- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03506789
Dexamethasone Twice for Pain Treatment of Total Knee Arthroplasty (DEX-2-TKA)
Dexamethasone Twice for Pain Treatment of Total Knee Arthroplasty - A Randomized Blinded Placebo-controlled Clinical Trial
Study Overview
Status
Conditions
Intervention / 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
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
-
Brøndbyvester, Denmark, 2605
- Gildhøj Privathospital
-
Copenhagen, Denmark, 2400
- Bispebjerg Hospital
-
Køge, Denmark, 4600
- Sjællands Universitetshospital, Køge
-
Næstved, Denmark, 4700
- Næstsved Sygehus
-
Odense, Denmark, 5000
- Odense Universitetshospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
Placebo (isotonic saline) i.v.
perioperatively and placebo (isotonic saline) i.v. on the first postoperative day
|
Isotonic saline
|
Active Comparator: Treatment A:
24 mg dexamethasone i.v.
perioperatively and 24 mg dexamethasone i.v. on the first postoperative day
|
Dexamethasone 24 mg
|
Active Comparator: Treatment B:
24 mg dexamethasone i.v.
perioperatively and placebo (isotonic saline) i.v. on the first postoperative day
|
Dexamethasone 24 mg
Isotonic saline
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cumulative usage of morphine 0-48 hours postoperatively
Time Frame: 0-48 hours postoperatively
|
Morphine administered both as patient-controlled analgesia (PCA) i.v. morphine 0-24 hours and oral morphine on demand 24-48 hours, and any other supplemental morphine administered postoperatively. Consumption in mg |
0-48 hours postoperatively
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
VAS-pain scores (visual analogue scale (VAS))
Time Frame: 24 and 48 hours postoperatively
|
|
24 and 48 hours postoperatively
|
Adverse events, patient-reported
Time Frame: 0-48 hours postoperatively
|
Number of patients with one or more patient-reported adverse event in the intervention period
|
0-48 hours postoperatively
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of patients with one or more serious adverse events (SAE)
Time Frame: 90 days postoperatively
|
Number of patients with one or more serious adverse events (SAE), including death, within 90 days after surgery defined as SAE (according to ICH-GCP-guidelines), except "prolongation of hospitalisation"
|
90 days postoperatively
|
90 days follow-up
Time Frame: 90 days postoperatively
|
Number of patients with need for medical attention and/or intervention including need for anti-biotics and/or re-operation
|
90 days postoperatively
|
Total need of i.v. morphine 0-24 hours postoperatively
Time Frame: 0-24 hours postoperatively
|
Consumption in mg
|
0-24 hours postoperatively
|
Total need of oral morphine 24-48 hours postoperatively
Time Frame: 24-48 hours postoperatively
|
Consumption in mg
|
24-48 hours postoperatively
|
VAS-pain scores (visual analogue scale (VAS))
Time Frame: 6, 24 and 48 hours postoperatively hours postoperatively
|
|
6, 24 and 48 hours postoperatively hours postoperatively
|
Timed up and go (TUG) test at 24 and 48 hours including maximum pain during the TUG test.
Time Frame: 24 and 48 hours postoperatively
|
The timed up and go test is performed at 24 and 48 hours postoperatively. The participant will be placed on a chair, 3 meters from a line. After the command "Go" the participant will
The time will be measured from "Go" to the participant is sitting again. |
24 and 48 hours postoperatively
|
Adverse events, nausea
Time Frame: 0-48 hours postoperatively
|
Level of nausea at 6, 24 and 48 hours postoperatively Scale: none, mild, moderate, severe |
0-48 hours postoperatively
|
Adverse events, sedation
Time Frame: 0-48 hours postoperatively
|
Level of sedation at 6, 24 and 48 hours postoperatively Scale: none, mild, moderate, severe |
0-48 hours postoperatively
|
Adverse events, dizziness
Time Frame: 0-48 hours postoperatively
|
Level of dizziness at 6, 24 and 48 hours postoperatively Scale: none, mild, moderate, severe |
0-48 hours postoperatively
|
Adverse events, vomiting
Time Frame: 0-48 hours postoperatively
|
Number of vomiting episodes (0-48 hours) measured in the periods 0-24 and 24-48 hours postoperatively
|
0-48 hours postoperatively
|
Consumption of antiemetics in the period 0-24 and 24-48 hours postoperatively
Time Frame: 0-48 hours postoperatively
|
Use of ondansetron and DHB (Dehydrobenzperidol)
|
0-48 hours postoperatively
|
Quality of sleep 0-24 and 24-48 hours postoperatively
Time Frame: 0-48 hours postoperatively
|
Scale: very bad, fairly bad, fairly good, very good
|
0-48 hours postoperatively
|
Level of fatigue at 24 and 48 hours postoperatively
Time Frame: 24 and 48 hours postoperatively
|
Scale: none, mild, moderate, severe
|
24 and 48 hours postoperatively
|
NRS-pain scores 3-7 days postoperatively
Time Frame: 3-7 days postoperatively
|
Two daily NRS-scores: One in the morning and one in the evening
|
3-7 days postoperatively
|
Quality of sleep 3-7 days postoperatively
Time Frame: 3-7 days postoperatively
|
Scale: very bad, fairly bad, fairly good, very good
|
3-7 days postoperatively
|
Satisfaction with postoperative pain treatment after 7 days
Time Frame: 7 days postoperatively
|
Scale: very bad, fairly bad, fairly good, very good
|
7 days postoperatively
|
Proportion of participants with permanent use of opioids 90 days after surgery
Time Frame: 90 days postoperatively
|
Number of patients with prescripción for painkillers
|
90 days postoperatively
|
90 days follow-up using EQ5D5L
Time Frame: 90 days postoperatively
|
Qualitative participant reported assessments using EQ5D5L (Questionaire - with one NRS (0-100))
|
90 days postoperatively
|
90 days follow-up using Oxford-Knee-Score
Time Frame: 90 days postoperatively
|
Qualitative participant reported assessments using Oxford-Knee-Score (Questionaire, scale 12-60 points)
|
90 days postoperatively
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Daniel Hägi-Pedersen, MD, PhD, Department of Anaesthesiology, Næstved Hospital
- Study Chair: Ole Mathiesen, MD, PhD, Assoc Prof, Department of Anaesthesiology, Zealand University Hospital, Køge
- Study Chair: Jørgen B Dahl, DMSc, Department of Anaesthesiology, Bispebjerg Hospital
- Principal Investigator: Kasper S Gasbjerg, MD, Department of Anaesthesiology, Næstved Hospital
- Study Chair: Troels H Lunn, DMSc, Department of Anaesthesiology, Bispebjerg Hospital
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Postoperative Complications
- Pain
- Neurologic Manifestations
- Pain, Postoperative
- Physiological Effects of Drugs
- Autonomic Agents
- Peripheral Nervous System Agents
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Dexamethasone
Other Study ID Numbers
- SM1-KAKG-2018
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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