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Determine the optimal dose of IV N-acetylcysteine (NAC) to produce opioid reduction following spine surgery and estimate the difference in opioid consumption between placebo and the selected optimal dose.
First 20 subjects: 5 participants will be randomized to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose.
If the dose response curve is adequate and the optimal dose identified, 15 additional participants will be randomized to placebo and 15 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (Total of 50 subjects with 20 from dose response curve and 30 to estimate the difference in opioid consumption.)
If the dose response curve is not adequate after the initial 20 subjects 5 per each dose group, then an additional 5 participants will be randomized and to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. Once the optimal dose is identified with these initial 40 patients, 10 additional participants will be randomized to placebo and 10 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (60 patients total with 40 to create the dose response curve and 20 more to estimate the difference in opioid consumption.)
A sample size of 20 subjects per group (placebo and optimal dose) allows us to estimate a 95% confidence interval for the mean difference in opioid consumption with a width of + 0.64 standard deviations from the mean. 70 subjects may be enrolled to account for withdrawal but the study will be completed once 50 or 60 subjects (based on the number of subjects required to create the dose response curve) have completed the protocol.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose Response Curve Placebo | Placebo Comparator | 5 participants will be randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. |
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| Dose Response Curve N-acetylcysteine 50 mg/kg | Active Comparator | 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
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| Dose Response Curve N-acetylcysteine 100 mg/kg | Active Comparator | 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
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| Dose Response Curve N-acetylcysteine 150 mg/kg | Active Comparator | 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
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| Opioid Reduction with Optimal N-acetylcysteine Dose | Active Comparator | Once the optimal N-acetylcysteine dose is identified, 15 additional participants will be randomized to the optimal dose to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose. Primary and secondary outcomes will only be evaluated for the placebo group and optimal NAC group. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dose Response Curve Placebo | Drug | 5 participants will be randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. |
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| Measure | Description | Time Frame |
|---|---|---|
| Opioid Consumption 12 Hours Post Operative | Post operative opioid consumption in the 12 hours that occur post-operatively. | 12 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Opioid Consumption Every 6 Hours Post Operative | Post operative opioid consumption ry 6 hours post operative. Data are reported as mean (95% CI) or mean difference (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sylvia Wilson, MD | Medical University of South Carolina | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University of South Carolina | Charleston | South Carolina | 29425 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19066381 | Background | Hall AJ, Logan JE, Toblin RL, Kaplan JA, Kraner JC, Bixler D, Crosby AE, Paulozzi LJ. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008 Dec 10;300(22):2613-20. doi: 10.1001/jama.2008.802. | |
| 27281491 | Background | Pieralisi A, Martini C, Soto D, Vila MC, Calvo JC, Guerra LN. N-acetylcysteine inhibits lipid accumulation in mouse embryonic adipocytes. Redox Biol. 2016 Oct;9:39-44. doi: 10.1016/j.redox.2016.05.006. Epub 2016 May 27. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Period 1: NAC (0mg/kg) | (n=5) 5 participants randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. |
| FG001 | Period 1: NAC (50mg/kg) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 8, 2022 | Nov 18, 2022 |
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PHASE I. First 20 subjects (4 arms): We will initially randomize 5 patients to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. After enrollment of the first 20 patients, the study will undergo review by the study team and statistician.
PHASE II: (2 arms) If the dose response curve is adequate and the optimal dose identified, 15 additional participants will be randomized to placebo and 15 to the optimal dose to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose.
Primary and secondary outcomes will be evaluated only for the placebo and optimal NAC groups.
