Study of Peri-Articular Anaesthetic for Replacement of the Knee

Study Overview
=================
Brief Summary
-----------------
The clinical and cost effectiveness of peri-articular liposomal bupivacaine plus bupivacaine hydrochloride compared with bupivacaine hydrochloride alone for post-operative recovery after knee replacement surgery: A multi-centre, patient-blinded, randomised controlled trial.

Detailed Description
-----------------
The trial design is a patient-blinded multi-centre, active comparator, randomised controlled two-arm parallel group superiority trial of liposomal bupivacaine plus bupivacaine hydrochloride versus bupivacaine alone for post-operative pain in patients undergoing knee replacement surgery. Patients will be randomised in a 1:1 ratio. The randomised controlled trial (RCT) design is robust and reduces any potential bias. Patients will be blinded as to which treatment they receive. Blinding of patients is possible as they will be under general anaesthetic for their knee replacement surgery at the time of the drug administration. Blinding of surgeons, who administer the medication and outcome assessors was not necessary as the primary outcome is a patient reported outcome measure.

Official Title
-----------------
Study of Peri-Articular Anaesthetic for Replacement of the Knee

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

Intervention / Treatment
-----------------
* Drug: Liposomal bupivacaine
* Drug: Bupivacaine hydrochloride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Unilateral primary knee replacement, including both total knee replacement (TKR) or unicompartmental knee replacement (UKR), for end stage osteoarthritis American Society of Anaesthesiologists (ASA) Grade I to III Participant is willing and able consent for themselves Male or Female, aged 18 years or above In the Investigator's opinion, is able and willing to comply with all trial requirements Exclusion Criteria: Allergy or intolerance to amide type local anaesthetics Objective evidence of nerve damage in the affected lower limb. Rheumatoid arthritis Any other significant disease, disorder or condition which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the results of the trial, or the participant's ability to participate in the trial. Participants who have participated in another research trial involving an investigational product in the past 6 months. Participants who have significant cognitive impairment or language issues Contra-lateral knee replacement within the trial or within 12 months prior to randomisation

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liposomal bupivacaine (EXPAREL)<br>266mg/20ml EXPAREL mixed with 80ml 0.9% normal saline and 100mg/20ml 0.5% plain bupivacaine hydrochloride. Administered as a single dose intra-operatively by periarticular infiltration. | Drug: Liposomal bupivacaine<br>* 266mg/20ml vial of EXPAREL<br>* Other names: EXPAREL;Drug: Bupivacaine hydrochloride<br>* 100mg/20ml 0.5% bupivacaine hydrochloride. Branded or generic, must be plain (cannot contain adrenaline/epinephrine)<br>* Other names: Marcain;|
| Active Comparator: Bupivacaine hydrochloride alone<br>100ml 0.9% normal saline mixed with 100mg/20ml 0.5% plain bupivacaine hydrochloride. Administered as a single dose intra-operatively by periarticular infiltration. | Drug: Bupivacaine hydrochloride<br>* 100mg/20ml 0.5% bupivacaine hydrochloride. Branded or generic, must be plain (cannot contain adrenaline/epinephrine)<br>* Other names: Marcain;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Recovery 40 (QoR-40) | A 40-item instrument which encompass most aspects of a good quality of recovery after surgery. Consists of five clinically relevant dimensions: Physical comfort (12 items) Emotional state (9 items) Physical independence (5 items) Psychological support (7 items) Pain (7 items). The QoR-40 has a possible score of 40 (extremely poor quality of recovery) to 200 (excellent quality of recovery). | Change in score between 0, 24, 48 and 72 hours post-operatively | 
| Cumulative 0-10 pain Visual Analogue Score (VAS) | Cumulative daily pain score at rest. A 10 point scale where 0 = no pain, 5 = moderate pain and 10 = worst possible pain. | Cumulative score at 0, 24, 48 and 72 hours post-operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean 0-10 pain Visual Analogue Score (VAS) | Mean daily pain score at rest. A 10 point scale where 0 = no pain, 5 = moderate pain and 10 = worst possible pain. | 0, 24, 48 and 72 hours post-operatively | 
| Opioid consumption | Cumulative consumption | Change in consumption between 0, 24, 48 and 72 hours post-operatively | 
| Fitness for discharge (as per routine clinical care) | Against pre-defined criteria. Patients would be considered fit for discharge when they meet the following criteria: Ability to mobilize independently; pain score less than or equal to 3mm on a 10 VAS; ability to straight leg raise and ability to bend knee to 90 degrees | Assessed at 0, 24, 48 and 72 hours post-operatively | 
| Oxford Knee Score (OKS) | Functional outcome using validated, patient reported questionnaire | Change in score between baseline, 72 hours, 6 weeks, 6 months, 1 year post-operatively | 
| American Knee Society Score (AKSS) | Functional outcome using validated, patient reported questionnaire | Change in score between baseline, 72 hours, 6 weeks, 6 months, 1 year post-operatively | 
| EuroQol 5 Dimension scale | Validated patient reported quality of life questionnaire | Change in score between baseline, 72 hours, 6 weeks, 6 months, 1 year post-operatively | 
| Health economics | Cost utility analysis | Change in cost utility between baseline, 6 weeks, 6 months, 1 year post-operatively | 
| Serious Adverse Events (SAE) | Specifically cardiovascular or wound complications | Within 30 days of surgery |