Osteoarthritis, KneePhase 4NCT06083480
Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty
A Phase 4 study testing GlyNAC (combination of glycine and n-acetylcysteine) in people with Osteoarthritis, Knee and Total Knee Arthroplasty, run by Vanderbilt University Medical Center at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Osteoarthritis, Knee, Total Knee Arthroplasty, Chronic Postsurgical Pain
- What is being tested?
- GlyNAC (combination of glycine and n-acetylcysteine)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 148 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Dec 2024to Mar 2029
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Vanderbilt University Medical Center
Nashville, Tennessee, 37212
Stephen Bruehl, PhD
About this study
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).
Read the 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).
- Being tested
- GlyNAC (combination of glycine and n-acetylcysteine), Placebo
- Medical subject headings
- Osteoarthritis, Knee, Pain, Postoperative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlyNAC (combination of glycine and n-acetylcysteine)Drug
Also called GlyNAC
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| GlyNAC (combination of glycine and n-acetylcysteine) | Experimental | 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. Receives: Drug: GlyNAC (combination of glycine and n-acetylcysteine) |
| Placebo (alanine) | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours
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").
Measured: Baseline to 6 months post TKA (approximately 7 months)
Secondary outcomes (10)
Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours
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")
Measured: Baseline to 6 weeks and 12 months post TKA (13 months)
Numeric Rating Scale of Average Pain in the past 24 hours
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").
Measured: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Numeric Rating Scale of Least Pain in the past 24 hours
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").
Measured: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement.
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.
Measured: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR)
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.
Measured: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
PROMIS Short Form V1.0 - Pain Interference 8a scale
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.
Measured: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Postsurgical Opioid Use (pill count)
Number of prescribed opioid pills used since hospital discharge following TKA. This is based on a combination of prescribed postsurgical opioid amounts and number of refills recorded in the electronic health record combined with pill counts conducted at each in-person post-TKA follow-up assessment.
Measured: Post-TKA discharge to 6 weeks, 6 months and 12 months post-TKA (12 months)]
Postsurgical Opioid Use (days of opioid use in the past week)
Number of days opioids were used in the past week at each in-person post-TKA follow-up assessment.
Measured: 6 weeks, 6 months and 12 months post-TKA (12 months)
F2-Isoprostane/Isofuran (IsoP/IsoF) levels
Changes in mean IsoP/IsoF levels from initial pre-intervention baseline. This is a measure of oxidative stress and is a mechanistic marker of the effects of the study antioxidant intervention (GlyNAC).
Measured: Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months)
Glutathione levels
Changes in mean glutathione levels from initial pre-intervention baseline. This is a measure of antioxidant capacity and is a mechanistic marker of the effects of the study antioxidant intervention (GlyNAC).
Measured: Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Oct 2023
- Study start6 Dec 2024
- Primary completionSep 2028 (estimated)
- Study completionMar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Osteoarthritis, KneeStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective, randomized, controlled, mixed between/within-subject longitudinal trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 148 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Stephen Bruehl, PhD, Vanderbilt University Medical Center
- Investigators
- Stephen Bruehl, Ph.D., Principal investigator, Vanderbilt University Medical CenterFrederic T Billings, IV, MD, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06083480
- Sponsor's protocol ID
- 231668
- Other IDs
- 1R01AG085287-01
- Status last verified
- Dec 2025
- First submitted
- 5 Oct 2023
- Last updated
- 11 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Key data elements will be preserved in final analyzed form (e.g., combined OS outcomes \[mean of the two OS assays above\], summary scores on all measures). The study protocol, standardized data collection instruments, and data dictionary will be uploaded in the repository. to facilitate study interpretation. Shared data will be uploaded in SPSS format. Data from the project will be stored within the Open Science Framework (OSF) database. OSF provides a unique URL for all datasets which will be provided for those interested. OSF also includes an interface with a search engine for identify datasets by topic/keyword. The data will be made available in OSF upon publication of the project findings. The data will continue to be available indefinitely on OSF subject to any OSF limitations. The dataset will be de-identified, so there will be no privacy limitations. Data will be accessible after publication of project results so there will be no limits on re-use.
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty
- ClinicalTrials.gov ID
- NCT06083480
- Acronym / sponsor ID
- 231668
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 148 participants (estimated)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 6 Dec 2024 (actual)
- Primary completion
- Sep 2028 (estimated)
- Study completion
- Mar 2029 (estimated)
- First posted
- 16 Oct 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Prospective, randomized, controlled, mixed between/within-subject longitudinal trial
| Arm | Type | Receives |
|---|---|---|
| GlyNAC (combination of glycine and n-acetylcysteine) | Experimental | 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. |
| Placebo (alanine) | Placebo comparator | Drug: PlaceboPlacebo (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. |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlyNAC (combination of glycine and n-acetylcysteine)Also: GlyNACGlyNAC 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) |
| PlaceboPlacebo (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 (alanine) |
Primary outcome
Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours
Time frame: 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").
10 secondary outcomes
Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours
Time frame: Baseline to 6 weeks and 12 months post TKA (13 months)
Numeric Rating Scale of Average Pain in the past 24 hours
Time frame: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Numeric Rating Scale of Least Pain in the past 24 hours
Time frame: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Mean change in McGill Pain Questionnaire-2 (MPQ-2) ratings of knee pain for average pain over past week of measurement.
Time frame: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR)
Time frame: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
PROMIS Short Form V1.0 - Pain Interference 8a scale
Time frame: Baseline to 6 weeks, 6 months and 12 months post TKA (13 months)
Postsurgical Opioid Use (pill count)
Time frame: Post-TKA discharge to 6 weeks, 6 months and 12 months post-TKA (12 months)]
Postsurgical Opioid Use (days of opioid use in the past week)
Time frame: 6 weeks, 6 months and 12 months post-TKA (12 months)
F2-Isoprostane/Isofuran (IsoP/IsoF) levels
Time frame: Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months)
Glutathione levels
Time frame: Baseline to 4 week pre-TKA assessment, and 6 weeks, 6 months and 12 months post TKA (13 months)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2025.
- Individual participant dataSharing planned: Yes. Key data elements will be preserved in final analyzed form (e.g., combined OS outcomes [mean of the two OS assays above], summary scores on all measures). The study protocol, standardized data collection instruments, and data dictionary will be uploaded in the repository. to facilitate study interpretation. Shared data will be uploaded in SPSS format. Data from the project will be stored within the Open Science Framework (OSF) database. OSF provides a unique URL for all datasets which will be provided for those interested. OSF also includes an interface with a search engine for identify datasets by topic/keyword. The data will be made available in OSF upon publication of the project findings. The data will continue to be available indefinitely on OSF subject to any OSF limitations. The dataset will be de-identified, so there will be no privacy limitations. Data will be accessible after publication of project results so there will be no limits on re-use.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Stephen Bruehl, Ph.D. principal investigator
Vanderbilt University Medical Center
Frederic T Billings, IV, MD principal investigator
Vanderbilt University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing GlyNAC (combination of glycine and n-acetylcysteine) in people with Osteoarthritis, Knee and Total Knee Arthroplasty, run by Vanderbilt University Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Stephen Bruehl, Ph.D. ((615) 936-1821, stephen.bruehl@vumc.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Numeric Rating Scale (NRS) Rating of Worst Pain in the past 24 hours (time frame: Baseline to 6 months post TKA (approximately 7 months)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2025.