EXercise as TReatment for osteoArthritis

Study Overview
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Brief Summary
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Osteoarthritis (OA) of the knee is a chronic musculoskeletal disease, and a major cause of pain and disability worldwide. Exercise has previously demonstrated good effect in alleviating OA symptoms. However, optimal exercise modes in OA are currently unknown. This study seeks to evaluate the effects of supplementary focused, knee extensor strength training in addition to neuromuscular exercise (NEMEX) and education in people with OA of the knee as performed in Good Life with osteoArthritis in Denmark (GLA:D ᵀᴹ). Through a randomized design, study participants will either be allocated to 12 weeks (twice weekly) of NEMEX and education or 12 weeks (twice weekly) of NEMEX and education and focused, knee extensor strength training. The primary outcome measurement for this study is the Knee injury and Osteoarthritis Outcome Score, subscale Activities of Daily Living (KOOS-ADL), which is a self-reported questionnaire on daily life activities. Other outcomes include parameters of maximal muscle strength and muscle power, muscle imaging, physical function, pain and self-reported health status.

Detailed Description
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Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases worldwide. In Denmark, it is estimated that approximately 900.000 people, or 1 out of 5 residents are suffering from OA in one or more joints. The annual socio-economic costs (treatment and loss of labour) as a direct consequence of OA in Denmark are estimated to 11.5 billion Danish kroner (DKK). Osteoarthritis of the knee is the most frequently reported and disabling OA subgroup and is mainly reported in middle-aged adults (≥40 years) with an increasing prevalence with increasing age. Knee osteoarthritis is associated with knee pain, loss of lower limb muscle strength, activity limitations and reduced quality of life. Moreover, pain sensitization, i.e. increased responsiveness of nociceptive neurons, is another mechanism involved in pain and disability in knee-OA and may contribute to the frequently reported disparities between pain symptoms and radiographic signs of structural damage. The current non-surgical treatment recommendations in Denmark as well as internationally include offering one or more of: Patient education, dietary advice, weight loss counselling and exercise. Exercise has proven to be a potent stimulus to improve function, and general quality of life in people with knee-OA. Moreover, exercise has been shown to reduce pain sensitization in knee-OA subjects with clinical signs of sensitization. However, there is still a paucity of information on the exact exercise mode for greatest beneficial effects in the knee-OA population. Reduced lower limb muscle strength has repeatedly been suggested as one of the main working mechanisms behind knee-OA symptoms and quadriceps muscle strength is even suggested as a potential mediating factor in future knee joint space narrowing and longitudinal worsening of knee-joint pain. A recent systematic review revealed upper leg muscle strength along with joint proprioception to be two of the most potent mediating factors in symptomatic knee-OA. In a randomized controlled trial (RCT) design, this study seeks to investigate potential added benefits of supplementing NEMEX and education with focused knee extensor strength training in patients with knee-OA. 90 patients deemed ineligible for knee replacement surgery will be recruited from the ambulatory setting at Naestved Hospital. By random allocation, patients will be recruited to either 12 weeks (twice weekly) of NEMEX and education + focused knee extensor strength training (intervention group) or 12 weeks (twice weekly) of NEMEX and education only (control group). The main outcome is the change in KOOS-ADL from baseline to 12-week follow-up. Other outcomes include the remaining KOOS subscales, self-reported pain, health status, physical activity and patient satisfaction, knee extensor muscle power and knee extensor maximal contractile strength, pain sensitization, MRI assessed thigh muscle quality and physical function.

Official Title
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EXercise as TReatment for osteoArthritis

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Other: NEMEX and education + strength training
* Other: NEMEX and education


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with symptomatic and radiographically confirmed knee-OA who are found not eligible for knee replacement surgery by an orthopaedic surgeon in secondary health care. Exclusion Criteria: Kellgren & Lawrence score of <2 on radiography Less than mild symptoms (mean score >75 in 0-100 KOOS-ADL) Medication: Morphine for pain other than knee-joint pain Previous ipsilateral knee arthroplasty Rheumatoid arthritis Inability to comply with the protocol Inadequacy in written and spoken Danish

