A Pilot Trial to Determine the Effective N-acetylcysteine Dose for Opioid Reduction for Spine Surgery.

NCT04562597 | Completed Phase 1 Results FDA Drug

• 1 other identifier: Pro00099062
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Surgery

Outcome Measures

Primary Outcomes (1)

• Opioid Consumption 12 Hours Post Operative

  Post operative opioid consumption in the 12 hours that occur post-operatively.

  12 hours

Secondary Outcomes (1)

• Opioid Consumption Every 6 Hours Post Operative

  6-48 hours

Study Arms (6)

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.

Drug: Dose Response Curve Placebo

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.

Drug: Dose Response Curve N-acetylcysteine 50 mg/kg

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.

Drug: Dose Response Curve N-acetylcysteine 100 mg/kg

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.

Drug: Dose Response Curve N-acetylcysteine 150 mg/kg

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.

Drug: Opioid Reduction with Optimal N-acetylcysteine Dose

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.

Drug: Placebo

Interventions

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.

Dose Response Curve Placebo

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 50 mg/kg

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 100 mg/kg

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.

Dose Response Curve N-acetylcysteine 150 mg/kg

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.

Opioid Reduction with Optimal N-acetylcysteine Dose

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Undergoing elective spine surgery involving 4 levels or less of the thoracic, lumbar, or sacral spine.
• years of age and older.

You may not qualify if:

• Less than 40kg in weight.
• Unable to provide written, informed consent.
• History of an adverse or anaphylactoid reaction to acetylcysteine.
• Active asthma, wheezing, or using inhaled bronchodilators.
• Pregnant Women
• Known blood clotting deficiency

Sponsors & Collaborators

• Medical University of South Carolina: lead

Study Sites (1)

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Related Publications (23)

• 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.

  PMID: 19066381 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.

  PMID: 27281491 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.

  PMID: 1284756 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.

  PMID: 23382863 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.

  PMID: 24683506 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.

  PMID: 30551603 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.

  PMID: 31206613 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.

  PMID: 27309537 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.

  PMID: 23860343 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.

  PMID: 28940353 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.

  PMID: 31679408 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.

  PMID: 27075430 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.

  PMID: 32009537 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.

  PMID: 28499416 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.

  PMID: 28886718 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.

  PMID: 2887913 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.

  PMID: 31381364 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.

  PMID: 28980294 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.

  PMID: 28643376 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.

  PMID: 31819599 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.

  PMID: 15795719 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.

  PMID: 12802041 BACKGROUND

• 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.

  PMID: 37877260 DERIVED

Limitations and Caveats

* Opioid consumption was highly variable. This is likely due to the small sample size. * Data only collected up to 48 hours postoperative, and this limits our ability to comment more on the usefulness of NAC as an agent for patients with chronic pain.

Results Point of Contact

• Title: Dr. Sylvia Wilson
• Organization: Medical University of South Carolina

wilsosh@musc.edu

843-792-2322

Study Officials

• Sylvia Wilson, MD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: September 10, 2020
• First Posted: September 24, 2020
• Study Start: January 20, 2021
• Primary Completion: May 20, 2022
• Study Completion: May 21, 2022
• Last Updated: February 14, 2023
• Results First Posted: February 14, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)