Surgical RecoveryPhase 2NCT04732000
Oxidative Stress and Surgical Recovery
A Phase 2 study testing N-acetyl cysteine and Normal Saline in people with Surgical Recovery and Pain, Postoperative, run by Stanford University at 1 site in United States.
Trial summary
Chronic pain, functional impairment and slow rates of recovery are key issues for patients after surgery and trauma. No preventative strategy in current use unequivocally modifies these rates, and few novel approaches have been tested. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Surgical Recovery, Pain, Postoperative
- What is being tested?
- N-acetyl cysteine and Normal Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jul 2021to 1 Mar 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Over 18
- Male of female
- Planning to undergo primary total hip arthroplasty
- Fluent in English
- Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
Who cannot join
- Infectious disease within the last month
- Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
- Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
- Major surgery within the last 3 months or minor surgery within the last month.
- History of substance abuse (e.g., alcoholism, drug dependency)
- Pregnancy
Show all 11Show fewer
- Autoimmune disease interfering with data interpretation (e.g. lupus)
- Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function
- Active malignancy
- Participation in another clinical trial of an investigational drug or device within the last month that, in the investigator's opinion, would create an increased risk to the participant or compromise the integrity of the study
- Other conditions compromising a participant's safety or the integrity of the study
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University School of Medicine
Stanford, California, 94305
About this study
Chronic pain, functional impairment and slow rates of recovery are key issues for patients after surgery and trauma. No preventative strategy in current use unequivocally modifies these rates, and few novel approaches have been tested. Furthermore, persistent postsurgical pain is a major route to chronic opioid use, opioid use disorder and, regrettably, opioid overdose. Most strategies designed to limit chronic pain or enhance functional recovery after surgery are directed at modulating peripheral and central nervous system activity and do not strongly modify the underlying tissue pathophysiology or fundamental systemic responses. Strategies limiting oxidative stress in the perioperative period, on the other hand, might limit tissue damage, organ dysfunction and immune system activation.
N-acetyl cysteine (NAC) is an antioxidant well-studied in the perioperative period; it is very safe, relatively inexpensive and widely available. The central hypothesis is, therefore, that perioperative administration of NAC will reduce perioperative oxidative stress, limit immune system activation and improve key indices of surgical recovery. Although the planned work will not comprehensively address this hypothesis, it will identify the most useful tools and help the researchers estimate the required sample sizes for more definitive externally funded efforts.
Read the detailed description
This is a randomized, double-blind, placebo controlled interventional pilot study in 20 patients undergoing first-time total hip arthroplasty (THA) for chronic osteoarthritis at Stanford Medicine. The researchers will screen, enroll and collect biologic and behavioral data from 20 participants as outlined in previous observational and interventional clinical studies undertaken in close collaboration with the Department of Orthopedic Surgery. In particular, standard operating procedures for screening, recruiting, laboratory assessments, and clinical data collection are in place including eligibility screening via EPIC (EHR) ahead of patients' preoperative visit, coordinated recruitment and consenting during the pre-surgery visit including study- related laboratory work, further preoperative assessments after the visit (e.g. remote completion of questionnaires and direct import of results into REDCap), and real-time tracking of the data collection and storage process (e.g. including phone/email reminders if data are missing).
Repeated assessments of pain, physical function, and analgesic medication will be made before surgery, daily on postoperative days 1-3, and then twice a week in post-op weeks 1 - 6. Delirium will be measured days 1-3 while in-hospital. Additional data will include demographics (age, BMI, sex, race, and ethnicity), surgical/anesthesia data (e.g. duration), and medical/medication history.
Peripheral blood samples will be collected before surgery and 1hr and 24hr after surgery based on our prior study showing that monocyte activation (including STAT3, CREB and NFkB signaling responses in CD14+CD16- monocytes) early after surgery strongly correlates with delayed pain resolution and functional impairment. Exhaled breath samples will be collected intraoperatively prior to incision and at wound closure as well as at 1 and 24 hours after surgery.
N-Acetylcysteine infusion: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours. This is a standard dosing paradigm that is safe when used intraoperatively and rarely causes significant adverse effects (mainly allergic reactions).
Surgery and anesthesia: Participants will undergo unilateral hip arthroplasty performed by three surgeons using the same approach. The anesthetic and perioperative management of patients is standardized and follows ERAS-based recommendations.
