Improving Sleep After TKA Using Mirtazapine and Quetiapine

Study Overview
=================
Brief Summary
-----------------
Use of mirtazapine and quetiapine for improvement of sleep quality after TKA

Detailed Description
-----------------
Background After knee replacement surgery there is a loss of quantity and quality of sleep. Loss of sleep is associated with increased pain perception. Subsequently, patients use more analgesic medication and it takes them longer to fully recover from surgery. Low doses of the tetracyclic antidepressant mirtazapine and the neuroleptic quetiapine are nowadays off-label prescribed for insomnia and improve length and quality of deep sleep phases. Quetiapine and mirtazapine could improve sleep after knee replacement surgery and improve patient recovery. This placebo-controlled, randomized, double-blind study investigates the effect of quetiapine and mirtazapine on functional recovery after total knee arthroplasty. Methods This is a prospective, single center, double-blinded randomized controlled trial. 165 patients with knee osteoarthritis scheduled for total knee arthroplasty will be randomly allocated to a low-dose quetiapine (LDQ), a low-dose mirtazapine (LDM) group or a placebo group. Outcomes will be evaluated at baseline, 2, 4, 6 and 12 weeks after surgery. Functional outcome after total knee arthroplasty is measured using a patient related outcome measure through the Oxford Knee Score (OKS). In order to measure postoperative sleep quality, patients will be monitored using the Leeds Sleep evaluation questionnaire (LSEQ). Furthermore, pain is registered using a visual analogue scale (VAS), weekly opioid use is monitored, and general health status is reported through the EQ-5D. Analyses will be conducted on an intention-to-treat basis using logistic and linear mixed regression models. This trial complies with the SPIRIT guidelines for randomized controlled trials. Discussion This study will provide clinicians with evidence whether quetiapine contributes to rehabilitation of patients undergoing fast-track knee replacement surgery.

Official Title
-----------------
Mirtazapine and Quetiapine as Treatment for Postoperative Sleep Disturbance After Fast-track Knee Replacement

Conditions
-----------------
Osteo Arthritis Knee, Insomnia

Intervention / Treatment
-----------------
* Drug: Mirtazapine
* Drug: Quetiapine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Indication for TKA Exclusion Criteria: use of benzodiazepines use of anti-depressants use of oxycodone patients diagnosed with obstructive sleep apnea syndrome, severe respiratory insufficiency, or myasthenia a known hypersensitivity to mirtazapine, quetiapine and/or related to the gelatinous (placebo) capsule insufficient understanding of the Dutch language.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>use of placebo during first 2 weeks after TKA surgery | Drug: Placebo<br>* a gelatinous capsule without an active ingredient<br>|
| Experimental: Low dose Mirtazapine<br>Use of Mirtazapine 3.75mg before lights-out, allowed to increase medication to 7.5mg | Drug: Mirtazapine<br>* Use of 3.75mg mirtazapine before lights-out during first 2 weeks after TKA surgery. With insufficient effect on sleep, patients are allowed to increase medication to 7.5mg mirtazapine.<br>|
| Experimental: Low dose Quetiapine<br>use of Quetiapine 3.125mg before lights-out, allowed to increase medication to 6.25mg | Drug: Quetiapine<br>* Use of 3.125mg quetiapine before lights-out during first 2 weeks after TKA surgery. With insufficient effect on sleep, patients are allowed to increase medication to 6.25mg mirtazapine.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxford Knee Score (OKS) | Validated functional knee score after TKA, minimum score 12 (best outcome), maximum score 60 (worst outcome) | 6 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leeds Sleep Evaluation questionnaire (LSEQ) | Validated sleep score in 3 dimensions of sleep | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Visual Analogue Scale (VAS) for fatigue | Visual analogue reporting of fatigue after sleep, indicated on a 0 (best outcome) to 100 (worst outcome) mm line | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Visual Analogue Scale (VAS) for sleep quality | Visual analogue reporting of quality sleep, indicated on a 0 (worst outcome) to 100 (best outcome) mm line | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Visual Analogue Scale (VAS) for pain in rest | Visual analogue reporting of knee pain while resting, indicated on a 0 (best outcome) to 100 (worst outcome) mm line | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Visual Analogue Scale (VAS) for pain during activity | Visual analogue reporting of knee pain during exercises, indicated on a 0 (best outcome) to 100 (worst outcome) mm line | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| EuroQol (EQ) 5D | General well being score, full health represented by 11111 score (overall score for the Netherlands of 1,000), worst health represented by 55555 score (overal score for the Netherlands of -0,329) | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Morphine use | Total amount (mg) morphine use after surgery is documented | 1 week before surgery; first day postoperative; 2; 4; 6; 12 weeks after surgery | 
| Oxford knee score | Validated functional knee score after TKA, minimum score 12 (best outcome), maximum score 60 (worst outcome) | 1 week before surgery; first day postoperative; 2; 4; 12 weeks after surgery |