Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06083480

Collaborator

National Institute on Aging (NIA) (NIH)

148

Enrollment

Location

Arms

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective randomized controlled trial that will assess preoperative, perioperative, and long-term oxidative stress (OS); pain; and functional outcomes over a 12 month period and test the hypothesis that a potent antioxidant intervention (glycine + N-acetyl-cysteine(GlyNAC)) reduces oxidative stress and chronic post surgical pain (CPSP) in patients undergoing total knee arthroplasty (TKA).

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis, Knee Total Knee Arthroplasty Chronic Postsurgical Pain	Drug: GlyNAC (combination of glycine and n-acetylcysteine) Drug: Placebo	Phase 4

Detailed Description

One of the most common surgical procedures performed in older adults is total knee arthroplasty (TKA), with an estimated 1 million TKAs performed annually in the United States. TKA directly addresses the pathology underlying knee joint pain and mobility limitations resulting from osteoarthritis. For most patients, TKA is effective for pain reduction and increasing function. However, a subgroup of 15-20% of TKA patients report unsatisfactory long-term pain outcomes well after postsurgical healing has occurred despite technical success of the procedure. Chronic postsurgical pain (CPSP) following TKA has been reported to be worse than the preoperative pain in 7% of TKA patients at up to 4-years. A potential biological mechanism is perioperative oxidative stress (OS),

The proposed project seeks to confirm the mechanistic role of OS in post-TKA CPSP and test the hypothesis that a perioperative intervention to reduce OS may reduce risk for CPSP post-TKA. This is a prospective randomized controlled trial that will assess preoperative, perioperative, and long-term oxidative stress (OS); pain; and functional outcomes over a 12 month period and test the hypothesis that a potent antioxidant intervention (GlyNAC) reduces OS and CPSP in patients undergoing total knee arthroplasty (TKA).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

148 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, randomized, controlled, mixed between/within-subject longitudinal trialProspective, randomized, controlled, mixed between/within-subject longitudinal trial

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty

Anticipated Study Start Date :

Mar 1, 2024

Anticipated Primary Completion Date :

Sep 1, 2028

Anticipated Study Completion Date :

Mar 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GlyNAC (combination of glycine and n-acetylcysteine) GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine.	Drug: GlyNAC (combination of glycine and n-acetylcysteine) GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine. Other Names: GlyNAC
Placebo Comparator: Placebo (alanine) Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.	Drug: Placebo Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Arm

Intervention/Treatment

Experimental: GlyNAC (combination of glycine and n-acetylcysteine)

GlyNAC 200 mg/kg/day (100mg glycine and 100mg N-acetyl-cysteine) will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively. The preparation will be a commercially available product of 1:1 ratio of glycine and N-acetyl-cysteine.

Drug: GlyNAC (combination of glycine and n-acetylcysteine)

Other Names:

GlyNAC

Placebo Comparator: Placebo (alanine)

Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Drug: Placebo

Placebo (alanine) 200 mg/kg/day will be administered orally in two divided doses each day for four weeks prior to TKA and six weeks postoperatively.

Outcome Measures

Primary Outcome Measures

Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours [Baseline to 6 months post TKA (approximately 7 months)]
Mean within participant changes in NRS intensity ratings of worst pain in past 24 hours of measurement at 6 months post TKA. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = "no pain" and 100 = "worst possible pain").

Secondary Outcome Measures

Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours [Baseline to 6 weeks and 12 months post TKA (13 months)]
Mean within participant changes in NRS intensity ratings of worst pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = "no pain" and 100 = "worst possible pain")
Numeric Rating Scale of Average Pain in the past 24 hours [Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)]
Mean within participant changes in NRS intensity ratings of average pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = "no pain" and 100 = "worst possible pain").
Numeric Rating Scale of Least Pain in the past 24 hours [Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)]
Mean within participant changes in NRS intensity ratings of least pain in past 24 hours of measurement. The score is a rating of current acute pain using a 0-100 numeric rating scale (NRS) (0 = "no pain" and 100 = "worst possible pain").
Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement. [Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)]
Mean within participant changes in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement. The MPQ-2 score ranges from 0-10 where 0 represents no pain and 10 represents the most intense pain.
Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) [Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)]
Mean within participant changes in KOOS-JR ratings to assess movement evoked pain and functional limitations. Scores range from 0 to 100 with a score of 0 indicating total knee disability and 100 indicating perfect knee health.
PROMIS Short Form V1.0 - Pain Interference 8a scale [Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)]
Mean within participant changes in PROMIS Short Form V1.0 - Pain Interference 8a scale to assess pain-related life interference over the week preceding assessments. This is an 8 item questionnaire with scores ranging from 0-40. 0 indicates no pain interference and 40 indicates the highest level of pain interference.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 50 or older
Intact cognitive status and ability to provide informed consent (based on cognitive screening with the Mini Mental State Examination)
Ability to read and write in English sufficiently to understand and complete study questionnaires
Undergoing unilateral primary TKA
Medical diagnosis of osteoarthritis
Past 24 hour worst numeric rating scale (NRS) pain of at least 4/10.

Exclusion Criteria:

Diagnosis of pre-existing neuropathy
Untreated hypo/hyperthyroidism
Untreated heart disease
Alanine transaminase/aspartate transaminase >2x upper-limit of normal range
serum creatinine >1.5 mg/dl
Pregnancy
Complex Regional Pain Syndrome (CRPS) diagnosis prior to undergoing TKA
Presence of lower extremity vascular disease, inflammatory or autoimmune disorders, or malignancy
Presence of current clinically significant chronic pain conditions outside of the lower extremity ( daily pain for >3 months and greater ≥3/10 in intensity or the focus of medical care)
Presence of other medical conditions that in the opinion of the orthopedic surgeon co-investigators would make a patient's study participation unsafe

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212

Sponsors and Collaborators

Vanderbilt University Medical Center
National Institute on Aging (NIA)

Investigators

Principal Investigator: Stephen Bruehl, Ph.D., Vanderbilt University Medical Center
Principal Investigator: Frederic T Billings, IV, MD, Vanderbilt University Medical Center