Accepted for/Published in: JMIR Research Protocols
Date Submitted: Apr 18, 2020
Date Accepted: Jul 7, 2020
Protocol for a randomised pilot trial to evaluate a telomerase activator to reverse immunosenescence in elderly patients with acute coronary syndrome
ABSTRACT
Background:
Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation-acute coronary syndrome (ACS). Ageing is associated with a decline of the immune system, a process known as immunosenescence. This is characterised by an increase in highly pro-inflammatory T cells that are involved in CHD progression, plaque destabilisation and myocardial ischemia-reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T-lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilatation in microvasculature.
Objective:
The TACTIC trial will investigate whether a telomerase activator (TA-65MD®) can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD® on decreasing telomere shortening, reducing oxidative stress and improving endothelial function.
Methods:
The study was designed as a single centre, randomised, double-blind, parallel group, placebo-controlled phase II trial. Recruitment started in January 2019. Ninety patients aged ≥ 65 with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomised to either TA-65MD® oral therapy (8mg BD) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP, systemic inflammation, oxidative stress and telomerase activity.
Results:
The study received National Health Service ethics approval on 09.08.2018, MHRA approval on 19.10.2018, and NHS Health Research Authority approval on 22.10.18. The trial began recruiting in January 2019 and is expected to recruit until March 2020; the trial is due to report in 2021.
Conclusions:
This pilot trial in older patients with CHD, will explore outcomes not previously investigated outside in-vitro or pre-clinical models. The robust design ensures that bias has been minimised. Should the results indicate reduced frequency of immunosenescent CD8+ T cells and improvements in telomere length as well as endothelial function, we will plan a larger, multi-centre trial in patients to determine if TA-65MD® is beneficial in the treatment of CHD. Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN) 16613292; http://www.isrctn.com/ISRCTN16613292
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