Home-based EXergames To impRove cognitivE Function in MUltiple Sclerosis (EXTREMUS)

Home-based EXergames To impRove cognitivE Function in MUltiple Sclerosis: the EXTREMUS Study. A Multicenter, Randomized, Single-blind Non-inferiority Trial

Study design: Phase II, multicenter, randomized, sham-controlled, single-blind, parallel arm, multicenter study to test the hypothesis that home-based exergames is not inferior to home-based cognitive rehabilitation delivered by a software application (app) for mobile devices and both interventions are superior to a placebo-analogue cognitive intervention in improving cognitive function and reducing cognitive-motor interference in people with multiple sclerosis (MS).

Procedures: Participants will be randomized in a 1:1:1 ratio to receive an 8-week home-based training with exergames (intervention of interest) or adaptive COGNI-TRAcK (comparator intervention) or sham COGNI-TRAcK (placebo-analogue intervention). Study assessment will be done at study enrolment (baseline), at the end of the 8-week intervention period (immediate post-training, Week 8) and after 16 weeks from randomization (post-training follow-up, Week 16).

Investigational interventions:

1. Exergames: home-based repetition of several games delivered by the Nintendo © Wii Balance Board, a commercial off-the-shelf video game console for re-training of balance and postural strategies
2. Adaptive COGNI-TRAcK: adaptive (i.e. automatic adjustment of tasks difficulty) working memory training delivered by a customized application software for mobile devices to self-administer at-home
3. Sham COGNI-TRAcK: non-adaptive (i.e. constant difficulty level) working memory training delivered by the same app as afore described

Primary endpoint: changes at the Symbol Digit Modalities Test (SDMT), a measure of sustained attention and information processing speed.

Secondary endpoint: changes at the BICAMS (z-scores), a brief, practical and universal assessment tool for cognitive impairment in MS.

Additional endpoints: magnitude of cognitive-motor interference estimated as dual-task cost of balance and walking.

Sample size estimation: The investigators estimated a pre-defined 8-point non-inferiority margin, based on a significant effect of the COGNI-TRAcK in inducing an about 8-point mean increase at SDMT score (with respect to a sham intervention). Accordingly, 35 participants per arm are required to ensure, with an approximately 85%-power level, that the lower limit of a one-side 95% confidence interval will be above the pre-defined non-inferiority margin. Therefore, considering also a drop-out rate of 25%, a total of 132 subjects should be enrolled.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Exergames; Behavioral: Adaptive COGNI-TRAcK; Behavioral: Sham COGNI-TRAcK

• Study Type: Interventional
• Enrollment (Anticipated): 135
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Letizia Castelli, MD, PhD; Phone Number: +39658704272; Email: letizia.castelli@gmail.com
• Study Contact Backup: Name: Shalom Haggiag, MD; Phone Number: +39658704272; Email: lvshalom@hotmail.com

Study Locations

• Italy
  • GE
    • Genova, GE, Italy, 16149
      • Recruiting
      • Italian MS Foundation
      • Contact: Giampaolo Brichetto; Phone Number: +39-10-2713832; Email: giampaolo.brichetto@aism.it
  • MI
    • Milano, MI, Italy, 20148
      • Recruiting
      • LaRiCE Lab, Don Gnocchi Foundation IRCCS
      • Contact: Davide Cattaneo; Phone Number: +39-2-40308095; Email: dcattaneo@dongnocchi.it
  • RM
    • Rome, RM, Italy, 00152
      • Recruiting
      • A.O. San Camillo, MS Center
      • Contact: Luca Prosperini, M; Phone Number: +39-6-58704272; Email: luca.prosperini@gmail.com
  • VC
    • Moncrivello, VC, Italy, 13040
      • Recruiting
      • Dept. of Rehabilitation, M.L. Novarese
      • Contact: Claudio Solaro; Phone Number: +39-161-426161; Email: csolaro.centrosm@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age between 18 and 55 years (inclusive);
• cognitive impairment, defined as failure in the SDMT, defined as a corrected score less than 38, i.e. below the 5th percentile of normative value;
• Expanded Disability Status Scale (EDSS) score between 2.0 and 5.5;
• ability to stand upright for at least 180 seconds without any support;
• ability to understand and comply with study requirements;
• ability to provide a valid informed consent before any study procedure.

Exclusion Criteria:

• relapse in the previous 6 months;
• initiation of disease-modifying or symptomatic treatments or physiotherapy programme in the 3 months prior to study entry;
• any medication/physiotherapy changes occurring over the previous 3 months;
• significant visual impairment, defined as a Visual System scoring more than 2 at the Kurtzke Functional Systems Score;
• clinically relevant depression, defined as Beck Depression Inventory-II (BDI-II) score equal or more than 14;
• overt dementia, defined as an adjusted Mini Mental State Examination (MMSE) score equal or less than 24;
• history of epilepsy or seizures;
• any medical condition, including musculoskeletal disorders that can interfere with the study conduction.

