Clinical trial NCT03506789: Dexamethasone Twice for Pain Treatment of Total Knee Arthroplasty
Official title: Dexamethasone Twice for Pain Treatment of Total Knee Arthroplasty - A Randomized Blinded Placebo-controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Postoperative Pain
Lead sponsor: Naestved Hospital
Sponsor class: OTHER
First posted: 2018-04-24
Enrollment: 485
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Dexamethasone twice for pain treatment after total knee arthroplasty - A Placebo-controlled, randomised, parallel 3-group multicentre trial of one and two doses of dexamethasone for postoperative treatment

Detailed description: Trial name: Dexamethasone twice for pain treatment of total knee arthroplasty - A randomized blinded placebo-controlled clinical trial

Trial Acronym: DEX-2-TKA

Background: Effective postoperative pain management is essential for the well-being and rehabilitation of the surgical patient. No "gold standard" exists for pain treatment after total knee arthroplasty (TKA) since combinations of different analgesic treatments are used with nearly no evidence for combined analgesic efficacy. A single perioperative dose of glucocorticoid (GCC) (i.e. dexamethasone) has well established effects on postoperative nausea and vomiting, and may be beneficial for postoperative pain. A recent trial suggested that an additional postoperative dose of GCC improved postoperative pain treatment. Recent systematic reviews, sub-studies of RCTs and cohort studies of perioperative GCC raised no concern regarding serious adverse events of a single dose GCC for non-cardiac surgery. However, optimal dose, combination and regimen of perioperative GCC remains unsettled.

Objective: To establish the analgesic effect and safety of one and two consecutive days of a single dose of dexamethasone after TKA. GCC will be administered in combination with paracetamol, NSAID (ibuprofen), and local infiltration analgesia.

Intervention: The participants will be randomised in three groups: A) 24 mg dexamethasone i.v. perioperative (POD0) and 24 mg dexamethasone i.v. on the first postoperative day (POD1); B) 24 mg dexamethasone i.v. POD0 and placebo (isotonic saline) i.v. on POD1; and C) placebo i.v. on POD0 and POD1.

Design and trial size: Placebo-controlled, randomised, parallel 3-group multicentre trial with adequate centralised computer-generated allocation sequence and allocation concealment with unknown block size. Assessor, investigator, caregivers and participants will all be blinded. A total of 423 eligible participants are needed to detect a difference of 10 mg morphine for the first 48 hours postoperatively with a standard deviation of 23 mg, an overall familywise type 1 error rate of 0.05 and a type 2 error rate of 0.10. To compensate for uncertainty of the distribution a surplus of 15 % is added, thus a total of 486 patients will be included. To maintain an overall familywise error rate of 0.05 the sample size estimation is based on pairwise comparisons of the primary outcome between the three groups (three comparisons) with an individual type I error rate of 0.0167.

Sub studies: The investigators plan the following substudies

* One-year follow-up with EQ-5D-5L (EuroQuols - 5 dimension - 5 level score), Oxford-Knee-Score and mortality including need for medical attention.
* Troponin (TnI) levels 24 and 48 hours postoperatively (only at Naestved Hospital).
* Analysis of high and low pain responders.
* Establishment of a bio-bank (blood-samples) for future studies (only at Naestved Hospital).

Due to decisions made by the Steering Committee at our meeting the 14th of May 2019 in Køge, Region Zealand, Denmark, the secondary outcomes have been rearranged and divided into secondary outcomes and other (eksplorative) outcomes. Furthermore an additional explorative endpoint is added: Number of patients with a permanent use of opioids 90 days after surgery.

No data was unblinded or analyzed to aid the decisions.

After the last patient was included, but prior to data analysis and unmasking, the Steering Committee decided to include the following explorative outcomes in the main article reporting results from this trial. The decision was made by consensus via email 4th of October 2020:

* proportion of participants with one or more severe adverse event (SAE), including death, within 90 days after surgery (SAE defined according to ICH-GCP-guidelines, except 'prolongation of hospitalisation')
* opioid related adverse events (AE)

  * level of nausea, sedation and dizziness at 24 and 48 h
  * number of vomiting episodes 0-24 and 24-48 h"
  * use of anti-emetics 0-24 and 24-48 h

Eligibility criteria: Inclusion Criteria:

* Scheduled for unilateral, primary total knee arthroplasty
* ASA 1-3
* BMI ≥ 18.0 and ≤ 40.0
* Negative urine HCG pregnancy test and use of anti-conception for women in the fertile age
* Patients who gave their written informed consent to participating in the trial after having fully understood the contents of the protocol and restrictions

Exclusion Criteria:

* Patients who cannot cooperate with the trial
* Concomitant participation in another trial involving medication
* Patients who cannot understand or speak Danish
* Patients with allergy to medication used in the trial
* Patients with daily use of high dose opioid (\> oral morphine 30 mg/day or oxycodone 30 mg/day or tramadol 150 mg/day) or any use of other opioids including methadone and transdermal opioids.
* Patients with at daily use of systemic glucocorticoids
* Contraindications against ibuprofen or paracetamol, for example previous ulcer, known heart failure, known liver failure, or known renal failure (eGRF \< 60 ml/kg/1,73m2), known thrombocytopenia (\<100 bil/l); or against treatment with glucocorticoids.
* Dysregulated diabetes (investigators judgement)
* Patients suffering from alcohol and/or drug abuse - based on the investigator's judgement

