of deltoid, 
bicep, triceps, carpal extensors 
and carpal flexors (3 sets of 5 
repetitions for each muscular 
group) 

9 
 
Sitting   
  
If MB = 5: active-resisted 
exercises with 2 kg of deltoid, 
bicep, triceps, carpal extensors 
and carpal flexors (3 sets of 5 
repetitions for each muscular 
group) 
 If Motor Assessment Scale 
score 
(MAS)≤ 
4: 
sitting 
program low level 
Propioceptive 
neuromuscular 
facilitation exercices (Kabat): 
diagonal on flexion-abduction-
external rotation with shoulder 
pivot; 
diagonal 
on 
flexion-
adduction-external rotation with 
elbow pivot (3 sets of 5 
repetitions for each muscular 
group) 
 If Motor Assessment Scale 
score (MAS) > 4: sitting 
program medium-high level  
  
Standing   
 If Berg scale score ≤ 32: 
standing program low level 
If Berg scale score 33-43: 
standing program medium level 
 If Berg scale score ≥ 44: 
standing program high level 
Goa
l 
To re-educate the gait    
To normalize lower limbs 
muscle tone  
To improve the lower limbs 
muscular balance (MB) 
Intervention 
Spastic 
gait 
re-education 
exercises with emphasis on 
triple flexion during swing 
phase and initial heel strike to 
prevent foot drag (5 minutes) 
Local 
cryotherapy 
application to the most 
affected muscles using cold-
packs (15 minutes) 
If BM = 1: isometrical exercises 
of 
major 
glutes, 
psoas, 
quadriceps, 
hamstrings 
and 
anterior tibial (3 sets of 5 
repetitions for each muscular 
group) 
Walking on parallel bars with 
obstacles with emphasis on the 
triple 
flexion, 
on 
the 
dissociation of the shoulder and 
pelvic girdles and on the 
locking and unlocking of the 
knees (5 minutes) 
Inhibitory postural treatment 
in 
abduction, 
external 
rotation and triple flexion for 
the extensor patterns during 
cryotherapy application   
If MB = 2: discounted exercises 
and/or active-assisted of major 
glutes, 
psoas, 
quadriceps, 
hamstrings and anterior tibial (3 
sets of 5 repetitions for each 
muscular group) 
Ataxic 
gait 
exercises 
(5 
minutes) 
Passive mobilizations and 
myotendinous stretching of 
spastic 
musculature 
(5 
minutes) 
If 
MB= 
3: 
active-resisted 
exercises with ½ kg of major 
glutes, 
psoas, 
quadriceps, 
hamstrings and anterior tibial (3 
sets of 5 repetitions for each 
muscular group) 
Incorporation of the 
most 
appropriate technical aid if 
necessary 
Gastrocnemius 
kneading 
and adductors, hamstrings, 
sural triceps, quadriceps and 
psoas 
stretching 
(5-10 
minutes for each limb) 
If MB = 4: active-resisted 
exercises with 1 kg of major 
glutes, 
psoas, 
quadriceps, 
hamstrings and anterior tibial (3 
sets of 5 repetitions for each 
muscular group) 

10 
 
Running treadmill with speed 
and inclination according to 
tolerance (2-6 minutes)   
Passive verticalization at 
standing or inclined plain to 
reduce 
the 
flexor 
musculature hypertonia (10 
minutes) 
If MB = 5: active-resisted 
exercises with 2 kg of major 
glutes, 
psoas, 
quadriceps, 
hamstrings and anterior tibial (3 
sets of 5 repetitions for each 
muscular group)  
 Weight-bearing walking (5 
minutes). 
Active verticalization at the 
shoulders or parallel bars in 
order 
to 
reduce 
the 
hypertonia of the flexor 
muscle (5-10 minutes)  
Step from sitting to standing (3 
sets of 5 repetitions) 
Vibratory 
stimulation 
in 
bilateral 
plantar 
zone 
(5 
minutes) 
Antero-posterior and lateral 
pelvic tilting exercises to 
encourage 
straightening 
reactions and reduce upper 
limbs 
hypertonia. 
(5-10 
minutes) 
Go up and down 20 stair’s steps 
  
Pelvic and trunk rotations to 
decrease 
trunk extension 
hypertonia (5 minutes) 
Active-resisted 
cycloergotherapy, 
resistance 
according to symmetry (10 
minutes)   
Passive cycle ergotherapy 
adapting speed to tolerance 
and avoiding spasms during 
exercises (10 minutes). 
  