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| Placebo | Placebo Comparator | 15 Participants will be randomized to placebo to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose. Primary and secondary outcomes will only be evaluated for the placebo group and optimal NAC group. |
|
| Dose Response Curve N-acetylcysteine 50 mg/kg | Drug | 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
|
| Dose Response Curve N-acetylcysteine 100 mg/kg | Drug | 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
|
| Dose Response Curve N-acetylcysteine 150 mg/kg | Drug | 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
|
| Opioid Reduction with Optimal N-acetylcysteine Dose | Drug | Once the optimal N-acetylcysteinedose is identified, 15 participants will be randomized to the optimal dose (50,100, or 150 mg/kg) to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo. |
|
| Placebo | Drug | 15 Participants will be randomized to placebo to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo. |
|
| 6-48 hours |
| 1284756 | Background | Heim MU, Alraun K, Leeping M, Schwarzfischer G, Bock M, Kling A, Mempel W. [Incidence of the detection of erythrocyte antibodies in relation to screening test cells]. Beitr Infusionsther. 1992;30:443-5. German. |
| 23382863 | Background | Guo F, Li Y, Wang J, Li Y, Li Y, Li G. Stanniocalcin1 (STC1) Inhibits Cell Proliferation and Invasion of Cervical Cancer Cells. PLoS One. 2013;8(1):e53989. doi: 10.1371/journal.pone.0053989. Epub 2013 Jan 29. |
| 24683506 | Background | Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav. 2014 Mar;4(2):108-22. doi: 10.1002/brb3.208. Epub 2014 Jan 13. |
| 30551603 | Background | Tardiolo G, Bramanti P, Mazzon E. Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases. Molecules. 2018 Dec 13;23(12):3305. doi: 10.3390/molecules23123305. |
| 31206613 | Background | Monti DA, Zabrecky G, Kremens D, Liang TW, Wintering NA, Bazzan AJ, Zhong L, Bowens BK, Chervoneva I, Intenzo C, Newberg AB. N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease. Clin Pharmacol Ther. 2019 Oct;106(4):884-890. doi: 10.1002/cpt.1548. Epub 2019 Jul 17. |
| 27309537 | Background | Monti DA, Zabrecky G, Kremens D, Liang TW, Wintering NA, Cai J, Wei X, Bazzan AJ, Zhong L, Bowen B, Intenzo CM, Iacovitti L, Newberg AB. N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data. PLoS One. 2016 Jun 16;11(6):e0157602. doi: 10.1371/journal.pone.0157602. eCollection 2016. |
| 23860343 | Background | Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Oz G, Cloyd JC, Tuite PJ. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013 Jul-Aug;36(4):103-6. doi: 10.1097/WNF.0b013e31829ae713. |
| 28940353 | Background | Coles LD, Tuite PJ, Oz G, Mishra UR, Kartha RV, Sullivan KM, Cloyd JC, Terpstra M. Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress. J Clin Pharmacol. 2018 Feb;58(2):158-167. doi: 10.1002/jcph.1008. Epub 2017 Sep 22. |
| 31679408 | Background | Halboub E, Alkadasi B, Alakhali M, AlKhairat A, Mdabesh H, Alkahsah S, Abdulrab S. N-acetylcysteine versus chlorhexidine in treatment of aphthous ulcers: a preliminary clinical trial. J Dermatolog Treat. 2021 Sep;32(6):649-653. doi: 10.1080/09546634.2019.1688231. Epub 2019 Nov 21. |
| 27075430 | Background | Li J, Xu L, Deng X, Jiang C, Pan C, Chen L, Han Y, Dai W, Hu L, Zhang G, Cheng Z, Liu W. N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases. Pain. 2016 Aug;157(8):1711-1723. doi: 10.1097/j.pain.0000000000000575. |
| 32009537 | Background | Notartomaso S, Scarselli P, Mascio G, Liberatore F, Mazzon E, Mammana S, Gugliandolo A, Cruccu G, Bruno V, Nicoletti F, Battaglia G. N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy. Mol Pain. 2020 Jan-Dec;16:1744806920904292. doi: 10.1177/1744806920904292. |
| 28499416 | Background | Dludla PV, Nkambule BB, Dias SC, Johnson R. Cardioprotective potential of N-acetyl cysteine against hyperglycaemia-induced oxidative damage: a protocol for a systematic review. Syst Rev. 2017 May 12;6(1):96. doi: 10.1186/s13643-017-0493-8. |
| 28886718 | Background | Hoffer BJ, Pick CG, Hoffer ME, Becker RE, Chiang YH, Greig NH. Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine. J Biomed Sci. 2017 Sep 9;24(1):71. doi: 10.1186/s12929-017-0377-1. |
| 2887913 | Background | Howard RJ, Blake DR, Pall H, Williams A, Green ID. Allopurinol/N-acetylcysteine for carbon monoxide poisoning. Lancet. 1987 Sep 12;2(8559):628-9. doi: 10.1016/s0140-6736(87)93018-2. No abstract available. |
| 31381364 | Background | Hamamsy ME, Bondok R, Shaheen S, Eladly GH. Safety and efficacy of adding intravenous N-acetylcysteine to parenteral L-alanyl-L-glutamine in hospitalized patients undergoing surgery of the colon: a randomized controlled trial. Ann Saudi Med. 2019 Jul-Aug;39(4):251-257. doi: 10.5144/0256-4947.2019.251. Epub 2019 Aug 5. |
