NAC Treatment and Outcomes in Patients With Advanced Atherosclerosis and DM

NCT05908513 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 2072662
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

Atherosclerosis and diabetes are related to coronary artery disease and peripheral artery disease. The mechanisms are related to increased reactive oxygen species (ROS) formation and inflammatory cytokine secretion. However, simply using antioxidant or anti-inflammatory therapies has no optimal outcomes. On the other hand, N-acetylcysteine (NAC) which has both antioxidant and anti-inflammatory effects could effectively attenuate ROS production and reduce vascular inflammation. Hence, we will investigate the effect of NAC treatment on the outcomes in patients with advanced atherosclerotic heart diseases and patients with diabetes combined with significant peripheral artery disease.

Conditions

Atherosclerosis of Artery; Peripheral Artery Disease; Diabetes Mellitus; Inflammation; Oxidative Stress

Keywords

Atherosclerosis, ROS, Inflammation, Diabetes

Outcome Measures

Primary Outcomes (4)

• Change of blood pressure over time points

  Diastolic and systolic blood pressure

  baseline, 3 months, 6 months, and 12 months

• Change of biomarkers over time points

  Blood samples (5ml) will be taken for biomarkers analysis (complete blood cell count \[CBC\], biochemistry, Thyroid stimulating hormone \[TSH\], renal function, C-reactive protein \[CRP\], IL-1β, IL-6, TNF-α, and lipids profiles).

  baseline, 3 months, 6 months, and 12 months

• Change of heart rate over time points

  Number of beats per minute

  1 baseline, 3 months, 6 months, and 12 months

• Change of body weight over time points

  Measured in kg

  baseline, 3 months, 6 months, and 12 months

Study Arms (2)

NAC treatment

ACTIVE COMPARATOR

N-acetylcysteine capsule, 600mg/day, oral, 5 years

Drug: N-acetylcysteine

Placebo

PLACEBO COMPARATOR

Similar chemical structure of NAC but without function

Drug: Placebo

Interventions

N-acetylcysteine DRUG

Will be used as capsule form, 600mg per day if the patient can tolerate it. If not, we may decrease the dosage.

Also known as: Acetadote

NAC treatment

Placebo DRUG

Similar chemical structure of NAC but without function

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \) significant coronary artery disease (CAD) and not a candidate for revascularization (CABG or PCI), or 2) significant peripheral artery disease (PAD) with or without critical limb ischemia (CLI) or chronic ulcers.

You may not qualify if:

• \) Pregnant or nursing (lactating) women, confirmed by a positive hCG laboratory test 2). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are a. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone or partial or total hysterectomy, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• ). Planned coronary revascularization (PCI or CABG) or any other major surgical procedure.
• ). Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior to the initial visit (Visit 1) 5). Multi-vessel CABG surgery within the past 3 years 6). Symptomatic patients with Class IV heart failure (HF) (New York Heart Association).
• ). Uncontrolled hypertension (defined as an average SBP \>180 mmHg or an average diastolic blood pressure (DBP) \>110 mmHg at Visit 1. Patients are allowed to be re-evaluated, at the discretion of investigator for this criterion if anti-hypertensive therapy has been started or increased as a result of initial screening blood pressure above these limits.
• ). Uncontrolled diabetes with persistent fasting blood glucose level of 300 or A1C of 7.5 for 3 months or defined by the investigator 9). Kidney or other organ transplant (due to anti-immune therapy) at Visit 1 10). Prior malignancy other than basal cell skin carcinoma. 11). A history of alcohol and/or substance abuse that could interfere with the conduct of the trial.
• ). History of ongoing, chronic or recurrent infectious disease except hepatitis.
• ). History of hypersensitivity to NAC. 14). Patients who have received an investigational drug or device within 30 days (inclusive) of Visit 1, or who are expected to participate in any other investigational drug or device study during the conduct of this trial, except for patients who have an investigational drug eluting stent (DES), provided that they have completed the DES trial. FDA/country-specific drug regulatory authority approved DES devices are permitted.
• ). Any life threatening condition with life expectancy \< 3 years, other than vascular disease that might prevent the patient from completing the study.

Sponsors & Collaborators

• University of Missouri-Columbia: lead
• Shandong Provincial Hospital: collaborator
• Central South University: collaborator

Study Sites (2)

The Second Xiangya Hospital of Central South University

Changsha, Hunan, 410011, China

Location

Shandong Provincial Hospital

Jinan, Shandong, 250021, China

Location

Related Publications (21)

• Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596. doi: 10.1161/CIR.0000000000000757. Epub 2020 Jan 29.

