Effect of Steroid Injections in a Knee With Osteoarthritis

Study Overview
=================
Brief Summary
-----------------
A steroid (triamcinolone) 40 mg will be compared to placebo in a randomized placebo-controlled clinical trial testing the effect of this steroid versus placebo given into the study knee joint that has osteoarthritis (OA). The knee injection will be given once every 12 weeks over two years for a total of eight knee injections. How well each participant tolerates each injection and all the injections over time will be assessed. The safety of getting a knee injection every 12 weeks will be assessed by collecting reported adverse effects, knee examinations, and clinical laboratory tests. Participants will complete questionnaires, X-ray, MRIs, and bone density tests as part of this study.

Detailed Description
-----------------
This study was a two-year stratified and block-randomized double-blind, placebo controlled clinical trial of the effect of intra-articular triamcinolone 40 mg injectable suspension, administered every 3 months over two years (for a total of 8 doses). The randomization was stratified by the baseline radiographic severity of knee OA (Kellgren and Lawrence grade of 2 or 3) and gender. An interim analysis would have been conducted after the first half of participants has completed the trial. This interim analysis would have allowed the trial to be stopped early for either success or futility, or allow the trial to continue if neither success nor futility has been established. However, the plan for interim analysis was eliminated with the support of the DSMB because of feasibility issues for completing cartilage measurements contemporaneously and because early trial cessation would preclude analysis of informative secondary outcomes. The primary structural outcome objective in this study was cartilage volume loss; secondary structural outcomes included peri-articular bone marrow lesions (BML), tibial peri-articular bone density ratio (paBMD). The primary clinical outcome objective was the pain domain of the WOMAC© LK3.1; secondary clinical outcomes included WOMAC© LK3.1 stiffness and function scores and physical function tests.

Official Title
-----------------
Effect of Intra-articular Steroids on Structural Progression of Knee OA: A Randomized Controlled Trial

Conditions
-----------------
Osteoarthritis (OA) of the Knee

Intervention / Treatment
-----------------
* Drug: Triamcinolone Acetonide
* Drug: 0.9% Sodium Chloride Injection as Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female or Male, Age ≥ 45 years Chronic knee discomfort based on affirmative response to the question During the past 12 months, have you had any pain, aching, or stiffness in or around your knee(s) on most days for at least one month? Baseline (Month 0) Pain score >2 on at least one of the WOMAC weight-bearing pain questions; and total weight-bearing pain score <8 Tibiofemoral or patellofemoral OA on posterior-anterior weight-bearing semi-flexed or lateral knee radiographs with severity equivalent to Kellgren and Lawrence grade 2 or 3 Evidence of synovitis on ultrasound at screening Clinical examination confirming knee pain or discomfort referable to the knee joint Prepared to discontinue NSAID(s)/analgesic(s) for 2 days prior to each assessment Exclusion Criteria: Prior septic (study) knee joint Prior reconstructive surgery in the study knee Prior osteonecrosis (avascular necrosis of bone) Chronic use of oral corticosteroids; knee intra-articular corticosteroid injection within 3 months of Month 0 (baseline) visit Ongoing use of doxycycline, indomethacin, glucosamine and/or chondroitin; or use of these within 2 months of Screening visit Evidence of other inflammatory joint disease (e.g., gout, CPPD) Serious medical conditions or impairments that, in the view of the investigator, would obstruct their participation in the trial such as uncontrolled diabetes, uncontrolled hypertension, opiate dependency Plan to permanently relocate from the region, or take an extended vacation for greater than 3 months during the trial period Planned arthroscopy and/or arthroplasty in the study knee. Any contra-indication to having an MRI Inability to speak or comprehend English

