Longstanding Exercise Therapy in Patients with Axial SpondyloArthritis

Rationale:
Axial Spondyloarthritis (axSpA) is a collective term for a group of chronic inflammatory diseases, mainly characterized by arthritis of the sacroiliac joints and spine, with back pain and stiffness as leading symptoms. In addition, arthritis of the peripheral joints may occur, and the condition may be associated with a variety of extraarticular manifestations involving the eye, bowel, lungs and heart. It affects about 0.1% of the population, with men being more often affected than women. During the course of their disease, some patients use short, intermittent physical therapy treatment (active exercise therapy) whereas others use longstanding weekly group exercise therapy, in order to prevent or diminish limitations in activities or participation. However, there is a substantial subgroup of patients with axSpA (<5 %) with persistent high disease activity, ossification of the spine, peripheral joint damage and/or complications of the disease or its treatment or comorbidity, resulting in complex limitations in activities and participation. Due to the individual nature of the problems and resulting disability, in this group the exercise therapy treatment is currently individual, highly personalized and usually longstanding (i.e. longer than 12 weeks and more than 20 sessions per year). Various systematic literature reviews have concluded that overall exercise in patients with axSpA is effective with respect to pain, aerobic capacity, spinal mobility, muscle strength, pulmonary function, physical functioning and quality of life (Regel 2017). Research on effectiveness of longstanding exercise therapy in the abovementioned patient group with complex limitations in activities and participation is however absent.

Objectives:
This study aims to underpin the delivery of longstanding exercise therapy in the subgroup of patients with axSpA and complex disability.
There are 3 research questions to be addressed:
1. Is longstanding, optimized active exercise therapy more effective with respect to functional ability than usual care in patients with axSpA with severe functional disability over a period of 52 weeks?
2. Which option (longstanding, optimized active exercise therapy or usual care) is more cost-effective?
3. What is the long-term course of functional ability, health status and health care consumption of patients using longstanding, optimized active exercise therapy?

Study design:
Randomized, controlled trial comparing longstanding, active exercise therapy with usual care (1:1). After the experimental period of 52 weeks at which the primary end-point is assessed, the intervention will be continued in the intervention group. Effects will be monitored at follow-up measurements after 104 weeks and after 156 and 208 weeks or at the end of the study (variable follow-up duration with a maximum of 156 weeks, depending on date of inclusion). At 52 weeks, the intervention will also be offered to the patients allocated to the usual care group.

Study population:
215 patients with a confirmed diagnosis of axSpA, with persistent, high disease activity, joint damage, complications of the disease or its treatment or comorbidity, resulting in complex limitations in activities and participation.

Intervention and control conditions:
The intervention concerns longstanding, intensive active exercise therapy (52 weeks), aimed at the improvement of specific individual limitations in daily activities and participation. It consists of a standardized program comprising active modalities (functional exercises, aerobic exercises, muscle strengthening and flexibility/joint range of motion exercises), with the type of exercises, their intensity, frequency, duration, site of delivery (practice or at home) and progression being tailored to the individual patients’ functional disability and ensuing needs and goals. The control condition consists of care as usual, left to the discretion of the treating physicians and the patients.

Main study parameters/endpoints:
Assessments are done at 0, 12, 26, 52, 104, and 156 and 208 weeks or end of the study (48 months). The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument (PSC) at 52 weeks.
Secondary outcome measures include the 10-item Patient Reported Outcomes Measurement Information System (PROMIS), the BASFI (Bath Ankylosing Spondylitis Functional Index) and a 6 minute walk test for functional ability; and the SF-36 for health related Quality of life. In order to address the topic of cost-effectiveness, the EuroQol (EQ-5D-5L) for health valuation and comprehensive measurements of costs for an economic analysis will be administered as well.
Apart from the primary and secondary outcome measures, sociodemographic and disease characteristics, will be recorded. The presence of comorbidity will be recorded by means of the comorbidity questionnaire developed by the Dutch Central Bureau of Statistics.
In addition, an anchor question regarding the perceived effectiveness will be added in all cases where longstanding exercise therapy was used (intervention and control group if starting after 52 weeks ) (“has the exercise therapy changed your daily functioning”), as well as a short questionnaire on patient satisfaction with treatment.
Furthermore, we will evaluate the content of care provided and the compliance of the pa-tients in the intervention group by asking the patients to fill out a registration form on the fre-quency, duration, and content of treatment. In a random sample of 10% we will validate the registration form with the records of the physical therapist (content, duration). The perception of any side effects of exercise therapy will be recorded. If treatment is discontinued, the rea-sons will be recorded.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The intervention concerns exercise therapy delivered by trained primary care physical therapists according to a standardized protocol, with no extra risks as compared to the regular delivery of primary care exercise therapy. Regarding the burden, the assessments mainly consist of the completion of questionnaires at home (max. 1 hour) and a site visit with one performance test (6-minute walk test) and the answering of a number of questions (max. total visit duration ½ hour). The maximum number of site visits is 5 (1 screening and maximum 4 evaluation visits at: baseline, 26 weeks, 52 weeks (primary endpoint) and 104 weeks. Evaluations at 156 and 208 weeks/end of study only consist of questionnaires.

This study aims to underpin the delivery of longstanding exercise therapy in the subgroup of patients with axSpA and complex disability.
There are 3 research questions to be addressed:
1. Is longstanding, optimized active exercise therapy more effective with respect to functional ability than usual care in patients with axSpA with severe functional disability over a period of 52 weeks?
2. Which option (longstanding, optimized active exercise therapy or usual care) is more cost-effective?
3. What is the long-term course of functional ability, health status and health care consumption of patients using longstanding, optimized active exercise therapy?

Assessments are done at 0, 12, 26, 52, 104, and 156 and 208 weeks or end of the study (48 months). The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument (PSC) at 52 weeks.

Longstanding optimized active exercise therapy (intervention) or usual care (control)