 
 
 
Atalante Gait training (RAGT):  
 
Participants randomize to receive a Atalante gait training, will be trained 3-times per week, with an 
intensity of 40 to 60 minutes, and duration over 8-weeks. Progression will occur by increasing the session 
intensity weekly. Training intensity will be monitored and standardized using the Borg Rating of 
Perceived Exertion scale, and will progress from ‘fairly light’ to ‘somewhat hard’. This prescription is 
consistent and appropriate for individuals with MS with mobility impairment and low fitness levels. 
Progression will occur by increasing the intensity of the session increase the number of steps in each 
session and decrease the level of assistance. Sessions will not exceed 60 minutes. We will record all 
training parameters.  
Using the Atalante System, participants will be secured with the appropriately sized harness and attached 
to an overhead body-weight support system. Each session will begin with a 3–5-minute warm-up in the 
continuous passive mode (cadence ~40-45 steps/minute). The participant will then be transitioned into 
the adaptive training phase for practicing repetitive floor walking for up to 30 minutes. During this phase, 
the force produced by the robot is modulated to support the effort of the patient in producing a typical 
walking pattern. 
 
 
 
 
 
 
 
 
 
 
 
 

11 
 
 
Goals 
Session 
nº/time 
1 session. "Take in 
contact"/40 min 
2nd 
and 
3rd 
session / 30 min  
2nd week / 30 -
35 min  
3rd week / 35-40 
min approx) 
Improve the 
muscular 
balance of the 
deficient 
muscles 
of 
the 
lower 
limbs. 
Robotmins 
assistance 
level  
(adapted to 
the 
patientmin
s capacity) 
100% 
95% 
90% 
85% 
Reeducate 
the balance in 
standing. 
Activities 
Take 
patient 
measurements and 
create the APP’s 
profile 
the 
accelerometer 
training 
Walking 
with 
earlygait 5 for 
10  min 
Walking 
with 
earlygait mode 
5min 
Achieve 
a 
stable active 
bipedestation
. 
Learn 
how 
to 
change 
position 
from sitting (ST) to 
standing (SD) and 
back to ST. 
Squat exercise 1 
series x 5 rep. 
Squat exercise 1 
series x 10 rep. 
The 
exoskeletonmin
s controller is 
introduced to the 
patient 
in 
earlygait mode 
5min. 
Improve 
walking 
speed 
and 
gait pattern. 
Learn 
how 
the 
accelerometer 
works from SD. 
Trunk 
control 
exercises 
with 
balloon for 5 
min 
Trunk 
control 
exercises 
with 
ball 5min 
Squat exercise 1 
series x 10 rep. 
Improve 
stability and 
safety while 
driving. 
Learn 
how 
the 
movements 
and 
weight 
transfer 
work to activate the 
different 
functions/exercises
. 
Introduce 
the 
realgait 
mode 
walking (100% 
assisted) 
Squat exercise 1 
series x 5 rep. 
Trunk 
control 
exercises 
with 
ball for 5 min. 
Increase 
resistance to 
fatigue 
during 
walking. 
Start by walking 
for 5 min with 
early-gait 
mode. 
Learn the turns, 
lateral steps, and 
"reverse march." 
Walking 
with 
earlygait 5 for 5 
min 
Trunk 
control 
exercises 
with 
balloon for 5 
min. 
Squat exercise 1 
series x 10 rep. 
  
Start trunk control 
exercises with a 
ball for 5 min, and 
learn how to squat 
and lateral 
transfers. 
  
Realgait 
mode 
walk for 5 min 
(100% assisted) 
Trunk 
control 
exercises 
with 
balloon 5min. 
A series of squats x 
5 reps. 
Realgait 
walk 
for 
5 
min. 
(Introduce 
assistance 
levels, 95% if 
the 
patient 
tolerates) 
March 
with 
earlygait mode 
5min dual task. 
Trunk 
control 
exercises 
with 
balloon 5min. 
  