| 28980294 | Background | Soleimani A, Habibi MR, Hasanzadeh Kiabi F, Alipour A, Habibi V, Azizi S, Emami Zeydi A, Sohrabi FB. The effect of intravenous N-acetylcysteine on prevention of atrial fibrillation after coronary artery bypass graft surgery: a double-blind, randomised, placebo-controlled trial. Kardiol Pol. 2018;76(1):99-106. doi: 10.5603/KP.a2017.0183. Epub 2017 Oct 5. |
| 28643376 | Background | Sins JWR, Fijnvandraat K, Rijneveld AW, Boom MB, Kerkhoffs JH, van Meurs AH, de Groot MR, Heijboer H, Dresse MF, Le PQ, Hermans P, Vanderfaeillie A, Van Den Neste EW, Benghiat FS, Kesse-Adu R, Delannoy A, Efira A, Azerad MA, de Borgie CA, Biemond BJ. Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. Br J Haematol. 2018 Aug;182(3):444-448. doi: 10.1111/bjh.14809. Epub 2017 Jun 23. No abstract available. |
| 31819599 | Background | Heidari N, Sajedi F, Mohammadi Y, Mirjalili M, Mehrpooya M. Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy. J Pain Res. 2019 Nov 19;12:3147-3159. doi: 10.2147/JPR.S228255. eCollection 2019. |
| 15795719 | Background | Kerr F, Dawson A, Whyte IM, Buckley N, Murray L, Graudins A, Chan B, Trudinger B. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005 Apr;45(4):402-8. doi: 10.1016/j.annemergmed.2004.08.040. |
| 12802041 | Background | Yip L, Dart RC. A 20-hour treatment for acute acetaminophen overdose. N Engl J Med. 2003 Jun 12;348(24):2471-2. doi: 10.1056/NEJM200306123482422. No abstract available. |
| 37877260 | Derived | Wilson SH, Sirianni JM, Bridges KH, Wolf BJ, Valente IE, Scofield MD. The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: a randomized pilot trial. Pain Manag. 2023 Oct;13(10):593-602. doi: 10.2217/pmt-2023-0061. Epub 2023 Oct 25. |
(n=5) 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose.
| FG002 | Period 1: NAC (100mg/kg) | (n=5) 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
| FG003 | Period 1: NAC (150mg/kg) | (n=5) 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
| FG004 | Period 2: NAC (0mg/kg) | (n=15) 15 additional participants randomized to placebo |
| FG005 | Period 2: NAC (150mg/kg) | (n=15) Since optimal not identified with dose response curve, 15 more subjects enrolled in 150 mg/kg group for final comparison with placebo. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | NAC (0mg/kg) | (n=20) 5 participants randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. Then 15 more patients enrolled for final comparison versus optimal dose. |
| BG001 | NAC (50mg/kg) | (n=5) 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
| BG002 | NAC (100mg/kg) | (n=5) 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. |
| BG003 | NAC (150mg/kg) | (n=20) 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. Since optimal not identified with dose response curve, 15 more subjects enrolled in 150 mg/kg group for final comparison with placebo. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Home opioid use (yes) | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Opioid Consumption 12 Hours Post Operative | Post operative opioid consumption in the 12 hours that occur post-operatively. | Primary and secondary outcomes were only be evaluated for the placebo and optimal NAC groups. Data are reported as mean (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect. | Posted | Mean | 95% Confidence Interval | IV morphine mg equivalents | 12 hours |
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| Secondary | Opioid Consumption Every 6 Hours Post Operative | Post operative opioid consumption ry 6 hours post operative. Data are reported as mean (95% CI) or mean difference (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect. | Primary and secondary outcomes were only be evaluated for the placebo and optimal NAC groups. Data are reported as mean (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect. | Posted | Mean | 95% Confidence Interval | IV morphine mg equivalents | 6-48 hours |
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48 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | N-acetylcysteine (NAC) 0 mg/kg | 0 | 20 | 0 | 20 | 0 | 20 |
| EG001 | NAC 50 mg/kg | N-acetylcysteine (NAC) 50 mg/kg | 0 | 5 | 0 | 5 | 0 | 5 |
| EG002 | NAC 100 mg/kg | N-acetylcysteine (NAC) 100 mg/kg | 0 | 5 | 0 | 5 | 0 | 5 |
| EG003 | NAC 150 mg/kg | N-acetylcysteine (NAC) 150 mg/kg | 0 | 20 | 0 | 20 | 0 | 20 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Sylvia Wilson | Medical University of South Carolina | 843-792-2322 | wilsosh@musc.edu |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 1, 2020 | Nov 18, 2022 | SAP_001.pdf |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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