Measures: Well-validated instruments will be used to assess pain, pain interference and function of the affected and operated joint including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) adapted for patients undergoing lower extremity joint surgery, the Brief Pain Inventory (BPI) and the Surgical Recovery Scale (SRS). Opioid consumption will be quantified as intravenous hydromorphone equivalents (milligram/day) using widely accepted opioid conversion tables.
Sample analysis: Blood and plasma will be collected and processed for analysis with mass cytometry as previously described. A 39-parameter human CyTOF antibody panel will be applied that will allow the simultaneous analysis of 1) all major immune cell phenotypes 2) endogenous intracellular signaling responses (including the pSTAT3, pCREB and pNF-kB signal) and 3) intracellular markers of reactive aldehydes (i.e. 4-HNE and MDA signal).
Breath samples will be analyzed for aldehydes including formaldehyde, crotenaldehyde, and benzaldehyde using mass spectroscopy in the laboratory of Dr. Gross.
Plasma samples will be analyzed for free MDA and 4- HNE in baseline, 1 and 24-hour plasma samples in the laboratory of Dr. Clark.
Analysis and modeling of outcome data: Self-reported outcomes will be analyzed using the validated models associated with each outcome to extract a quantified and normalized number associated with recovery. The 60Htz actigraphy data will first be mined for patterns associated with daily activities (e.g. step counts) and intensity levels. Next, a baseline will be established using the data collected during and prior to surgery, for each variable. All variables will be normalized to this baseline to account for patient-specific effects. Finally, a multivariate linear model (with days passed since surgery as the response variable) will be used to model the entire actigraphy dataset. The area under the respective recovery curve of each patient according to this model will be used as an objective recovery outcome. In our preliminary studies (data not shown) this outcome has been found to be correlated with several aspects of the immune system.
Analysis and modeling of CyTOF data: The large number of data points (millions of cells per patient) and measured variables (tens of signaling pathways in hundreds of cell types) pose unique computational challenges that cannot be addressed using traditional bioinformatics tools. The researchers will develop a Bayesian framework that will combine a priori knowledge of the immune system with state-of-the-art mass cytometry profiling to build a predictive model of innate and adaptive immune cell signaling responses for each of the recovery outcomes.
- Conditions
- Surgical Recovery, Pain, Postoperative
- Being tested
- N-acetyl cysteine, Normal Saline
- Medical subject headings
- Pain, Postoperative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-acetyl cysteineDrug
Also called NAC
Intravenous infusion started during the clinically indicated surgery at a rate of 50mg/kg over 1 hour followed by 50mg/kg over 3 hours. This will be an accumulated total of 100 mg/kg over 4 hours.
Normal SalineOther
Also called NS
Intravenous infusion at a time and rate to mimic the active treatment. The infusion will be given over 4 hours beginning during the clinically indicated surgery
| Study group | Role | What they receive |
|---|---|---|
| N-acetyl cysteine | Active comparator | N-acetyl cysteine will be administered as follows: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours. Receives: Drug: N-acetyl cysteine |
| Normal Saline | Placebo comparator | Normal will be administered as follows: A normal saline infusion will administered at a rate and duration to mimic the N-acetyl cysteine administration. Receives: Other: Normal Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells)
STAT3 phosphorylation in MDSC cells is measured in all MDSC cells before (T0) and one day after surgery (T1) using mass cytometry. The median phosphorylation in this cell population is then determined for each time point. The change in phosphorylation is expressed as the arc sinh ratio of these two medians (ratio = arc sinh [median pSTAT3-T1/median pSTAT3-T0]).
Measured: Measurements will be made in samples collected before and 24 hours after surgery.
Brief Pain Inventory Pain Score
The Brief Pain Inventory was used to measure pain and pain interference following surgery. BPI Pain Composite Score was derived from worst pain, least pain, average pain, and pain right now subscale scores. BPI Pain Interference Composite Score (representing how pain interferes with daily life) was derived from general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life subscale scores. Each composite score is the median value of the combined median values for each participant of the respective subscale scores (range for subscale and overall scores: 0 to 10, higher scores indicate more severe pain/pain interference).
