Doxepin Alone or Combined With Ramelteon Versus Placebo for Improving Sleep Quality After Primary Total Knee Arthroplasty

NCT07598734 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: STUDY00024373
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 1

Brief Summary

Many patients experience poor sleep during recovery after total knee arthroplasty (TKA). Disturbed sleep can last weeks to months and may worsen pain, slow healing, and reduce overall quality of life. Few safe, effective, evidence-based options exist to improve sleep during this recovery period. This study aims to determine whether the medications doxepin, either alone or in combination with ramelteon, can improve sleep quality during early recovery after TKA. The investigators will also evaluate whether improved sleep leads to better pain control, knee function, and overall quality of life.

Conditions

Sleep Quality Post-TKA; Postoperative Knee Function; Quality of Life After Primary TKA

Outcome Measures

Primary Outcomes (1)

• Insomnia Severity Index (ISI) scores (sleep quality)

  Insomnia Severity Index (ISI) The Insomnia Severity Index is a 7-item self-reported questionnaire assessing the nature, severity, and impact of insomnia. * Score range: 0 to 28 * Interpretation: Higher scores indicate worse insomnia severity Score categories: * 0-7: No clinically significant insomnia * 8-14: Subthreshold insomnia * 15-21: Clinical insomnia (moderate severity) * 22-28: Clinical insomnia (severe)

  Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively

Secondary Outcomes (3)

• Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS)

  Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively.

• Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR)

  Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively

• Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10)

  Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively

Other Outcomes (12)

• 90-Day Hospital Readmission Status

  Within 90 days postoperatively

• Medication Compliance

  2 weeks postoperatively; 6 weeks postoperatively

• Length of Stay (LOS)

  Perioperative/Periprocedural

Study Arms (3)

Doxepin 6 mg

EXPERIMENTAL

Participants receive doxepin 6 mg and matching placebo orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.

Drug: Doxepin 6 mg

Doxepin 6 mg and Ramelteon 8mg

EXPERIMENTAL

Participants receive doxepin 6 mg and ramelteon 8 mg orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.

Drug: Doxepin 6 mg; Drug: Ramelteon 8 mg

Placebo

PLACEBO COMPARATOR

Participants receive 2 matching placebos orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.

Drug: Placebo Tablets

Interventions

Doxepin 6 mg DRUG

Doxepin 6 mg administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty

Doxepin 6 mg; Doxepin 6 mg and Ramelteon 8mg

Ramelteon 8 mg DRUG

Ramelteon 8 mg administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty

Doxepin 6 mg and Ramelteon 8mg

Placebo Tablets DRUG

Placebo administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Those receiving primary total knee arthroplasty (TKA)
• years or less, age 18 or greater

You may not qualify if:

• History of cardiovascular bundle branch block
• Actively taking selecrtive serotoin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or having treatment via counseling/psychotherapy for major depression or anxiety, bipolar, or psychotic disorder
• Pre-operative narcotics (defined as more than 1 prescription in the past 3 months)
• Self-reported use of alcohol in excess of \>2 drinks/day (in men) and \> 1 drink/day (in women)
• Use of prescription sleep aids (e.g., Ambien, Trazadone) prior to surgery (i.e., melatonin or other OTC sleep aids are permitted)
• History of major sleep disorder (e.g., obstructive sleep apnea (OSA), restless leg syndrome, narcolepsy)
• Pregnant, breastfeeding or planning to become pregnant in the next 3 months post-surgery. No pregnancy testing will be performed; screening will rely solely on participant self-report.
• Unable to take the study medication(s) due to contraindications with other medications the patient uses
• Have been diagnosed with (or are at risk of) narrow-angle or angle-closure glaucoma. In order to be eligible, participants must be able to report that they have had their eyes dilated within the past year without problems.
• Have severe urinary retention or difficulty emptying your bladder.
• Had glaucoma-related eye procedures (e.g., laser iridotomy)
• Ongoing use of glaucoma eye drops.

Sponsors & Collaborators

• University of Washington: lead

Study Sites (1)

University of Washington Medical Center Hip & Knee Center

Seattle, Washington, 98133, United States

Location

MeSH Terms

Interventions

Doxepin; ramelteon

Intervention Hierarchy (Ancestors)

Oxepins; Ethers, Cyclic; Ethers; Organic Chemicals; Dibenzoxepins; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Nicholas M Hernandez, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gerald Y Liao, MS

CONTACT

617-710-7211; liaog@uw.edu

Nicholas M Hernandez, MD

CONTACT

530-514-1275; nichern@uw.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Orthopaedic Surgery and Sports Medicine

Model Details: This is a randomized, double blind (surgeon and patient), placebo-controlled, parallel-group clinical trial comparing two medications against a placebo, enrolling sequential patients undergoing primary total knee arthroplasty, with outcomes assessed over a 3-month postoperative period to evaluate sleep quality.

Study Record Dates

• First Submitted: May 1, 2026
• First Posted: May 20, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: May 20, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)