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group, assessor- and patient blinded randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEMEX and education + strength training<br>Participants will undergo 12 weeks of twice weekly exercise. Each exercise session will last for 70-90 min. and will consist of 1 hour of specific exercises to optimize sensorimotor control and achieve compensatory functional stability performed in a multiple-joint weight-bearing specific manner. The final part of the session will consist of focused knee extensor strength training performed in gym machines (knee extension & leg-press) in a combination of low-load fatiguing exercises (knee-extension) followed by high-load exercises (leg-press). Additionally, participants will receive 2 educational sessions, which include disease- and exercise specific counseling. | Other: NEMEX and education + strength training<br>* Optimizing sensorimotor control and achieving functional stability. Increasing knee extensor muscle strength. Teaching everyday disease management.<br>* Other names: GLA:D + strength training;|
| Active Comparator: NEMEX and education<br>Participants will undergo 12 weeks of twice weekly exercise. Each exercise session will last for approximately 60 min. and will consist of 1 hour of specific exercises to optimize sensorimotor control and achieve compensatory functional stability performed in a multiple-joint weight-bearing specific manner. Additionally, participants will receive 2 educational sessions, which include disease- and exercise specific counseling. | Other: NEMEX and education<br>* Optimizing sensorimotor control and achieving functional stability. Teaching everyday disease management.<br>* Other names: GLA:D;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Knee injury and Osteoarthritis Outcome Score (KOOS) - subscale Activities of daily living (ADL) | KOOS is a validated and extensively used self-reported outcome measure for people with knee OA. KOOS consists of five subscales, of which the subscale KOOS-ADL will be the primary outcome for this study. KOOS-ADL consists of 17 questions, which are answered on a 4-point likert scale (0=no problems, 4=extreme problems). KOOS-ADL has demonstrated a test-retest reliability (ICC) of 0.84-0.94 as well as demonstrating responsiveness to change following physical therapy in knee osteoarthritis. | Primary endpoint: Change from baseline to 12 weeks. Secondary endpoints: 6 weeks & 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle power (watt/kg. bodyweight) | Knee extensor muscle power (force times acceleration) will be measured using the Nottingham Power Rig (NPR). The NPR measures the power output in total watt and watt pr. bodyweight in kilograms from a seated push on a flat pedal which is transmitted by a lever and chain to spin a flywheel. The NPR is a safe and reliable method to measure explosive knee extensor muscle power and has been validated as a clinically important measure of muscle function in elderly individuals. | Primary endpoint: Change from baseline to 12 weeks. Secondary endpoint: Baseline to 6 weeks. | 
| Functional performance (40 m walk & stair-climbs) | Assessment of functional performance involves time (in seconds) taken to complete a 40 m course at fast walking pace as well as time taken to negotiate 9 steps on a standard step-height stair-way. The tests are part of the recommended functional performance tests in knee osteoarthritis. | Primary endpoint: Change from baseline to 12 weeks. Secondary endpoint: 6 weeks. | 
| Pain medication | Assessment of pain medication intake specific for knee pain. Derived as part of self-reported outcome measure. | Primary endpoint: Change from baseline to 12 weeks. Secondary endpoints: 6 weeks & 12 months. | 
| KOOS (remaining four subscales) | The four remaining subscales of the validated KOOS questionnaire (see primary outcome for further info on KOOS). The 4 remaining subscales cover: symptoms, pain, sport & recreation and quality of life. | Primary endpoint: Change from baseline to 12 weeks. Secondary endpoints: 6 weeks & 12 months. | 
| AE (adverse events) & Serious Adverse Events (SAE) | Continous registration of health issues and injuries. Physiotherapists in charge of the training sessions will monitor potential AE and SAE. Also, during the follow-up visits at week 6 and week 12, the participants will be asked about potential AE's and SAE's using open-probe questions. Finally, the 12 month follow-up will include questions regarding AE's and SAE's during the preceding period from baseline to 12 months. | Primary endpoint: From baseline to 12 weeks.. Secondary endpoint: 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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knee, osteoarthritis, exercise, quadriceps, strength, activities of daily living, treatment outcome