Exercise Therapy for Osteoarthritis Pain: How Does it Work?

Knee Osteoarthritis Clinical Trial

— KOA-PAIN  

Official title:

Exercise Therapy for Osteoarthritis Pain: How Does it Work?

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04362618
• Other study ID #: G040919N_KOA_PAIN
• Status: Recruiting
• Phase: N/A
• Start date: March 5, 2020
• Est. completion date: December 31, 2023

Study information

• Verified date: May 2023
• Source: Vrije Universiteit Brussel
• Contact: Ivan Bautmans, PhD
• Phone: +3224774207
• Email: ivan.bautmans[@]vub.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

International guidelines recommend exercise as the first choice treatment for knee osteoarthritis (KOA). Muscle strengthening training (MST) and behavioural graded activity (BGA) show comparable effects on KOA pain, but the mechanisms of action are unclear. Understanding these mechanisms is necessary to tailor exercise therapy towards specific mediators and thereby optimize treatment effects. Based on previous studies, both exercise-induced anti-inflammation and endogenous analgesia are promising pathways for pain reduction after exercise therapy. This study aims to examine (anti)-inflammation and endogenous analgesia as mediators for the effect of MST and/or BGA on pain in patients with KOA. Therefore, a 3-arm randomized clinical trial is established: 12 weeks of muscle strengthening training, behavioural graded activity or control. Mediator analysis will be performed. Unravelling the mechanisms of action of exercise therapy in KOA will not only be extremely valuable for researchers, but also for exercise immunology and pain scientists. The results of this research will also find their way into clinical practice: thanks to the current project, tailoring exercise therapy programs towards specific mechanistic factors and thereby optimizing treatment effects will be at the horizon for patients suffering from KOA.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

1. KOA according to the clinical American College of Rheumatology (ACR) criteria. The clinical ACR criteria for KOA are: knee pain and at least 3 of the 6 following features: age =50, morning stiffness <30 minutes, crepitus, bony tenderness, bony enlargement, no palpable warmth. KOA will be confirmed with radiographs, including anterior-posterior (AP) and medio-lateral (ML) radiographs for imaging the tibiofemoral joint, and an axial view for imaging the patellofemoral joint. Kellgren and Lawrence (K&L) grading system for OA will be applied, with K&L grade 2 or higher defined as OA; radiographic KOA is defined as definite osteophytes and possible joint space narrowing.

2. pain, nominated by the patient as 3 /10 or higher on a visual analogue scale on most days of the last 3 months

3. aged = 50 years.

Exclusion Criteria:

1. treatment with exercise therapy or joint infiltrations (e.g., corticosteroids, hyaluronic acid) in the preceding 6 months;

2. being on a waiting list for knee replacement;

3. any contra-indication for exercise therapy as established by the treating physician;

4. corticosteroid infiltrations in the last 6 months;

5. cognitive impairment (unable to understand the test instructions and/or Mini Mental State Examination score <23/30);

6. unable to understand the Dutch language;

7. inflammation unrelated to OA (e.g. due to acute or chronic infection) established by CRP>10mg/L.

8. presence of a disorder and/or medication that influences pain and/or the immune system

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Other:
• Muscle Strengthening Training
Muscle strengthening training will take place for a period of 12 weeks, in which participants will have 36 exercise sessions (18 at the hospital under supervision of a physiotherapist; 18 unsupervised at home) planned. Muscles of the leg (i.e. quadriceps, hip ab- and adductors) will be trained at 3 set of 10 repetitions at 80% of 1RM with the use of elastic bands. 1RM will be assessed at baseline and the exercise intensity will be progressively increased by 10% of 1RM every two sessions from 50 up to 70-80 % of 1RM. Every 6 sessions, the 1RM will be reassessed and the training resistances will be adapted.