Measured: post-operative week 6
Secondary outcomes (1)
Pain Score
The Brief Pain Inventory will be used to measure pain following surgery at various time points. A composite score will be calculated 24 hours post op and will constitute the secondary end point. Overall score: median and interquartile range are reported across scores for worst pain, least pain, average pain, and right now pain. Pain interference score: represents how pain interferes with daily life. Score ranges: 0 to 10, higher scores indicate more severe pain.
Measured: Baseline through post-op day 1 (composite scores over 24 hours following surgery)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Feb 2021
- Study start1 Jul 2021
- Primary completion1 Mar 2023
- Study completion1 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Surgical RecoveryStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe 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 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Martin Angst, Stanford University
- Investigators
- Martin S Angst, MD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04732000
- Sponsor's protocol ID
- 59401
- Status last verified
- Apr 2025
- First submitted
- 26 Jan 2021
- Last updated
- 30 Apr 2025
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kim DH, Pearson-Chauhan KM, McCarthy RJ, Buvanendran A. Predictive Factors for Developing Chronic Pain After Total Knee Arthroplasty. J Arthroplasty. 2018 Nov;33(11):3372-3378. doi: 10.1016/j.arth.2018.07.028. Epub 2018 Aug 4.
PubMed 30143334Zambelli VO, Gross ER, Chen CH, Gutierrez VP, Cury Y, Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain. Sci Transl Med. 2014 Aug 27;6(251):251ra118. doi: 10.1126/scitranslmed.3009539.
PubMed 25163478Guo TZ, Wei T, Huang TT, Kingery WS, Clark JD. Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain. 2018 Oct;19(10):1147-1156. doi: 10.1016/j.jpain.2018.04.006. Epub 2018 Apr 30.
PubMed 29715519Gaudilliere B, Fragiadakis GK, Bruggner RV, Nicolau M, Finck R, Tingle M, Silva J, Ganio EA, Yeh CG, Maloney WJ, Huddleston JI, Goodman SB, Davis MM, Bendall SC, Fantl WJ, Angst MS, Nolan GP. Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med. 2014 Sep 24;6(255):255ra131. doi: 10.1126/scitranslmed.3009701.
PubMed 25253674Geiger-Maor A, Levi I, Even-Ram S, Smith Y, Bowdish DM, Nussbaum G, Rachmilewitz J. Cells exposed to sublethal oxidative stress selectively attract monocytes/macrophages via scavenger receptors and MyD88-mediated signaling. J Immunol. 2012 Feb 1;188(3):1234-44. doi: 10.4049/jimmunol.1101740. Epub 2012 Jan 4.
PubMed 22219328Aghaeepour N, Kin C, Ganio EA, Jensen KP, Gaudilliere DK, Tingle M, Tsai A, Lancero HL, Choisy B, McNeil LS, Okada R, Shelton AA, Nolan GP, Angst MS, Gaudilliere BL. Deep Immune Profiling of an Arginine-Enriched Nutritional Intervention in Patients Undergoing Surgery. J Immunol. 2017 Sep 15;199(6):2171-2180. doi: 10.4049/jimmunol.1700421. Epub 2017 Aug 9.
PubMed 28794234Fragiadakis GK, Gaudilliere B, Ganio EA, Aghaeepour N, Tingle M, Nolan GP, Angst MS. Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery. Anesthesiology. 2015 Dec;123(6):1241-55. doi: 10.1097/ALN.0000000000000887.
PubMed 26655308Pereira JEG, El Dib R, Braz LG, Escudero J, Hayes J, Johnston BC. N-acetylcysteine use among patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized trials. PLoS One. 2019 May 9;14(5):e0213862. doi: 10.1371/journal.pone.0213862. eCollection 2019.
PubMed 31071081Kapstad H, Rokne B, Stavem K. Psychometric properties of the Brief Pain Inventory among patients with osteoarthritis undergoing total hip replacement surgery. Health Qual Life Outcomes. 2010 Dec 9;8:148. doi: 10.1186/1477-7525-8-148.
PubMed 21143926Baca Q, Marti F, Poblete B, Gaudilliere B, Aghaeepour N, Angst MS. Predicting Acute Pain After Surgery: A Multivariate Analysis. Ann Surg. 2021 Feb 1;273(2):289-298. doi: 10.1097/SLA.0000000000003400.
