Saline Injections vs Education and Exercise in Knee Osteoarthritis

Study Overview
=================
Brief Summary
-----------------
Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition mainly affecting older people, causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended by leading international organisations and authorities based on extensive research that documents that exercise and education are superior to no-attention control groups. In Denmark, an initiative to implement these recommendations was initiated in 2013. The initiative is called Good Life with osteoArthritis in Denmark (GLA:D) and aims at facilitating high quality care of patients with OA in the Danish population. The core components of the GLA:D program are 8 weeks of education (2 sessions) and supervised neuromuscular exercise delivered by GLA:D certified physiotherapists. The GLA:D concept has been exported to Canada, China and Australia. While several randomised controlled trials have investigated exercise and education for knee OA none have used a placebo comparison group. The effect size of exercise plus education therapy is in line with the current theories that the contact with a caring clinician that believes in efficacy of the treatments he/she provides can result in beneficial health effects. In exercise and education programs (such as the GLA:D program) frequent and lengthy contacts with a physiotherapist are typically necessary. Hence, a significant proportion of the beneficial effects can be expected to be attributable to placebo or placebo.like effects. In trials of intra-articular treatment of knee OA (e.g. in trials of corticosteroids, viscosupplementation, or platelet-rich-plasma) saline injections are a commonly used as placebo comparator. While saline is recognised as a pharmacologically inert agent, a recent systematic review and meta-analysis concluded that although intra-articular saline injection is often used as a placebo treatment in clinical trials for knee OA it can provide substantial pain relief. The effect size of saline injections is in line with the current theories that the invasiveness of a procedure is an important determinant for the magnitude of placebo effects. This trial aims to compare a widely used 8-week education plus exercise program (the GLA:D program) with 4 intra-articular saline injections as treatments of knee OA symptoms. Outcomes are taken at baseline, after 8-weeks of treatment (week 9) and after additionally 4 weeks of follow-up (week 12).

Official Title
-----------------
A Randomized, Open Label, Parallel Group Study in Patients With Knee Osteoarthritis to Compare Intra-articular Saline Injections With Education Plus Exercise Therapy