Behavioral:
• Behavioral graded activity
Subjects will receive a behavioural treatment integrated within the concepts of operant conditioning with exercise therapy for a period of 12 weeks, in which the subjects will have maximum 36 BGA sessions (min. 13- max. 18 at the hospital under supervision of a physiotherapist; 18 unsupervised at home) planned. The purpose of BGA is to increase the level of activities in a time-contingent manner and increase the level of physical activity in the subject's daily lives. BGA consists of 3 phases: pain education (phase 1), treatment phase in which subjects increase their level of activity gradually (phase 2) and integration of learned principles in daily live (phase 3).

Locations

Country	Name	City	State
Belgium	Vrije Universiteit Brussel (VUB)	Jette	Brussels Capital Region

Sponsors (3)

Lead Sponsor	Collaborator
Vrije Universiteit Brussel	AZ St.-Dimpna Geel, Universitair Ziekenhuis Brussel

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pain catastrophizing (explanatory outcome)	Pain catastrophizing will be assessed using the Pain Catastrophizing Scale (PCS-DV).	Assessed at baseline, at week 13, 26 and 64
Other	Pain hypervigilance (explanatory outcome)	Pain hypervigilance will be assessed using the Pain Vigilance and Awareness Questionnaire (PVAQ).	Assessed at baseline, at week 13, 26 and 64
Other	Illness perceptions (explanatory outcome)	Illness perceptions will be assessed using the Illness Perception Questionnaire-revised (IPQ-R).	Assessed at baseline, at week 13, 26 and 64
Other	Dietary intake (explanatory outcome)	Dietary intake will be assessed with the use of the Food Frequency Questionnaire (FFQ).	Assessed at baseline, at week 13, 26 and 64
Other	Inflammation (as treatment mediator)	Inflammation will be tested by a blood-based biomarker panel (e.g. ELISA) for chronic low-grade inflammatory profile.	Assessments will be performed at baseline, during intervention (at week 2 or week 3 and at week 10 or week 11; pre- and post-treatment for the acute effects), at week 13 (at least 48 hours after the last intervention) and at week 64
Other	Endogenous analgesia as treatment mediator: electrical detection threshold	Endogenous pain modulation will be evaluated by determining the electrical detection threshold. Electrical stimulation (Surpass LT Stimulator) will start at 0mA and will be gradually increased until the patient is experiencing a faint sensation.	Assessments will be performed at baseline, during intervention (at week 2 or week 3 and at week 10 or week 11; pre- and post-treatment for the acute effects), and at week 13 (at least 48 hours after the last intervention) and week 64
Other	Endogenous analgesia as treatment mediator: electrical pain threshold	Endogenous pain modulation will be evaluated by determining the electrical pain threshold. Electrical stimulation (Surpass LT Stimulator) will start at 0 mA and will be gradually increased until the patient is experiencing the stimulus as painful.	Assessments will be performed at baseline, during intervention (at week 2 or week 3 and at week 10 or week 11; pre- and post-treatment for the acute effects), and at week 13 (at least 48 hours after the last intervention) and at week 64
Other	Endogenous analgesia as treatment mediator: temporal summation	Endogenous pain facilitation will be evaluated by the temporal summation paradigm. Electrical stimuli (Surpass LT Stimulator) will be given at the intensity (mA) of the electrical pain threshold. A verbal numeric rating scale (VNRS) from 0 to 10 will be asked at the first stimulus, at the middle and at the last electrical stimulus.	Assessments will be performed at baseline, during intervention (at week 2 or week 3 and at week 10 or week 11; pre- and post-treatment for the acute effects), at week 13 (at least 48 hours after the last intervention) and at week 64
Other	Endogenous analgesia as treatment mediator: conditioned pain modulation	The efficacy of endogenous analgesia will be evaluated by the conditioned pain modulation paradigm. Conditioned pain modulation will be tested with the electrical stimulator as test stimulus and the cold pressor (12 °C) as conditioning stimulus. The difference between the electrical pain threshold (baseline) and the electrical pain threshold during the cold pressor (baseline + cold pressor) is called the conditioned pain modulation effect. After electrical stimulation (Surpass LT Stimulator), a VNRS score from 0 to 10 will be asked.	Assessments will be performed at baseline, and at week 13 (at least 48 hours after the last intervention) and at week 64.
