Clinical trial NCT05806021: The Efficacy of Intra-articular Triamcinolone Acetonide 5mg vs. 10 mg vs. 40 mg in Patients With Knee Osteoarthritis
Official title: The Efficacy of Intra-articular Triamcinolone Acetonide 5mg vs. 10 mg vs. 40 mg in Patients With Knee Osteoarthritis: a Non-inferiority Randomized Controlled Double-blind Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Primary Gonarthrosis
Keywords: corticosteroid injection
minimal dose
non-inferiority
Lead sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
Sponsor class: OTHER
First posted: 2023-04-10
Enrollment: 327
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Osteoarthritis of the knee is a common problem that is increasing in prevalence as the population ages. In a knee with osteoarthritis, there is variable damage to the articular cartilage and underlying bone that can cause varying degrees of pain. When pain is bothersome, osteoarthritis is treated to improve functional abilities.

One of the most recognized and used treatments is intra-articular cortisone injection. Cortisone is a powerful anti-inflammatory drug that is used to reduce pain.

Unfortunately, cortisone can have significant side effects, even when injected locally. The frequency and intensity of these side effects depend largely on the total dose injected. The main side effects include increased blood sugar levels, increased blood pressure and a temporary decrease in the secretion of the stress hormone, cortisol. In the long term, a decrease in articular cartilage thickness in the injected join and overall bone density reduction is also reported.

Despite many years of routine use, the smallest effective dose of cortisone injected into the knee joint is unknown.

The main objective of the study is to determine the impact on pain and function of different doses of cortisone injected into the knee. The cortisone chosen for this study is triamcinolone acetonide (TA).

Detailed description: Gonarthrosis is a very prevalent condition affecting especially people over the age of 60 years old. It is a major cause of pain and functional impairment in Canada. The prevalence and associated economic burden continue to increase.

Despite the prevalence of this condition, the management of symptomatic gonarthrosis remains a controversial subject. Multiple treatment alternatives are available, none of which has been proven to be superior to the others beyond any doubt. However, certain therapeutic modalities are better recognized and more frequently used, such as intra-articular corticosteroid injections. In 2022, an expert consensus review of the available literature concluded that the use of intra-articular corticosteroids is effective in the treatment of symptomatic gonarthrosis. This is also the conclusion of the most recent American College of Rheumatology (ACR) guideline, which "strongly recommends" the use of this type of injection in gonarthrosis .

Despite decades of use, there is insufficient evidence to recommend a specific type and dose of corticosteroid. The choice of cortisone type in the usual practice of physicians performing intra-articular knee infiltrations is therefore based on experience and the biochemical properties of the different cortisones. Those with larger particles due to esterification of the corticoid, such as triamcinolone acetonide (TA) and methylprednisolone acetate, are known to have a longer duration of action. They are therefore the two most frequently used in studies on the subject. The dose used is based on historical use and is not, to our knowledge, based on any fundamental evidence. This dose of TA injected into a joint is usually 40 mg. Some authors have shown us that it is not useful to inject higher doses than this into a knee because increasing the dose does not improve the outcome of the injection. However, there was no literature related to the minimally effective intra-articular TA dose in the knee, until recently. Indeed, Utamawatin et al. recently reported that 10mg of TA did not appear to be less effective than 40mg when injected into knees with primary osteoarthritis.

This minimally effective dose is important because side effects associated with cortisone use have been reported. The adverse effects of oral corticosteroids are better known and documented than intra-articular ones. By a mechanism that is only partially elucidated, intra-articular infiltrations can produce the same systemic effects as oral. Habib et al. reports that systemic side effects increase with the concentration and time of exposure to the substance. To our knowledge, the minimal dose of intra-articular corticosteroid to produce a systemic effect is not documented.

Systemic effects occur in multiple systems. They affect several metabolisms such as glucose, gastrointestinal, lipid, adipose tissue, bone, immune, cardiovascular, sex hormones and the hypothalamic-pituitary axis. The mood can also be affected.

Thus, intra-articular infiltrations can cause both local and systemic problems that are directly related to the dose injected.

PRIMARY OBJECTIVE

○ To demonstrate the non-inferiority of a 10 mg and 5 mg intra-articular corticosteroid injection compared to the standard 40 mg dose on patient function at 1 month post-injection.

SECONDARY OBJECTIVES

* To demonstrate the non-inferiority of a 10 mg and 5 mg intra-articular corticosteroid injection compared to the standard 40 mg dose on patient function at 2, 3 and 6 months post-injection.
* To demonstrate the non-inferiority of a 10 mg and 5 mg intra-articular corticosteroid injection compared to the standard 40 mg dose on pain and stiffness in patients at 1, 2, 3 and 6 months post-injection.
* To know the patient's satisfaction with the treatment at 3 and 6 month post-injection METHODOLOGY Type of study

  * Randomized clinical trial
  * Non-inferiority study Recruiting
  * Outpatient clinic of the physiatry, rheumatology or orthopedics departments of the University of Montreal Hospital.

Participants

* Patients referred to physiatry for symptomatic primary gonarthrosis
* Physiatrists will complete a history and physical examination for each participant.