  PMID: 31992061 BACKGROUND

• Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007 Feb 28;297(8):842-57. doi: 10.1001/jama.297.8.842.

  PMID: 17327526 BACKGROUND

• Thompson PL, Nidorf SM. Colchicine: an affordable anti-inflammatory agent for atherosclerosis. Curr Opin Lipidol. 2018 Dec;29(6):467-473. doi: 10.1097/MOL.0000000000000552.

  PMID: 30320614 BACKGROUND

• Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.

  PMID: 28845751 BACKGROUND

• Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL; LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847. doi: 10.1056/NEJMoa2021372. Epub 2020 Aug 31.

  PMID: 32865380 BACKGROUND

• Salamon S, Kramar B, Marolt TP, Poljsak B, Milisav I. Medical and Dietary Uses of N-Acetylcysteine. Antioxidants (Basel). 2019 Apr 28;8(5):111. doi: 10.3390/antiox8050111.

  PMID: 31035402 BACKGROUND

• Voghel G, Thorin-Trescases N, Farhat N, Mamarbachi AM, Villeneuve L, Fortier A, Perrault LP, Carrier M, Thorin E. Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients. Mech Ageing Dev. 2008 May;129(5):261-70. doi: 10.1016/j.mad.2008.01.004. Epub 2008 Jan 20.

  PMID: 18302967 BACKGROUND

• Sung HJ, Kim J, Kim Y, Jang SW, Ko J. N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression. Mol Biol Rep. 2012 Mar;39(3):3001-7. doi: 10.1007/s11033-011-1062-1. Epub 2011 Jun 17.

  PMID: 21681422 BACKGROUND

• Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Apr 2;127(13):1425-43. doi: 10.1161/CIR.0b013e31828b82aa. Epub 2013 Mar 1. No abstract available.

  PMID: 23457117 BACKGROUND

• Hoffstad O, Mitra N, Walsh J, Margolis DJ. Diabetes, lower-extremity amputation, and death. Diabetes Care. 2015 Oct;38(10):1852-7. doi: 10.2337/dc15-0536. Epub 2015 Jul 22.

  PMID: 26203063 BACKGROUND

• Geiss LS, Li Y, Hora I, Albright A, Rolka D, Gregg EW. Resurgence of Diabetes-Related Nontraumatic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. Diabetes Care. 2019 Jan;42(1):50-54. doi: 10.2337/dc18-1380. Epub 2018 Nov 8.

  PMID: 30409811 BACKGROUND

• Malik RA, Tesfaye S, Ziegler D. Medical strategies to reduce amputation in patients with type 2 diabetes. Diabet Med. 2013 Aug;30(8):893-900. doi: 10.1111/dme.12169.

  PMID: 23445087 BACKGROUND

• Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1126-35. doi: 10.1161/ATVBAHA.114.303090. Epub 2014 Mar 27.

  PMID: 24675660 BACKGROUND

• Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ Res. 2018 Mar 16;122(6):877-902. doi: 10.1161/CIRCRESAHA.117.311401.

  PMID: 29700084 BACKGROUND

• Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545.

  PMID: 21030723 BACKGROUND

• Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol. 2011 Mar;7(3):176-84. doi: 10.1038/nrendo.2010.212. Epub 2010 Dec 14.

  PMID: 21151200 BACKGROUND

• Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev. 2011 Sep;7(5):291-304. doi: 10.2174/157339911797415620.

  PMID: 21916837 BACKGROUND

• Frey RS, Ushio-Fukai M, Malik AB. NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal. 2009 Apr;11(4):791-810. doi: 10.1089/ars.2008.2220.

  PMID: 18783313 BACKGROUND

• Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 2018 Jan;100:1-19. doi: 10.1016/j.vph.2017.05.005. Epub 2017 Jun 1.

  PMID: 28579545 BACKGROUND

• Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol. 2015 Aug;89(8):1209-26. doi: 10.1007/s00204-015-1520-y. Epub 2015 Jun 6.

  PMID: 26047665 BACKGROUND

• Kunkemoeller B, Kyriakides TR. Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition. Antioxid Redox Signal. 2017 Oct 20;27(12):823-838. doi: 10.1089/ars.2017.7263. Epub 2017 Aug 10.

  PMID: 28699352 BACKGROUND

MeSH Terms

Conditions

Peripheral Arterial Disease; Diabetes Mellitus; Inflammation; Atherosclerosis

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: We will use double blind for this study. Neither the participants nor the researcher knows which treatment or intervention participants are receiving until the clinical trial is over.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 4, 2021
• First Posted: June 18, 2023
• Study Start: October 15, 2021
• Primary Completion: October 15, 2021
• Study Completion: October 15, 2021
• Last Updated: June 18, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (2)