Conditions
-----------------
Osteoarthritis, Knee

Intervention / Treatment
-----------------
* Behavioral: GLA:D
* Drug: Intra-articular saline injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥50 years. Body Mass index ≤ 35 A clinical diagnosis of tibiofemoral OA in the target knee according to the American College of Rheumatology (12). Average knee pain in the last week during weight bearing activities of at least 4 on a 0 to 10 points scale (0=no pain; 10=worst possible pain). Verification of clinical diagnosis by definite tibiofemoral OA on posterior-anterior weight bearing semi-flexed knee radiographs with severity equivalent to Kellgren and Lawrence grade 2 or more. Exclusion Criteria: Intra-articular treatments of any kind of either knee 3 months before inclusion Scheduled surgery during study participation Knee joint fluid aspiration within 3 month of baseline visit Participation in exercise therapy within 3 months of baseline visit Evidence of other inflammatory joint disease (e.g. rheumatoid arthritis or gout) History of knee surgery within 12 months History of arthroplasty in the target knee Use of oral glucocorticoids Use of synthetic or non-synthetic opioids Other musculoskeletal, neurological, medical conditions precluding participation in exercise Contraindications to intra-articular injections, such as wounds or skin rash over injection site. Contraindications to exercise Planning to start other treatment for knee OA in the study participation period Regional pain syndromes Generalised pain syndromes such as fibromyalgia Lumbar or cervical nerve root compression syndromes Any other condition or impairment that, in the opinion of the investigator, makes a potential participant unsuitable for participation or which obstruct participation, such as large knee joint effusion, uncontrolled diabetes, psychiatric disorders, or opiate dependency.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GLA:D<br>8 weeks of education (1 session/week for 2 weeks) and exercise therapy (2 sessions/week for 6 week) | Behavioral: GLA:D<br>* The GLA:D exercise and education program is an 8-week treatment program delivered by GLA:D certified physiotherapists. It consists of 2 educational sessions over 2 weeks (1/week in week 1 and 2) and 12 exercise sessions over 6 weeks (2/week in weeks 2 thru 8) The 2 educational sessions provide knowledge of OA, treatment and self-management, with a special focus on exercise and its benefits. The exercise part lasts for 6 weeks with 2 exercise sessions per week of approximately 1 hour (12 sessions total). The exercise sessions are group based at a facility supervised by a GLA:D certified physiotherapist. The goal is the obtain muscle control and stability in situations resembling daily life and/or more strenuous activities.<br>* Other names: Education and Exercise;|
| Placebo Comparator: Intra-articular saline injection<br>Intra-articular saline injection (5 ml of 0.9% sodium chloride) every 2 weeks over an 8-week period | Drug: Intra-articular saline injection<br>* Four [4] dosages of 5 ml intra-articular isotonic saline (0.9% (9 mg/mL) Sodium Chloride Injection (sterile, isotonic solution of sodium chloride and sterile water for injection)) every other week from baseline (week 1, 3, 5 and 7 = 4 injections). The injections will be carried out with a 21 gauge (38 mm) needle and a Luer-lock syringe under ultrasound guidance to ensure that the needle is inserted into the study knee joint cavity and document correct deposition of the bolus in the joint cavity. If the investigator detects presence of excessive joint fluid during the ultrasound guided preparation of the injection, this will be aspirated before injection of the saline - if possible.<br>* Other names: Physiological salinated water;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in knee pain | Assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale (patient-reported questionnaire). The KOOS pain subscale consists of 9 questions with a five-point Likert scale scoring system (ranging from 0 (least severe) to 4 (most severe)). The answers are summed and a 0-100 normalized score is calculated with 0 indicating extreme pain and 100 indicating no pain. | week 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in physical function | Assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) physical function subscale (patient-reported questionnaire)The KOOS physical function subscale consists of 17 questions with a five-point Likert scale scoring system (ranging from 0 (least severe) to 4 (most severe)). The answers are summed and a 0-100 normalized score is calculated with 0 indicating extreme functional impairment and 100 indicating no functional impairment. | week 9 and week 12 | 
| Change from baseline in symptoms | Assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) symptoms subscale (patient-reported questionnaire) The KOOS symptoms subscale consists of 7 questions with a five-point Likert scale scoring system (ranging from 0 (least severe) to 4 (most severe)). The answers are summed and a 0-100 normalized score is calculated with 0 indicating extreme symptoms and 100 indicating no symptoms. | week 9 and week 12 | 
| Change from baseline in knee related quality of life | Assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) knee related quality of life subscale (patient-reported questionnaire) The KOOS knee related quality of life subscale consists of 4 questions with a five-point Likert scale scoring system (ranging from 0 (least severe) to 4 (most severe)). The answers are summed and a 0-100 normalized score is calculated with 0 indicating extremely poor knee related quality of life pain and 100 indicating very good knee related quality of life . | week 9 and week 12 | 
| Change from baseline in patient's global assessment of impact of osteoarthritis | Assessed by a 0-100 mm visual analog scale (VAS)(patient-reported questionnaire) | week 9 and week 12 | 
| Number of treatment responders according to OMERACT-OARSI response criteria | following two conditions is observed at the post-baseline assessment: In either pain (KOOS pain subscale) or function (KOOS function subscale), a high improvement in the subscale, where high improvement in a subscale is achieved if there is both a > 50% improvement from Baseline and an absolute change from Baseline of > 20 points (0-100 scale), OR Improvement in at least two of the following three: Improvement in pain (KOOS pain subscale) defined as > 20% improvement from Baseline and an absolute change from Baseline of > 10 points (0-100 scale) Improvement in function (KOOS function subscale) defined as > 20% improvement from Baseline and an absolute change from Baseline of > 10 points (0-100 scale) Improvement in patient's global assessment defined as > 20% improvement from Baseline and an absolute change from Baseline of > 10 mm (0-100 scale) | week 9 and week 12 | 
| Change from baseline in 4x10 meter fast walk test | The 4x10 meter fast walk test (40mFWT) is a physical performance test that quantifies short distance walking performance. The 40mFWT is a measure of walking speed over short distances and changing direction during walking. It is recommended as a performance-based test to assess physical function in people diagnosed with hip or knee OA. The participant is asked to walk as quickly but as safely as possible to a mark 10 m away, return, and repeat for a total distance of 40 m. Regular walking aid is allowed and recorded. Time of one trial, with turn time excluded, is recorded and expressed as speed m/s by dividing distance (40 m) by time (s). | Week 9 and week 12 | 
| Change from baseline in the 30 seconds chair stand test | The 30 seconds chair stand test (30sCST) is a physical performance test that quantifies how many sit-to-stand movements an individual is able to perform within 30 seconds. The 30sCST is a measure of balance during functional activities and lower extremity function and strength. It is recommended as a performance-based test to assess physical function in people diagnosed with hip or knee OA. From the sitting position in the middle of seat with feet shoulder width apart, flat on the floor, arms crossed at chest, the participant is asked to stand completely up, then sit completely back down, repeatedly for 30 seconds. The total number of complete chair stands (up and down represents one stand) is counted. There is given only one trial. If a full stand is completed at 30 seconds, then this is counted in the total. The same chair is used at all assessments. | Week 9 and week 12 | 
| Change from baseline in Stair climbing test | A stair climbing test (SCT) is a physical performance test that quantifies how fast an individual is able to ascend and descend a flight of stairs in a usual manner. The SCT is a measure of balance during functional activities and lower extremity function and strength. It is recommended as a performance-based test to assess physical function in people diagnosed with hip or knee OA. The participant is asked to ascend and descend a flight of stairs in a usual manner, and at a safe and comfortable pace. Use of any walking aid and handrail is permitted and recorded. Total time to ascend and descend steps for one trial is recorded in seconds. The same flight of stairs is used at all assessments. | Week 9 and week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Exercise, Placebo, Injection