Realgait 
mode 
for 
10 
min 
(adjust levels of 
assistance based 
on 
tolerance 

12 
 
and/or 
patient 
characteristics). 
Session 
nº/time 
4th week / 
40 min  
5th week / 40 min  6th week / 40 
min  
7th week  / 40 
min  
8th week / 40 
min  
Robotmins 
assistance 
level 
(adapted 
to 
the 
patientmins 
capacity) 
80% 
75% 
70% 
65% 
60% 
Activities 
Walking in 
earlygait 
mode for 5 
min 
Walking 
in 
earlygait mode for 
10 min directed by 
patient 
Walking 
in 
earlygait mode 
for 
5 
min 
directed by the 
patient 
Walking 
in 
earlygait mode 
for 
5 
min 
directed by the 
patient 
Walking 
in 
earlygait mode 
for 
5 
min 
directed by the 
patient 
Walking in 
earlygait 
mode for 5 
min 
directed by 
the patient 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat 
exercise 1 
series x 10 
rep. 
Trunk 
control 
exercises with ball 
for 5 min. 
Trunk 
control 
exercises 
with 
ball for 5 min. 
Trunk 
control 
exercises 
with 
ball for 5 min 
Trunk 
control 
exercises 
with 
ball for 5 min. 
Trunk 
control 
exercises 
with 
ball 
for 5 min. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat 
exercise 1 
series x 10 
rep. 
Trunk 
control 
exercises 
with 
balloon 5min. 
Trunk 
control 
exercises 
with 
balloon 5min. 
Trunk 
control 
exercises 
with 
balloon for 5 
min 
Trunk 
control 
exercises 
with 
balloon for 5 
min 
Trunk 
control 
exercises 
with 
balloon for 
5 min. 
Squat exercise 1 
series x 5 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Squat exercise 1 
series x 10 rep. 
Walking in 
earlygait 
mode for 5 
min + dual 
task. 
Walking 
with 
earlygait 5min dual 
task. 
Trunk 
control 
exercises 
with 
racket/basketbal
l for 5 min. 
Trunk 
control 
exercises 
with 
racket/basketbal
l for 5 min. 
Trunk 
control 
exercises 
with 
racket/basketbal
l for 5 min 
Walking in 
earlygait 
mode 
for 
10 
min 
(We adjust 
assistance 
levels) 
Walking 
in 
earlygait mode for 
5 min (We adjust 
assistance levels) 
Walking 
in 
realgait 
mode 
for 
5 
min, 
introducing dual 
task. 
Walking 
in 
realgait 
mode 
for 
10 min 
directed by the 
patient (We 
adjust assistance 
levels). 
Walking 
in 
realgait 
mode 
for 
10 min 
directed by the 
patient (We 
adjust assistance 
levels). 

13 
 
  
Introduce use of the 
controller by the 
patient in realgait 
5min. 
Walking 
in 
realgait 
mode 
for 
10 min 
directed by the 
patient (We 
adjust assistance 
levels). 
Walking 
in 
realgait 
mode 
for 
5 
min, 
training dual 
task. 
Walking 
in 
realgait 
mode 
for 
5 
min, 
training dual 
task. 
 
 
 
 
 
 
 
 
 
 
4 
Statistical considerations 
 
The sample size calculation was based on the observed success rate (70%) in a previous evaluation of 
safety and performance of the self-balancing walking system Atalante in patients with spinal cord injury 
(i.e., 10 mWT with continuous walking mode)15 
 A sample size of 15 patients had been deemed necessary to demonstrate the performance with an alpha 
risk of 5% and a statistical power of 80% (Two-sided test). 
 
Descriptive statistics (i.e., mean, standard deviation) will be calculated for quantitative data 
(demographics and clinical characteristics and outcome measures). Frequencies will be calculated for 
qualitative variables. For the proportions, binomial proportion confidences will be calculated using the 
Wilson formulae. Proportions will be compared using the Newcombe formulae  
The Wilcoxon bilateral matched-pairs test will be used to compare repeated measurement on a single 
sample (mean, standard deviation). 
 
Study data were collected and managed using REDCapelectronic data capture tools hosted at the Mayo 
Clinic. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to   
data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless 
data downloads to common statistical packages; and 4) procedures for importing data from external 
sources (Harris et al., 2009). 
 
 
 

14 
 
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