Inflammation Reduction by TREhalose AdminisTration

NCT03700424 | Unknown Phase 2

• 1 other identifier: 964334
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Acute Coronary Syndrome

Keywords

Acute Coronary Syndrome; Trehalose; Arterial inflammation; Autophagy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Carotid intima-media thickness (cIMT)

  At the beginning and end of the intervention trial (Day 0 and week 12)

• Measuring beclin-1 to assess autophagy activation

  At the beginning and end of the intervention trial (Day 0 and week 12)

• 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)

• Measuring complete blood count (CBC) (Safety)

  At the beginning and end of the intervention trial (Day 0 and week 12)

• Assessing lipid profile (Safety)

  At the beginning and end of the intervention trial (Day 0 and week 12)

Study Arms (2)

Trehalose

EXPERIMENTAL

Participants will be received intravenous trehalose infusion weekly (15 g/week) for a period of 12 weeks

Drug: Trehalose

Placebo

PLACEBO COMPARATOR

Participants will be received equal volume of normal saline weekly for a period of 12 weeks

Drug: Normal saline

Interventions

Trehalose DRUG

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.

Also known as: Mycose

Trehalose

Normal saline DRUG

A solution of 0.90% w/v of sodium chloride (NaCl) in water

Also known as: Physiological saline, Isotonic saline

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mashhad University of Medical Sciences: lead

Study Sites (1)

Ghaem Educational, Research and Treatment Center

Mashhad, Razavi Khorasan Province, 9919991766, Iran

RECRUITING

Related Publications (14)

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

  PMID: 22895665 BACKGROUND

• 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. No abstract available.

  PMID: 29325641 BACKGROUND

• 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.

  PMID: 22445600 BACKGROUND

• 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.

  PMID: 23401644 BACKGROUND

• 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.

  PMID: 26750103 BACKGROUND

• Iwatsuka R, Matsue Y, Yonetsu T, O'uchi T, Matsumura A, Hashimoto Y, Hirao K. Arterial inflammation measured by 18F-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.

  PMID: 29175654 BACKGROUND

• 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.

  PMID: 26841377 BACKGROUND

• 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.

  PMID: 19443587 BACKGROUND

• 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. doi: 10.1242/jeb.01133.

  PMID: 15299033 BACKGROUND

• 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.

  PMID: 23851366 BACKGROUND

• 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.

  PMID: 26905424 BACKGROUND

• 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.

  PMID: 28589926 BACKGROUND

• 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.

  PMID: 27496857 BACKGROUND

• 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 18F-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.

  PMID: 27639759 BACKGROUND

MeSH Terms

Conditions

Acute Coronary Syndrome; Arteritis

Interventions

Trehalose; Saline Solution; Sodium Chloride

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Vasculitis

Intervention Hierarchy (Ancestors)

Glucans; Polysaccharides; Carbohydrates; Disaccharides; Oligosaccharides; Sugars; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Central Study Contacts

Amirhossien Sahebkar, PharmD, PhD

CONTACT

+985138002299; SahebkarA@mums.ac.ir

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study will be performed double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor at Mashhad University of Medical Sciences

Study Record Dates

• First Submitted: October 3, 2018
• First Posted: October 9, 2018
• Study Start: August 20, 2020
• Primary Completion: May 20, 2022
• Study Completion: August 1, 2022
• Last Updated: September 21, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

IR (1)