Randomization of participants

* Patients meeting the study inclusion criteria will be randomized into one of the three groups
* Group allocation will be done randomly by computer. The mechanism for running the allocation sequence for randomization will be with RedCAP software.
* Physiatrists evaluating outcomes, participants, and data analysis will be blinded.
* Syringes will be preassembled by someone external to the study. The syringes will be covered with opaque paper. The contents of the latter will therefore not be visible to the participant or the physician performing the procedure.
* Participants will be able to know at the end of the study in which group they were allocated.

Intervention

* For ethical reasons, considering the superiority of cortisone injections in the latest international recommendations, it was decided not to use a placebo group.
* All eligible patients will have a standing radiograph with weight-bearing anteroposterior view, lateral view, and patellar view that will be done at CHUM, unless a recent radiograph done at another center is available for review by a CHUM radiologist. This is to obtain standardized imaging results for our study.
* The technique of the procedure is done according to the practical guide Malanga and Mautner: Atlas of Ultrasound-Guided Musculoskeletal Injections.
* Ultrasound guidance will be used for all intra-articular knee injections. Canon I-700 ultrasound machine.
* Patients will be placed in the supine position with the knee resting on a towel for slight flexion.
* The procedure is performed under sterile conditions.
* The skin is disinfected with a CHUM-approved chlorhexidine-based product.
* The ultrasound probe is disinfected with an approved disinfectant product.
* With a sterile gel on the skin, the probe is positioned short-axis over the distal quadricipital tendon.
* The supra-patellar recess is visualized between the prefemoral fat pad posteriorly and the suprapatellar fat pad anteriorly as an area containing hypoechoic or anechoic fluid.
* If there is a significant intra-articular effusion, the fluid will by removed via punture prior to injection. This information will be noted on a sheet including the total volume removed.
* On the lateral border of the knee with an approach parallel to the probe, a 3ml syringe mounted on a 25G needle (or 18-20G if prior puncture) is inserted. A dermal point with 1% xylocaine will be made before the injection if prior puncture given the use of a larger needle gauge.
* In real time under ultrasound guidance, the needle is advanced from lateral to medial towards the supra-patellar recess.
* Once the needle is properly positioned in the recessus, the physiatrist injects the contents of the pre-mounted 3ml syringe.
* If there is no visible fluid in the supra-patellar recess, the medial mid-patellar region is targeted. This technique is not influenced by the presence or absence of effusion. The probe is placed in a short axis on the knee with the patella superior and the medial femoral condyle inferior. The joint space is located between the two structures under the patellar retinaculum. The needle is advanced parallel to the probe from medial to lateral to penetrate the joint space. This technique can also be performed lateral to the knee at the discretion of the physiatrist.
* After the injection, it is recommended to apply a cold water compress or ice to the injection site 5-10 min which can be repeated 3 to 4 times during the day in case of pain. Acetaminophen may be taken to reduce discomfort following the injection.
* All techniques under ultrasound guidance will be performed by a physiatrist trained in musculoskeletal ultrasound.
* Intra-articular cortisone infiltration is not the only treatment for gonarthrosis. Therefore, all patients will have as a recommendation some of the non-pharmacologic recommendations mentioned in the ACR8 guide.
* Patients will be suggested not to add other treatment modalities to avoid biasing the results such as orthotic, acupuncture, massage, anti-inflammatory or other medications, other injectable treatments etc. If the patient is already wearing an orthosis, he/she can continue to wear it.

Eligibility criteria: Inclusion Criteria:

* Symptomatic primary gonarthrosis of over 6 months duration (gonarthrosis according to the American College of Rheumatology criteria)
* Grade 1 to 3 Kellgren-Lawrence femorotibial osteoarthritis
* Knee pain provoked by activity over 4 and under 8 on 10 (Visual Analog Scale)

Exclusion Criteria:

* Bilateral symptomatic primary gonarthrosis
* Grade 4 Kellgren-Lawrence femorotibial osteoarthritis
* Isolated patellofemoral osteoarthritis
* Intra-articular corticosteroid infiltration to the knee within the past 3 months or chronic use of per os corticosteroid
* Intra-articular hyaluronic acid infiltration within the past 12 months.
* Intra-articular infiltration of platelet-rich plasma within the past 12 months.
* Disease affecting the study joint (systemic inflammatory disease, history of septic arthritis, osteonecrosis, etc.).
* Suspicion or presence of active local infectious process.
* Presence or suspicion of local neoplasia or metastasis
* Recent severe trauma to the knee (≤ 3 months)
* Significant cognitive impairment or inadequate language proficiency not allowing adequate response to study questionnaires
* Any other serious medical condition that does not allow participation in the study or may be a contraindication to cortisone injection

Primary outcomes:
measure: WOMAC Function
timeFrame: 1 month post-injection
Secondary outcomes:
measure: WOMAC Total
timeFrame: 1, 2, 3 and 6 months post-injection
measure: VAS
timeFrame: 1, 2, 3 and 6 months post-injection
measure: LIKERT
timeFrame: 3 and 6 months post-injection
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire de Montréal - Hôtel-Dieu
state: Quebec
Study officials:
affiliation: Centre hospitalier de l'Université de Montréal (CHUM)
name: Dien Hung Luong, MD
role: PRINCIPAL_INVESTIGATOR
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