Inflammation Reduction by TREhalose AdminisTration

Acute Coronary Syndrome Clinical Trial

— IR-TREAT  

Official title:

The Use of Intravenous Trehalose to Reduce Vascular Inflammation in Acute Coronary Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03700424
• Other study ID #: 964334
• Status: Recruiting
• Phase: Phase 2
• Start date: August 20, 2020
• Est. completion date: August 2022

Study information

• Verified date: September 2020
• Source: Mashhad University of Medical Sciences
• Contact: Amirhossien Sahebkar, PharmD, PhD
• Phone: +985138002299
• Email: SahebkarA[@]mums.ac.ir
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Arterial wall inflammation has been consistently suggested to serve a causal role in promoting atherosclerosis and predisposing to hard cardiovascular outcomes. Therefore, there is a global trend in the pharmaceutical industry to develop safe and effective anti-inflammatory agents that could lessen arterial wall inflammation and prevent its detrimental impact on atheroma growth and instability. To this end, autophagy has emerged as a key regulator of inflammation and dysfunctional autophagy machinery has been consistently reported as a contributing factor to atherosclerosis and inflammation. Trehalose, a natural disaccharide sugar found extensively among miscellaneous organisms, by preventing protein denaturation plays various protective roles against stress conditions. Numerous studies indicated trehalose's ability to induce macrophage autophagy-lysosomal biogenesis and reduce inflammation. Also, intravenous (IV) administration of trehalose showed beneficial effects in the reversal of atherosclerosis in atherosclerotic animals. Therefore, in this study, the investigators will explore the potential efficacy of IV trehalose administration on arterial inflammation by employing an positron emission tomography (PET) with 18F-labeled fluoro-2-deoxyglucose (18F-FDG) and computed tomography (18F-FDG PET/CT) technique which noninvasively characterizes vascular inflammation and atherosclerosis.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: August 2022
• Est. primary completion date: May 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Men and women aged between 18-55 years

• Having a history of acute coronary syndrome

• Having a baseline high-sensitivity C-reactive protein (hs-CRP) of = 2mg/L

• Willingness to participate in the trials.

Exclusion Criteria:

• Lactation or breastfeeding

• Diabetes mellitus

• Nephrotic syndrome or Estimated Glomerular Filtration Rate (eGFR) < 30/mL/min/1.73m2

• Active or recurrent hepatic disease or/and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (ALT/AST) of > 3 times upper normal limit or total bilirubin of > 2 times upper normal limit

• Active infectious or febrile disease

• Any type of malignancy

• History of transplantation

• Consumption of immunosuppressive drugs.

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Inflammation
• Syndrome

Intervention

Drug:
• Trehalose
Trehalose is a natural disaccharide sugar found extensively among miscellaneous organisms including bacteria, plants, insects, yeast, fungi, and invertebrates. By preventing protein denaturation, it plays various protective roles against stress conditions such as heat, freeze, oxidation, desiccation and dehydration. Owing to this capacity, trehalose is an FDA-approved pharmaceutical excipient that is used as a stabilizer in numerous medicines including parenteral products. In this study, all injections will be conducted by a trained nurse in the presence of a specialist physician at a duration of 45-90 minutes.
• Normal saline
A solution of 0.90% w/v of sodium chloride (NaCl) in water

Locations

Country	Name	City	State
Iran, Islamic Republic of	Ghaem Educational, Research and Treatment Center	Mashhad	Razavi Khorasan

Sponsors (1)

Lead Sponsor	Collaborator
Mashhad University of Medical Sciences

Country where clinical trial is conducted

Iran, Islamic Republic of, 

References & Publications (14)

Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court FA, van Zundert B, Hetz C. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013 Sep;9(9):1308-20. doi: 10.4161/auto.25188. Epub 2013 Jun 6. — View Citation

Chen Q, Haddad GG. Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J Exp Biol. 2004 Aug;207(Pt 18):3125-9. Review. — View Citation

Chrapko BE, Chrapko M, Nocun A, Stefaniak B, Zubilewicz T, Drop A. Role of 18F-FDG PET/CT in the diagnosis of inflammatory and infectious vascular disease. Nucl Med Rev Cent East Eur. 2016;19(1):28-36. doi: 10.5603/NMR.2016.0006. — View Citation