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: Exergames	Behavioral: Exergames; The training protocol will be delivered by the Nintendo ® Wii balance board and consists of repetitions of several games selected from the "Wii Fit Plus" package (http:// www.wiifit.com/training/balance-games.html). Each game starts at basic level, and when a certain score is reached, patients is automatically transferred to a more advanced level. Patients will be encouraged to play the next game if they have a level progress; otherwise, 10 minutes will be allocated for each game. During the first 4 weeks of training, patients will be allowed to play only "Zazen" (sitting position), "Table Tilt" and "Ski Slalom"; thereafter they will add the remaining games "Penguin Slide", "Tightrope Walk", "Balance Bubble" and "Soccer Heading".
Active Comparator: Adaptive COGNI-TRAcK	Behavioral: Adaptive COGNI-TRAcK; The training protocol will be delivered by a dedicated app for mobile devices (mobile phone or tablet). The app implements three different types of exercises (each one executed for about 10 min a session), consisting in a visuo-spatial working memory task, an "operation" N-back task and a "dual" N-back task. The adaptive training is structured so that the exercises difficulty level will increase by one step every time the user will perform a correct exercise. On the other hand, the difficulty level will decrease by one step if the exercise is incorrect for three times in a row.
Sham Comparator: Sham COGNI-TRAcK	Behavioral: Sham COGNI-TRAcK; The training protocol will be delivered by a dedicated app for mobile devices (mobile phone or tablet) as previously described for adaptive COGNI-TRAcK. However, the non-adaptive training (placebo-analogue intervention) consists in an algorithm implementing two low difficulty levels alternating every day regardless of the user's performance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symbol Digit Modalities Test	The participant is presented with a page headed by a key that pairs the single digits 1-9 with nine symbols. Rows below contain only symbols, the subject's task is to orally report the correct number in the spaces below. After completing the first 10 items with guidance, the subject is timed to determine how many responses can be made in 90 seconds. Range score: not applicable. Higher scores mean a better outcome. Explored domain: Sustained attention and information processing speed.	Change from randomization to 8-week visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief International Cognitive Assessment for Multiple Sclerosis	Brief cognitive assessment for multiple sclerosis that includes the Symbol Digit Modalities Test (SDMT) for exploring sustained attention, the initial learning trials of the second edition of the California Verbal Learning Test (CVLT2) for exploring auditory/verbal learning, and the revised Brief Visuospatial Memory Test (BVMTR) for exploring visual/spatial memory. Range score: not applicable. Higher scores mean a better outcome.	At randomization, 8 weeks and 16 weeks
Stroop Color-Word Test	The test explores some aspects of executive functions and consists of naming the color of the ink of words, indicating conflicting colors as quickly as possible. Range score: not applicable. Higher scores mean a better outcome.	At randomization, 8 weeks and 16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive-Motor Interference	Dual-task cost of walking (2-Meter Walking Test) and balance (static posturography) is calculated as percentage change in scores obtained under single-task condition minus dual-task condition divided by the score under single-task condition. Range score: not applicable (negative values are possible). Higher scores mean a better outcome.	At randomization, 8 weeks and 16 weeks
29-item Multiple Sclerosis Impact Scale	The Multiple Sclerosis Impact Scale (MSIS-29) is a 29-item self-administered questionnaire measuring physical and psychological impact of multiple sclerosis from the patient's perspective. Range score: 0 to 100. Higher scores mean worse outcome.	At randomization, 8 weeks and 16 weeks
21-item Modified Fatigue Impact Scale	The Modified Fatigue Impact Scale (MFIS) is a 21-item self-administered questionnaire based on items derived from interviews with patients with multiple sclerosis concerning how fatigue impacts their lives; it comprises three subscales (physical, cognitive, and psychosocial functioning). Range score: 0 to 84. Higher scores mean worse outcome.	At randomization, 8 weeks and 16 weeks
Work Productivity and Activity Impairment: Multiple Sclerosis	To quantify absenteeism (missing work because of health problems), presenteeism (impairment while working), overall work impairment, and daily activity impairment attributable to multiple sclerosis. Range score: 0 to 100. Higher scores mean worse outcome.	At randomization, 8 weeks and 16 weeks
Time to first accidental falls	Time to randomization to the first accidental falls reported by the participant, defined as an event which results in a person coming to rest inadvertently on the ground or floor or other lower level (WHO). Range score: not applicable.	From randomization to study termination (16 weeks)
Adverse events	Any untoward medical occurrence in participants which does not necessarily have a causal relationship with the administered intervention. Range score: not applicable.	From randomization to study termination (16 weeks)

Collaborators and Investigators

• Sponsor: San Camillo Hospital, Rome
• Collaborators: Fondazione Italiana Sclerosi Multipla; Fondazione Don Carlo Gnocchi Onlus; University of Chieti; Rehabilitation Unit 'Mons. L. Novarese' Hospital, Moncrivello (VC), IT
• Investigators: Principal Investigator: Luca Prosperini, MD, PhD, A.O. San Camillo-Forlanini

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Anticipated): June 30, 2022
• Study Completion (Anticipated): September 30, 2022

Study Registration Dates

• First Submitted: November 3, 2019
• First Submitted That Met QC Criteria: November 16, 2019
• First Posted (Actual): November 20, 2019

Study Record Updates

• Last Update Posted (Actual): October 1, 2021
• Last Update Submitted That Met QC Criteria: September 30, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Rehabilitation; Neuroplasticity; Cognitive impairment; Clinical Trial; Exergames
• 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: 2017/R/22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: After publication
• IPD Sharing Access Criteria: Upon request to PI
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)

Drug and device information, study documents

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