PubMed 31188202Aghaeepour N, Finak G; FlowCAP Consortium; DREAM Consortium; Hoos H, Mosmann TR, Brinkman R, Gottardo R, Scheuermann RH. Critical assessment of automated flow cytometry data analysis techniques. Nat Methods. 2013 Mar;10(3):228-38. doi: 10.1038/nmeth.2365. Epub 2013 Feb 10.
PubMed 23396282
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxidative Stress and Surgical Recovery
- ClinicalTrials.gov ID
- NCT04732000
- Acronym / sponsor ID
- 59401
- Conditions
- Surgical Recovery, Pain, Postoperative
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- 1 Jul 2021 (actual)
- Primary completion
- 1 Mar 2023 (actual)
- Study completion
- 1 Mar 2023 (actual)
- First posted
- 1 Feb 2021 (actual)
- Results
- Posted 30 Apr 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Chronic pain, functional impairment and slow rates of recovery are key issues for patients after surgery and trauma. No preventative strategy in current use unequivocally modifies these rates, and few novel approaches have been tested. Furthermore, persistent postsurgical pain is a major route to chronic opioid use, opioid use disorder and, regrettably, opioid overdose. Most strategies designed to limit chronic pain or enhance functional recovery after surgery are directed at modulating peripheral and central nervous system activity and do not strongly modify the underlying tissue pathophysiology or fundamental systemic responses. Strategies limiting oxidative stress in the perioperative period, on the other hand, might limit tissue damage, organ dysfunction and immune system activation.
N-acetyl cysteine (NAC) is an antioxidant well-studied in the perioperative period; it is very safe, relatively inexpensive and widely available. The central hypothesis is, therefore, that perioperative administration of NAC will reduce perioperative oxidative stress, limit immune system activation and improve key indices of surgical recovery. Although the planned work will not comprehensively address this hypothesis, it will identify the most useful tools and help the researchers estimate the required sample sizes for more definitive externally funded efforts.
Detailed description
This is a randomized, double-blind, placebo controlled interventional pilot study in 20 patients undergoing first-time total hip arthroplasty (THA) for chronic osteoarthritis at Stanford Medicine. The researchers will screen, enroll and collect biologic and behavioral data from 20 participants as outlined in previous observational and interventional clinical studies undertaken in close collaboration with the Department of Orthopedic Surgery. In particular, standard operating procedures for screening, recruiting, laboratory assessments, and clinical data collection are in place including eligibility screening via EPIC (EHR) ahead of patients' preoperative visit, coordinated recruitment and consenting during the pre-surgery visit including study- related laboratory work, further preoperative assessments after the visit (e.g. remote completion of questionnaires and direct import of results into REDCap), and real-time tracking of the data collection and storage process (e.g. including phone/email reminders if data are missing).
Repeated assessments of pain, physical function, and analgesic medication will be made before surgery, daily on postoperative days 1-3, and then twice a week in post-op weeks 1 - 6. Delirium will be measured days 1-3 while in-hospital. Additional data will include demographics (age, BMI, sex, race, and ethnicity), surgical/anesthesia data (e.g. duration), and medical/medication history.
Peripheral blood samples will be collected before surgery and 1hr and 24hr after surgery based on our prior study showing that monocyte activation (including STAT3, CREB and NFkB signaling responses in CD14+CD16- monocytes) early after surgery strongly correlates with delayed pain resolution and functional impairment. Exhaled breath samples will be collected intraoperatively prior to incision and at wound closure as well as at 1 and 24 hours after surgery.
N-Acetylcysteine infusion: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours. This is a standard dosing paradigm that is safe when used intraoperatively and rarely causes significant adverse effects (mainly allergic reactions).
Surgery and anesthesia: Participants will undergo unilateral hip arthroplasty performed by three surgeons using the same approach. The anesthetic and perioperative management of patients is standardized and follows ERAS-based recommendations.
Measures: Well-validated instruments will be used to assess pain, pain interference and function of the affected and operated joint including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) adapted for patients undergoing lower extremity joint surgery, the Brief Pain Inventory (BPI) and the Surgical Recovery Scale (SRS). Opioid consumption will be quantified as intravenous hydromorphone equivalents (milligram/day) using widely accepted opioid conversion tables.
