The aim of this study is to investigate if exercise therapy comprising the NEMEX program in combination with a CNS-targeted treatment using GMI and SDT is superior to exercise therapy alone in improving self-reported pain, function, quality of life and objective measures related to hyperexcitability of the CNS (e.g. central sensitization) in people with KOA.
Full Title of Study: “Randomized Controlled Trial of Exercise Therapy in Combination With Central Nervous System-targeted Treatment Compared With Exercise Therapy Alone for Treatment of People With Knee Osteoarthritis”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Treatment
- Masking: Double (Participant, Investigator)
- Study Primary Completion Date: October 2020
Participants will be randomized to one of two treatments initiated after randomization: the NEMEX program combined with a CNS-focused protocol or the NEMEX program alone.
The NEMEX program will consist of 12-weeks of individualized and supervised exercise sessions applied twice weekly (n=24 sessions). Each exercise session will last approximately 60minutes and include three parts: warming up, a circuit program and cooling down.
The CNS-targeted treatment will consist of 12-week individualized and supervised sessions applied twice weekly. Each training session will last approximately 30 minutes and include three parts, which are further explained below: 1) discussion of the participant's knee pain experience from a pain neuroscience perspective, 2) graded SDT and 3) GMI training.
- Other: NEMEX program combined with a CNS-focused protocol
- The NEMEX program will consist of 12-weeks of individualized and supervised exercise sessions applied twice weekly (n=24 sessions). Each exercise session will last approximately 60minutes and include three parts: warming up, a circuit program and cooling down. The CNS-targeted treatment will consist of 12-week individualized and supervised sessions applied once weekly. Each training session will last approximately 30 minutes and include three parts, which are further explained below: 1) discussion of the participant’s knee pain experience from a pain neuroscience perspective, 2) graded SDT and 3) GMI training.
- Other: NEMEX program
- The NEMEX program will consist of 12-weeks of individualized and supervised exercise sessions applied twice weekly (n=24 sessions). Each exercise session will last approximately 60minutes and include three parts: warming up, a circuit program and cooling down.
Arms, Groups and Cohorts
- Experimental: Exercise Therapy With CNS Treatment
- NEMEX program combined with a CNS-focused protocol
- Experimental: Exercise Therapy alone
- NEMEX program alone
Clinical Trial Outcome Measures
- The Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)
- Time Frame: baseline, post-intervention (after 12 weeks) and 6 and 12 months after initiating the treatment
- The primary outcome is the between-group difference in change in the mean score on four Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales, covering pain, symptoms, activities of daily living, and quality of life (KOOS4). The four patient-relevant subscales of KOOS are scored separately: Pain (9 items); Symptoms (7 items); ADL Function (17 items); Quality of Life (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the four scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as common in orthopaedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved.
- The Knee injury and Osteoarthritis Outcome Score (KOOS)
- Time Frame: baseline, post-intervention (after 12 weeks) and 6 and 12 months after initiating the treatment
- The KOOS is a knee-specific instrument, developed to assess the patients’ opinion about their knee and associated problems. It holds 42 items in 5 separately scored subscales; Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Recreation (Sport/Rec), and knee-related Quality of Life (QOL). The scores on all five patient-relevant subscales of KOOS are scored separately: Pain (9 items); Symptoms (7 items); ADL Function (17 items); Sport and Recreation Function (5 items); Quality of Life (4 items). A Likert scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme Problems) and each of the five scores is calculated as the sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee problems and 100 representing no knee problems as common in orthopaedic assessment scales and generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved.
- Pain intensity: NRS
- Participants will be presented with four numerical rating scales anchored with 0 (“no pain”) and 10 (“pain as bad as you can imagine”): 1) rating the most intense pain over the last week, 2) rating the least intense pain over the last week, 3) rating the average pain intensity over the last week, and 4) rating the pain right now. The scores will be averaged to calculate a final pain intensity score out of 10
- Sensitivity to physical activity
- Participants will be asked to rate their level of knee discomfort before, during, and after the 30-s chair-stand test in accordance with previous studies (Wideman et al., 2014). Knee discomfort will be ranked three times on a verbal rating scale that ranged from 0 (no discomfort) to 100 (extreme discomfort), once immediately before the task, once during the middle and once at the end of the task. An index of sensitivity to physical activity (SPA) will be calculated by subtracting participants’ first rating from their last rating.
- General health
- General health will be assessed using the Spanish version of the EuroQol Group 5-Dimension (EQ-5D-5L) self-reported questionnaire. EQ-5D-5L is a questionnaire with 5 dimensions (mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression) and 5 levels in each dimension (no problems, slight, moderate, severe, and un- able or extreme). Each health state is usually represented using a 5-digit number (profile) where 11111 indicates perfect health and 55555 the worst health state or pits state.
- Cortical representation
- The two-point discrimination (TPD) threshold is considered a clinical signature of cortical representation primary somatosensory representation. The TPD threshold will be measured using a mechanical sliding calliper (Duratech TA-2081, precision = 1 mm) in the vertical direction on the affected knee using suprathreshold (but non-noxious stimuli) and following an established protocol.