Other	Endogenous analgesia as treatment mediator: offset-analgesia	Endogenous analgesia will be assessed by offset analgesia. Offset analgesia can be described as the disproportionately large decrease in perceived pain following slight decreases in electrical intensity.; Painful electrical stimuli (Surpass LT Stimulator) will be given to the patients into 3 time intervals. The electrical intensity of time interval 1 and 3 will be the same, while the electrical intensity of time interval 2 will be higher. Participants need to report their intensity of pain according to the visual analogue scale ranging from 0 to 10 during the 3 intervals.	Assessments will be performed at baseline and at week 13 (at least 48 hours after the last intervention) and at week 64.
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	Baseline
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	during intervention: week 2 (acute)
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	during intervention: week 10 (acute)
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	post-intervention: week 13
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	post-intervention: week 26
Primary	Knee pain as primary study outcome	Pain is the primary outcome as it is the primary and most disabling symptom in OA. The pain subscale of the WOMAC Osteoarthritis Index LK3.0 questionnaire will be used for the assessment of pain severity. The Knee injury and Osteoarthritis Outcome Score (KOOS) includes WOMAC Osteoarthritis Index LK3.0 in its complete and original format (with permission). WOMAC (and therefore the pain and symptoms subscale of the KOOS) is a valid tool for subjects with KOA. The KOOS is proven to generate valid and reliable scores.	post-intervention: week 64
Secondary	Different subtypes of pain: pain	Pain will be measured using the Visual analogue scale (VAS).	Baseline, during intervention (week 2 and 10), post-intervention (week 13, 26 and 64)
Secondary	Different subtypes of pain: intermittent pain	Intermittent pain will be measured using a short and easily applicable self-reported measure, i.e. intermittent and constant pain (ICOAP).	Baseline, during intervention (week 2 and 10), post-intervention (week 13, 26 and 64)
Secondary	Different subtypes of pain: constant pain	Constant pain, will be measured using a short and easily applicable self-reported measure, i.e. Intermittent and constant pain (ICOAP).	Baseline, during intervention (week 2 and 10), post-intervention (week 13, 26 and 64)
Secondary	Different subtypes of pain: central sensitization	Central sensitization will be measured using an easily applicable self-reported measure i.e. Central Sensitization Inventory (CSI).	Baseline, during intervention (week 2 and 10), post-intervention (week 13, 26 and 64)
Secondary	Function in daily living (KOOS subscale)	Function in daily living will be measured using self-reported measures. The KOOS function in daily living (ADL) subscale and functioning in sports and recreation subscale are reliable and valid scales to measure function in people with osteoarthritis. The patient global assessment (PGA) is a recommended questionnaire in clinical trials of rehabilitation interventions for OA and it measures the improvement or deterioration of their condition.	Baseline, post-intervention (week 13, 26 and 64)
Secondary	Function in daily living (PGA)	Function in daily living will be measured using self-reported measures. The patient global assessment (PGA) is a recommended questionnaire in clinical trials of rehabilitation interventions for OA and it measures the improvement or deterioration of their condition.	Assessed at baseline and post-intervention (at week 13, 26 and 64)
Secondary	Treatment adherence	Patient adherence for the treatment sessions will be calculated as the ratio of the number of treatment sessions that were actually carried out versus the number of prescribed sessions. Compliance will be calculated as the ratio of the total training duration (recorded in the logbooks) versus the prescribed total training duration, multiplied by 100.	During the intervention (week 1-12) and at week 13
Secondary	Treatment compliance	Compliance will be calculated as the ratio of the total training duration (recorded in the logbooks) versus the prescribed total training duration, multiplied by 100.	During the intervention (week 1-12) and at week 13
Secondary	Health care cost effectiveness	Medical consumption, the type, dose, method of administration and frequency of analgesic, NSAID or symptom-modifying medication, as well as surgeries (total or partial knee replacements) will be recorded. Health care use will be evaluated using the combination of three questionnaires: (1) the Medical Consumption Questionnaire (2) the Productivity Cost Questionnaire and (3) the EuroQol EQ-5D.	Assessed at baseline, at week 13, 26 and 64