This study wants to investigate whether exercise booster sessions applied in the follow-up period after an exercise intervention can increase the sustainability of exercise induced effects in persons with multiple sclerosis.

The study will be a randomized, multi-site, controlled trial. Participants will from the beginning be allocated to either aerobic training group, resistance training group or control group. After a 12 week exercise intervention, the exercise groups will be additionally randomized to receive either exercise booster sessions + standard care or just standard care in the 40 week follow up period.

It is hypothesized that exercise booster sessions can increase the sustainability of exercise induced effects.

MS is a chronic, autoimmune, and inflammatory disease of the central nervous system, exemplified through marked demyelination and axonal loss. As a result, symptoms such as fatigue, numbness, weakness, depression, walking difficulties and spasticity frequently appear.

Although there is no cure for MS, several disease-modifying therapies are available. These can potentially slow the progression of disabilities and reduce the overall disease burden. This is of great interest from both an individual perspective, where increased disability is associated with a lowered health-related quality of life, and from a societal perspective, where increased disability is associated with larger costs.

Over the past decades exercise has been shown to be safe, tolerable and beneficial in persons with MS (PwMS). Hence, it is known to be an effective way of treating symptoms such as fatigue7, muscle weakness, walking impairments and depression. As with other chronic diseases, exercise for PwMS has been proposed as "medicine". However, in order to benefit from the positive effects of any kind of treatment (i.e. most medical drugs or exercise) one has to adhere to the prescriptions of the treatment (i.e. dose and timing). Despite all the potential benefits of exercise therapy for PwMS, one of the major challenges relate to long-term maintenance of exercise efforts.

An emerging concept that may hold the potential to increase the sustainability of exercise therapy is supervised "exercise booster sessions" (i.e. training sessions provided regularly throughout the follow-up period, to sustain effects of the preceding exercise intervention). These can be placed regularly during the follow-up period, where patients attend a number of supervised high-intensity exercise sessions, hereby trying to boost the effects of the preceding exercise intervention. Furthermore, exercise booster sessions can potentially motivate the patient to keep exercising throughout the follow up period.

However, the optimal way of utilizing this concept is still not fully understood, and has not yet been tried in neurological patients.

Therefore, the main purpose of the present study is to investigate how exercise booster sessions combined with usual care performed over a period of 40 weeks affects the sustainability of effects on functional capacity induced by a 12-week exercise intervention.

It is hypothesized that participants receiving exercise booster sessions + usual care during follow up will have a better functional capacity at follow up, than the participants receiving usual care only.

The study will be a randomized, multi-site, controlled trial. Participants will from the beginning be allocated to either aerobic training group, resistance training group or control group. After a 12 week exercise intervention, the exercise groups will be additionally randomized to receive either exercise booster sessions + standard care or just standard care in the 40 week follow up period.

The 12 week exercise intervention will consist of 2-3 weekly supervised exercise sessions. The training will be planned by exercise physiologists and performed in a progressive manner. To allow handling of a large number of participants, who is also geographically spread, the exercise intervention will be locally anchored, but at the same time supervised by student employees and controlled by internet- and telephonic communication.

Participants allocated to exercise booster sessions will receive two sessions every fifth week during the follow up period.

The power calculation is based on the primary purpose of the study which is to investigate the effect of frequently applied exercise booster sessions. To set the estimated number of participants, a two-sample two-sided power calculation has been conducted. Based on previous studies, a mean difference on functional capacity between the group receiving usual care and the group receiving exercise booster sessions + usual care, regardless of exercise intervention, is expected to be 6% with a standard deviation (SD) of ±10%.

The level of significance was set as 5% and a statistical power of 80%. According to the power calculation each group shall contain 60 participants (expected drop-out rate of 30 % is included).

The results of these studies can have great clinical implications in many ways. If we find that by adding exercise booster sessions in a follow up period, one can maintain, or maybe even improve, functional capacity over a long period, this would be a novel finding making ground for new rehabilitation opportunities

Inclusion Criteria:

• A definite diagnosis of MS, according to the McDonald criteria
• Walking <650m on 6MWT.
• Exercising ≤ two sessions per week of moderate-to-high intensity during the past six months.

Exclusion Criteria:

• Comprise comorbidities (cardiovascular-, respiratory-, orthopedic- or other neurological diseases.)

All data will be stored in The Danish National Archives after completion of the project, and data can be accessed through request to The Danish National Archives.

The data will become available after completion of the project, expectedly May 2024. The Danish National Archives stores data without a time frame (forever).

Sharing of data can happen upon request to The Danish National Archives.