- Pressure pain thresholds
- A standardized protocol for evaluating PPTs will be used. Two test sites in the peripatellar region (3 cm medial and lateral to the midpoint of the medial and lateral edge of patella, respectively) and one distant site on the ipsilateral trapezius muscle (midpoint between spinous process of C7 and lateral border of acromion) will be selected for measurement. The PPT will be measured using an analogue Fisher algometer (Force Dial model FDK 40) with a surface area of 1cm2. The algometer probe tip was applied perpendicular to the skin at a rate of 1kg/cm2/s until the first onset of pain. Three measures were performed on each site with a 30 s interstimulus interval between each measurement and the mean was taken for analysis.
- Central Sensitization Inventory
- To identify key symptoms associated with augmented central pain processing mechanisms (e.g.central sensitization), the Spanish version of the Central Sensitization Inventory will be used (Cuesta-Vargas et al., 2016). The CSI provides reliable and valid data that quantify the severity of several symptoms of CS (Scerbo et al., 2017).
- Conditioned Pain Modulation
- Conditioned pain modulation (CPM) was tested using the upper extremity submaximal effort tourniquet test. Three trials of PPT measures at the two sites in the peripatellar region (medial and lateral to the midpoint of the medial and lateral edge of patella) were taken immediately following deflation.
- Number of participants with adverse events and number of adverse events
- Time Frame: During follow-up
- Adverse events (AE) and serious adverse events (SAEs) will be recorded at all follow-ups by asking patients about potential AEs using open-probe questioning to ensure that all AEs are recorded. In addition, the physiotherapist will record any adverse events that the patient experiences or talks about during treatment.
- Global perceived effect, patient acceptable symptom state and treatment failure
- Time Frame: 12 months after initiating the treatment
- Global perceived effect will be assessed with the question: “How are your knee problems now compared with before you entered this study?” This question will be answered on a Likert scale ranging from 1 (“very much improved”) to 7 (“very much worse”). Satisfaction with current knee function will be evaluated by the following question: “When you think of your knee function, will you consider your current condition as satisfying?”
- Compliance, exercise level/intensity and other treatments received during the study
- Time Frame: Up to 12 weeks
- Compliance with treatment sessions will be monitored by the supervising physiotherapists using an individual treatment diary where the number of sessions, progression of the exercises (e.g. level of difficulty at which all specific exercises are performed each session), time of day and duration of each clinic session will be recorded.
- Knee flexor and extensor strength
- Time Frame: Baseline, post-intervention (after 12 weeks) and 6 and 12 months after initiating the treatment
- Isometric knee flexor and extensor strength testing with modified hand-held dynamometry will be performed.
- Number of chair stands in 30 seconds
- Time Frame: Baseline, post-intervention (after 12 weeks) and 6 and 12 months after initiating the treatment
- As performance-based tests of physical function, the number of chair stands will be assessed. These tests have been recommended as performance-based tests of physical function representing typical activities relevant to individuals diagnosed with KOA.
- 40 m fast-paced walk test
- As performance-based tests of physical function, the 40 m fast-paced walk test will be assessed in seconds. These tests have been recommended as performance-based tests of physical function representing typical activities relevant to individuals diagnosed with KOA.
Participating in This Clinical Trial
- Patients with symptomatic and radiographically-confirmed tibiofemoral KOA (e.g. Kellgren-Lawrence ≥2, scored by an orthopaedic surgeon, not scheduled for total knee replacement [decision among other factors based on pain, function and radiographic severity.
- Diagnosis of KOA according to the EULAR classification criteria: adults aged >40 years with usage-related knee pain, only short-lived (<30min) morning stiffness, functional limitation (based on yes/no to the following question: Is your functional level reduced as compared to before your knee symptoms first started?) and one or more typical examination findings (crepitus, restricted movement, bony enlargement). The presence of this cluster correctly diagnosed 99% of cases with KOA.
- Less than mild functional limitations (a score above 75 on a 0-100 worst to best scale in the Spanish version of the self-report questionnaire Knee injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living (ADL) and quality of life (QOL).
- Previous knee replacement or any other lower limb surgery in the affected knee within the previous 3 months.
- Fracture of the affected extremity within the previous 6 months.
- Initiation of opioid analgesia or any form of injection (i.e. corticosteroid, hyaluronic acid, platelet-rich plasma) for knee pain within the previous 30 days.
- Physical impairments unrelated to the knee that would prevent safe participation in exercise.
- Any comorbidity that prevents from participating in the interventions (e.g.uncontrolled hypertension, moderate to high risk for cardiac complications)
- Any skin or medical condition preventing tactile stimulation on the knee.
- Inability to comprehend and complete study assessments or comply with study instructions (e.g. illiteracy, cognitive or visual impairments).
- Inability to a priori attend or complete the proposed course of intervention and follow-up schedule.
Gender Eligibility: All
Minimum Age: 41 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- University of Valencia
- Provider of Information About this Clinical Study
- Principal Investigator: Enrique Lluch Girbés, PhD Professor – University of Valencia
- Overall Official(s)
- Enrique Lluch Girbés, PhD, Study Director, University of Valencia
- Søren Thorgaard Skou, PhD, Study Chair, University of Southern Denmark
- Javier Peral Pérez, PhD student, Principal Investigator, University of Alcalá
- Overall Contact(s)
- Javier Peral Pérez, PhD Student, +34650510292, firstname.lastname@example.org
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