Sample analysis: Blood and plasma will be collected and processed for analysis with mass cytometry as previously described. A 39-parameter human CyTOF antibody panel will be applied that will allow the simultaneous analysis of 1) all major immune cell phenotypes 2) endogenous intracellular signaling responses (including the pSTAT3, pCREB and pNF-kB signal) and 3) intracellular markers of reactive aldehydes (i.e. 4-HNE and MDA signal).
Breath samples will be analyzed for aldehydes including formaldehyde, crotenaldehyde, and benzaldehyde using mass spectroscopy in the laboratory of Dr. Gross.
Plasma samples will be analyzed for free MDA and 4- HNE in baseline, 1 and 24-hour plasma samples in the laboratory of Dr. Clark.
Analysis and modeling of outcome data: Self-reported outcomes will be analyzed using the validated models associated with each outcome to extract a quantified and normalized number associated with recovery. The 60Htz actigraphy data will first be mined for patterns associated with daily activities (e.g. step counts) and intensity levels. Next, a baseline will be established using the data collected during and prior to surgery, for each variable. All variables will be normalized to this baseline to account for patient-specific effects. Finally, a multivariate linear model (with days passed since surgery as the response variable) will be used to model the entire actigraphy dataset. The area under the respective recovery curve of each patient according to this model will be used as an objective recovery outcome. In our preliminary studies (data not shown) this outcome has been found to be correlated with several aspects of the immune system.
Analysis and modeling of CyTOF data: The large number of data points (millions of cells per patient) and measured variables (tens of signaling pathways in hundreds of cell types) pose unique computational challenges that cannot be addressed using traditional bioinformatics tools. The researchers will develop a Bayesian framework that will combine a priori knowledge of the immune system with state-of-the-art mass cytometry profiling to build a predictive model of innate and adaptive immune cell signaling responses for each of the recovery outcomes.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| N-acetyl cysteine | Active comparator | Drug: N-acetyl cysteineN-acetyl cysteine will be administered as follows: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours. |
| Normal Saline | Placebo comparator | Other: Normal SalineNormal will be administered as follows: A normal saline infusion will administered at a rate and duration to mimic the N-acetyl cysteine administration. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Over 18
- Male of female
- Planning to undergo primary total hip arthroplasty
- Fluent in English
- Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
Key exclusion criteria (11 listed)
- Infectious disease within the last month
- Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
- Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
- Major surgery within the last 3 months or minor surgery within the last month.
- History of substance abuse (e.g., alcoholism, drug dependency)
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 |
|---|---|---|
| N-acetyl cysteineAlso: NACIntravenous infusion started during the clinically indicated surgery at a rate of 50mg/kg over 1 hour followed by 50mg/kg over 3 hours. This will be an accumulated total of 100 mg/kg over 4 hours. | Drug | N-acetyl cysteine |
| Normal SalineAlso: NSIntravenous infusion at a time and rate to mimic the active treatment. The infusion will be given over 4 hours beginning during the clinically indicated surgery | Other | Normal Saline |
Primary outcome
Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells)
Time frame: Measurements will be made in samples collected before and 24 hours after surgery.
STAT3 phosphorylation in MDSC cells is measured in all MDSC cells before (T0) and one day after surgery (T1) using mass cytometry. The median phosphorylation in this cell population is then determined for each time point. The change in phosphorylation is expressed as the arc sinh ratio of these two medians (ratio = arc sinh [median pSTAT3-T1/median pSTAT3-T0]).
Brief Pain Inventory Pain Score
Time frame: post-operative week 6
The Brief Pain Inventory was used to measure pain and pain interference following surgery. BPI Pain Composite Score was derived from worst pain, least pain, average pain, and pain right now subscale scores. BPI Pain Interference Composite Score (representing how pain interferes with daily life) was derived from general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life subscale scores. Each composite score is the median value of the combined median values for each participant of the respective subscale scores (range for subscale and overall scores: 0 to 10, higher scores indicate more severe pain/pain interference).
1 secondary outcome
Pain Score
Time frame: Baseline through post-op day 1 (composite scores over 24 hours following surgery)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 30143334Kim DH, Pearson-Chauhan KM, McCarthy RJ, Buvanendran A. Predictive Factors for Developing Chronic Pain After Total Knee Arthroplasty. J Arthroplasty. 2018 Nov;33(11):3372-3378. doi: 10.1016/j.arth.2018.07.028. Epub 2018 Aug 4.