Primary outcomes:
measure: Cumulative usage of morphine 0-48 hours postoperatively
timeFrame: 0-48 hours postoperatively
Secondary outcomes:
measure: VAS-pain scores (visual analogue scale (VAS))
timeFrame: 24 and 48 hours postoperatively
measure: Adverse events, patient-reported
timeFrame: 0-48 hours postoperatively
Other outcomes:
measure: Number of patients with one or more serious adverse events (SAE)
timeFrame: 90 days postoperatively
measure: 90 days follow-up
timeFrame: 90 days postoperatively
measure: Total need of i.v. morphine 0-24 hours postoperatively
timeFrame: 0-24 hours postoperatively
measure: Total need of oral morphine 24-48 hours postoperatively
timeFrame: 24-48 hours postoperatively
measure: VAS-pain scores (visual analogue scale (VAS))
timeFrame: 6, 24 and 48 hours postoperatively hours postoperatively
measure: Timed up and go (TUG) test at 24 and 48 hours including maximum pain during the TUG test.
timeFrame: 24 and 48 hours postoperatively
measure: Adverse events, nausea
timeFrame: 0-48 hours postoperatively
measure: Adverse events, sedation
timeFrame: 0-48 hours postoperatively
measure: Adverse events, dizziness
timeFrame: 0-48 hours postoperatively
measure: Adverse events, vomiting
timeFrame: 0-48 hours postoperatively
measure: Consumption of antiemetics in the period 0-24 and 24-48 hours postoperatively
timeFrame: 0-48 hours postoperatively
measure: Quality of sleep 0-24 and 24-48 hours postoperatively
timeFrame: 0-48 hours postoperatively
measure: Level of fatigue at 24 and 48 hours postoperatively
timeFrame: 24 and 48 hours postoperatively
measure: NRS-pain scores 3-7 days postoperatively
timeFrame: 3-7 days postoperatively
measure: Quality of sleep 3-7 days postoperatively
timeFrame: 3-7 days postoperatively
measure: Satisfaction with postoperative pain treatment after 7 days
timeFrame: 7 days postoperatively
measure: Proportion of participants with permanent use of opioids 90 days after surgery
timeFrame: 90 days postoperatively
measure: 90 days follow-up using EQ5D5L
timeFrame: 90 days postoperatively
measure: 90 days follow-up using Oxford-Knee-Score
timeFrame: 90 days postoperatively
Locations:
city: Brøndbyvester
country: Denmark
facility: Gildhøj Privathospital
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Køge
country: Denmark
facility: Sjællands Universitetshospital, Køge
city: Næstved
country: Denmark
facility: Næstsved Sygehus
city: Odense
country: Denmark
facility: Odense Universitetshospital
Study officials:
affiliation: Department of Anaesthesiology, Zealand University Hospital, Køge
name: Ole Mathiesen, MD, PhD, Assoc Prof
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Næstved Hospital
name: Daniel Hägi-Pedersen, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Bispebjerg Hospital
name: Jørgen B Dahl, DMSc
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Næstved Hospital
name: Kasper S Gasbjerg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anaesthesiology, Bispebjerg Hospital
name: Troels H Lunn, DMSc
role: STUDY_CHAIR
References:
citation: Gasbjerg KS, Hagi-Pedersen D, Lunn TH, Laursen CC, Holmqvist M, Vinstrup LO, Ammitzboell M, Jakobsen K, Jensen MS, Pallesen MJ, Bagger J, Lindholm P, Pedersen NA, Schroder HM, Lindberg-Larsen M, Norskov AK, Thybo KH, Brorson S, Overgaard S, Jakobsen JC, Mathiesen O. Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial. BMJ. 2022 Jan 4;376:e067325. doi: 10.1136/bmj-2021-067325.
citation: Gasbjerg KS, Hagi-Pedersen D, Lunn TH, Overgaard S, Pedersen NA, Bagger J, Lindholm P, Brorson S, Schroder HM, Thybo KH, Mathiesen O, Jakobsen JC. 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. Acta Anaesthesiol Scand. 2020 Jul;64(6):839-846. doi: 10.1111/aas.13560. Epub 2020 Mar 3.
citation: Gasbjerg KS, Hagi-Pedersen D, Lunn TH, Jakobsen JC, Overgaard S, Pedersen NA, Bagger J, Lindholm P, Brorson S, Schroder HM, Thybo KH, Mathiesen O. DEX-2-TKA-DEXamethasone twice for pain treatment after Total Knee Arthroplasty: A protocol for a randomized, blinded, three-group multicentre clinical trial. Acta Anaesthesiol Scand. 2020 Feb;64(2):267-275. doi: 10.1111/aas.13481. Epub 2019 Oct 18.