DEX‐2‐TKA ‐ DEXamethasone twice for pain treatment after Total Knee Arthroplasty: Detailed statistical analysis plan for a randomized, blinded, three‐group multicentre clinical trial

Abstract

Background Optimization of post‐operative pain treatment is of upmost importance. Multimodal analgesia is the main post‐operative pain treatment principle, but the evidence on optimal analgesic combinations is unclear. With the “DEXamethasone twice for pain treatment after TKA” trial, we aim to investigate the role of one or two doses of glucocorticoid for post‐operative pain treatment after total knee arthroplasty. To ensure transparency and minimization of bias, we present this article with a detailed statistical analysis plan, to be published before the last participant is enrolled. Methods “DEXamethasone twice for pain treatment after TKA” (DEX‐2‐TKA) is a randomized, blinded, three‐group multicentre clinical trial. Participants will be randomized to one of three intervention groups: single dose of iv dexamethasone 24 mg, two consecutive doses of iv dexamethasone 24 mg or matching iv placebo. All three intervention groups will receive paracetamol, NSAID (ibuprofen) and local infiltration analgesia. Participants, treatment providers, outcome assessors, data managers, statisticians and conclusion drawers will be blinded to the allocated intervention. The primary outcome is total opioid consumption (iv morphine milligram equivalents) 0‐48 hours post‐operatively. Secondary outcomes are (1) visual analogue scale pain levels: (a) during active 45 degrees flexion of the knee at 24 and 48 hours post‐operatively, (b) at rest at 24 and 48 hours post‐operatively, and (c) during 0‐24 hours (highest score) and 24‐48 hours post‐operatively (highest score); and (2) the proportion of participants with one or more adverse events within 48 hours post‐operatively. Discussion The DEX‐2‐TKA trial will provide high quality data regarding benefits and harms of adding one or two high‐doses of dexamethasone to a multimodal analgesic regimen. Trial registration EudraCT: 2018‐001099‐39 (08/06‐18); ClinicalTrials.gov: NCT03506789 (24/04‐2019).

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial

“…Further details are provided in the statistical analysis plan. 18 Patient and public involvement A panel of three patients have read and commented on the participant information, and representatives for the public in the ethical committee (elected regional politicians) have ethically approved the trial. We did not further involve patients or patient unions in the design of the trial or analyses.…”

“…We did not specify how to estimate the median difference we would use to assess if our predefined minimal difference was reached. 17 18 The adjuvant analgesic effects of dexamethasone could be tested by comparing medians between groups (at group level). The real interest is the potential adjuvant analgesic effect at the individual level, however, and here the Hodges-Lehmann median difference analysis shows the median differences between individual patients.…”

“…Our methodology is described in detail in the protocol article, 17 in the protocol available at https://www.appraz.dk , and in the statistical analysis plan. 18 The trial was conducted at one private and four public Danish hospitals. Written informed consent was obtained from all participants before enrolment.…”

Effect of dexamethasone on intraoperative remifentanil dose in total knee arthroplasty surgery under general anaesthesia

“…12 The trial was approved by the Regional Committee on Health Research Ethics, Region Zealand (SJ-695; 07 May 2018), the Danish Medicines Agency (EudraCT-number 2018-001099-30; 25 May 2018) and the Danish Data Protection Agency (REG-034-2018; 14 August 2018) and was monitored by the Good Clinical Practice Units at Copenhagen and Odense University Hospitals, Denmark. The methodology has previously been described in detail in the published protocol, 12 the statistical analysis plan 13 and the main result publication. 4 In short, the trial was conducted at one private and four public Danish hospitals.…”

Risk of serious adverse events associated with non‐steroidal anti‐inflammatory drugs in orthopaedic surgery. A protocol for a systematic review

“…More than 300 million surgeries are performed annually worldwide 1 . Orthopaedic procedures are amongst the most frequent procedures, 2 including major planned procedures as total hip and knee arthroplasty that are being performed in more than 1.5 million patients annually 3 . Orthopaedic surgery consists of both planned and acute surgery involving damage to bones and surrounding tissue, and is associated with moderate to severe postoperative pain, which often is insufficiently treated 4 …”