Iwatsuka R, Matsue Y, Yonetsu T, O'uchi T, Matsumura A, Hashimoto Y, Hirao K. Arterial inflammation measured by (18)F-FDG-PET-CT to predict coronary events in older subjects. Atherosclerosis. 2018 Jan;268:49-54. doi: 10.1016/j.atherosclerosis.2017.11.016. Epub 2017 Nov 21. — View Citation

Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 2012 Apr 4;15(4):545-53. doi: 10.1016/j.cmet.2012.01.022. Epub 2012 Mar 22. — View Citation

Libby P, Hansson GK. Taming Immune and Inflammatory Responses to Treat Atherosclerosis. J Am Coll Cardiol. 2018 Jan 16;71(2):173-176. doi: 10.1016/j.jacc.2017.10.081. — View Citation

Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2045-51. doi: 10.1161/ATVBAHA.108.179705. Review. — View Citation

Maiuri MC, Grassia G, Platt AM, Carnuccio R, Ialenti A, Maffia P. Macrophage autophagy in atherosclerosis. Mediators Inflamm. 2013;2013:584715. doi: 10.1155/2013/584715. Epub 2013 Jan 21. Review. — View Citation

Mardones P, Rubinsztein DC, Hetz C. Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport. Sci Signal. 2016 Feb 23;9(416):fs2. doi: 10.1126/scisignal.aaf1937. Review. — View Citation

Menezes LJ, Kotze CW, Hutton BF, Endozo R, Dickson JC, Cullum I, Yusuf SW, Ell PJ, Groves AM. Vascular inflammation imaging with 18F-FDG PET/CT: when to image? J Nucl Med. 2009 Jun;50(6):854-7. doi: 10.2967/jnumed.108.061432. Epub 2009 May 14. — View Citation

Sergin I, Evans TD, Zhang X, Bhattacharya S, Stokes CJ, Song E, Ali S, Dehestani B, Holloway KB, Micevych PS, Javaheri A, Crowley JR, Ballabio A, Schilling JD, Epelman S, Weihl CC, Diwan A, Fan D, Zayed MA, Razani B. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nat Commun. 2017 Jun 7;8:15750. doi: 10.1038/ncomms15750. — View Citation

Shao BZ, Han BZ, Zeng YX, Su DF, Liu C. The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin. 2016 Feb;37(2):150-6. doi: 10.1038/aps.2015.87. Epub 2016 Jan 11. Review. — View Citation

van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LA, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ES. Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation. 2016 Aug 23;134(8):611-24. doi: 10.1161/CIRCULATIONAHA.116.020838. Epub 2016 Aug 5. — View Citation

van der Valk FM, Verweij SL, Zwinderman KA, Strang AC, Kaiser Y, Marquering HA, Nederveen AJ, Stroes ES, Verberne HJ, Rudd JH. Thresholds for Arterial Wall Inflammation Quantified by (18)F-FDG PET Imaging: Implications for Vascular Interventional Studies. JACC Cardiovasc Imaging. 2016 Oct;9(10):1198-1207. doi: 10.1016/j.jcmg.2016.04.007. Epub 2016 Sep 14. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Arterial wall inflammation in the aorta and carotid arteries	This will be assessed using the 18F-FDG PET/CT imaging technique	At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Carotid intima-media thickness (cIMT)	This will be assessed using doppler sonography	At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring beclin-1 to assess autophagy activation		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring high-sensitivity C-reactive protein (hs-CRP) to assess systemic inflammation		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring complete blood count (CBC) (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Assessing lipid profile (Safety)	Including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)	At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Assessing glucose (Safety)	Fasting blood glucose (FBS)	At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring thyroid-stimulating hormone (TSH) to assess thyroid function (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (Bil) to assess liver function (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring creatinine (Cr), urine (Ur) and blood urea nitrogen (BUN) to assess renal function (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Evaluating electrocardiogram (ECG) and heart rhythm to assess heart function (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)
Secondary	Measuring creatinine phosphokinase (CPK) to detect muscle damage (Safety)		At the beginning and end of the intervention trial (Day 0 and week 12)