Ages Eligible for Study
-----------------
Minimum Age: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Triamcinolone Acetonide<br>40 mg into the study knee joint every 12 weeks for a total of 8 injections. | Drug: Triamcinolone Acetonide<br>* 40 mg into the study knee joint every 12 weeks for a total of 8 injections.<br>* Other names: Kenalog;|
| Placebo Comparator: Sodium Chloride<br>0.9% Sodium chloride injection as Placebo will be given into the study knee once every 12 weeks for a total of 8 injections. | Drug: 0.9% Sodium Chloride Injection as Placebo<br>* Sodium chloride injection will be given into the study knee once every 12 weeks for a total of 8 injections.<br>* Other names: Normal Saline for injection;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Cartilage Thickness in the Index Compartment (Compartment With the Most Damage) | Mean cartilage thickness was measured on knee MRI (Philips Achieva X-Series 3.0 Tesla scanner). Missing data were imputed. | Baseline to 2 years | 
| Change in Knee Pain Severity During the Past 48 Hours From the WOMAC LK3.1 Pain Score Questionnaire. | Pain subscale score was calculated from patient's responses on the Western Ontario and McMaster Universities Osteoarthritis Index Likert-type 3.1 Questionnaire. The questionnaire includes 24 items divided into 3 subscales, Pain, Stiffness, Physical Function. Only the Pain subscale score was used for this outcome measure. The Pain subscale consists of five items, each ranging from 0 to 4, making the total Pain subscore 0 to 20. Higher scores represent higher levels of pain, whereas lower scores represent lower levels of pain. Missing data were imputed. | Baseline to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Volume of Peri-articular Bone Marrow Lesions Measured on Knee MRI. | Change in volume of peri-articular bone marrow lesions measured on knee MRI on the log scale. Missing data were imputed. | Baseline to 2 years. | 
| Change in Effusion Volume Measured on Knee MRI. | Change in effusion volume measured on knee MRI on the log scale. Missing data were imputed. | Baseline to 2 years | 
| Change in Area of Denudation Measured on Knee MRI in the Index Compartment (Compartment With the Most Damage). | Change in area of denudation measured on knee MRI in the index compartment (compartment with the most damage). Missing data were imputed. | Baseline to 2 years | 
| Change in Volumetric Cartilage Damage Index (CDI) Measured on Knee MRI in the Index Compartment (Compartment With the Most Damage). | Change in volumetric cartilage damage index (CDI) measured on knee MRI in the index compartment (compartment with the most damage). Missing data were imputed. | Baseline to 2 years | 
| Change in Function Severity During the Past 48 Hours From the WOMAC LK3.1 Function Score Questionnaire. | Physical Function subscale score was calculated from patient's responses on the Western Ontario and McMaster Universities Osteoarthritis Index Likert-type 3.1 Questionnaire. The questionnaire includes 24 items divided into 3 subscales, Pain, Stiffness, Physical Function. Only the Physical Function subscale score was used for this outcome measure. The Physical Function subscale consists of 17 items, each ranging from 0 to 4, making the total Function subscore 0 to 68. Higher scores represent higher levels of difficulty performing daily activities, whereas lower scores represent lower levels of difficulty performing daily activities. Missing data were imputed. | Baseline to 2 years | 
| Change in Knee Stiffness During the Past 48 Hours From the WOMAC LK3.1 Stiffness Score Questionnaire. | Stiffness subscale score was calculated from patient's responses on the Western Ontario and McMaster Universities Osteoarthritis Index Likert-type 3.1 Questionnaire. The questionnaire includes 24 items divided into 3 subscales, Pain, Stiffness, Physical Function. Only the Stiffness subscale score was used for this outcome measure. The Stiffness subscale consists of two items, each ranging from 0 to 4, making the total Stiffness subscore 0 to 8. Higher scores represent higher levels of stiffness, whereas lower scores represent lower levels of stiffness. Missing data were imputed. | Baseline to 2 years | 
| Change in Patient's Global Assessment (Visual Analogue Scale). | The response to the question, Considering all the ways your knee affects you, how much pain are you having today?, was measured and the change in the scoring was evaluated. The Patient's Global Assessment (PGA) is measured on a scale of 0 to 100 millimeters. Higher scores represent a higher level of disease activity or a worse global health. Missing data were imputed. | Baseline to 2 years | 
| Change in Time to Complete a Twenty-meter Walk. | Change in time (seconds) to complete a twenty-meter walk. Missing data were imputed. | Baseline to 2 years | 
| Change in Time to Complete 5 Chair Stands. | Change in time (seconds) to complete 5 chair stands. Missing data were imputed. | Baseline to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
OA, Knee arthritis, MRI, Steroid