- Background: PubMed 25163478Zambelli VO, Gross ER, Chen CH, Gutierrez VP, Cury Y, Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain. Sci Transl Med. 2014 Aug 27;6(251):251ra118. doi: 10.1126/scitranslmed.3009539.
- Background: PubMed 29715519Guo TZ, Wei T, Huang TT, Kingery WS, Clark JD. Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain. 2018 Oct;19(10):1147-1156. doi: 10.1016/j.jpain.2018.04.006. Epub 2018 Apr 30.
- Background: PubMed 25253674Gaudilliere B, Fragiadakis GK, Bruggner RV, Nicolau M, Finck R, Tingle M, Silva J, Ganio EA, Yeh CG, Maloney WJ, Huddleston JI, Goodman SB, Davis MM, Bendall SC, Fantl WJ, Angst MS, Nolan GP. Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med. 2014 Sep 24;6(255):255ra131. doi: 10.1126/scitranslmed.3009701.
- Background: PubMed 22219328Geiger-Maor A, Levi I, Even-Ram S, Smith Y, Bowdish DM, Nussbaum G, Rachmilewitz J. Cells exposed to sublethal oxidative stress selectively attract monocytes/macrophages via scavenger receptors and MyD88-mediated signaling. J Immunol. 2012 Feb 1;188(3):1234-44. doi: 10.4049/jimmunol.1101740. Epub 2012 Jan 4.
- Background: PubMed 28794234Aghaeepour N, Kin C, Ganio EA, Jensen KP, Gaudilliere DK, Tingle M, Tsai A, Lancero HL, Choisy B, McNeil LS, Okada R, Shelton AA, Nolan GP, Angst MS, Gaudilliere BL. Deep Immune Profiling of an Arginine-Enriched Nutritional Intervention in Patients Undergoing Surgery. J Immunol. 2017 Sep 15;199(6):2171-2180. doi: 10.4049/jimmunol.1700421. Epub 2017 Aug 9.
- Background: PubMed 26655308Fragiadakis GK, Gaudilliere B, Ganio EA, Aghaeepour N, Tingle M, Nolan GP, Angst MS. Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery. Anesthesiology. 2015 Dec;123(6):1241-55. doi: 10.1097/ALN.0000000000000887.
- Background: PubMed 31071081Pereira JEG, El Dib R, Braz LG, Escudero J, Hayes J, Johnston BC. N-acetylcysteine use among patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized trials. PLoS One. 2019 May 9;14(5):e0213862. doi: 10.1371/journal.pone.0213862. eCollection 2019.
- Background: PubMed 21143926Kapstad H, Rokne B, Stavem K. Psychometric properties of the Brief Pain Inventory among patients with osteoarthritis undergoing total hip replacement surgery. Health Qual Life Outcomes. 2010 Dec 9;8:148. doi: 10.1186/1477-7525-8-148.
- Background: PubMed 31188202Baca Q, Marti F, Poblete B, Gaudilliere B, Aghaeepour N, Angst MS. Predicting Acute Pain After Surgery: A Multivariate Analysis. Ann Surg. 2021 Feb 1;273(2):289-298. doi: 10.1097/SLA.0000000000003400.
- Background: PubMed 23396282Aghaeepour N, Finak G; FlowCAP Consortium; DREAM Consortium; Hoos H, Mosmann TR, Brinkman R, Gottardo R, Scheuermann RH. Critical assessment of automated flow cytometry data analysis techniques. Nat Methods. 2013 Mar;10(3):228-38. doi: 10.1038/nmeth.2365. Epub 2013 Feb 10.
- Individual participant dataSharing planned: No
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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. This study is not recruiting at the moment.
Martin S Angst, MD principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing N-acetyl cysteine and Normal Saline in people with Surgical Recovery and Pain, Postoperative, run by Stanford University 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 5 inclusion and 11 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: finished, as of the sponsor's last update on 30 Apr 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Apr 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells) (time frame: Measurements will be made in samples collected before and 24 hours after surgery.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04732000, which also lists 11 linked publications.
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 30 Apr 2025.