Clinical Trials Register

Summary
EudraCT Number:	2017-002876-26
Sponsor's Protocol Code Number:	2017-002876-26
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-10-25
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-002876-26

A.3

Full title of the trial

Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome: a double-blind, phase II, pilot randomised controlled trial (TACTIC)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Can we prevent immune cell ageing in patients with Coronary Heart Disease?

A.3.2

Name or abbreviated title of the trial where available

Telomerase activator TA-65MD® in patients with ACS (TACTIC)

A.4.1

Sponsor's protocol code number

2017-002876-26

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN16613292

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	South Tees Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	T.A, Sciences
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Newcastle Clinical Trials Unit
B.5.2	Functional name of contact point	Sarah Dunn
B.5.3	Address:
B.5.3.1	Street Address	1-4 Claremont Terrace
B.5.3.2	Town/ city	Newcastle
B.5.3.3	Post code	NE2 4AE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01912082521
B.5.6	E-mail	sarah.dunn2@newcastle.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TA-65MD
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cycloastrogenol
D.3.9.1	CAS number	78574-94-4
D.3.9.3	Other descriptive name	TA-65
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	Yes
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Immunosenescence in patients who have had an acute coronary syndrome diagnosed within the last 6 months.

E.1.1.1

Medical condition in easily understood language

The aging of immune cells

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10011968
E.1.2	Term	Decreased immune responsiveness
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

As people get older, the cells of their bodies lose the ability to renew and repair as well as they did when they were younger; this is known as cellular ageing. This leads to signs of ageing including the deterioration of organs such as the heart and a reduced ability of the immune system to fight infections and maintain overall health. One reason why cells age, is damage to the DNA that is contained inside them. DNA contains all of the information about how a cell will function, and can be thought of as a piece of string. At the ends of the DNA there are protective caps called telomeres that maintain the health of DNA. Cells need to divide in order to replace lost or dead cells, but during the process of dividing, some of the protective cap (telomeres) is lost and is not passed on to new cells. Therefore, throughout life, the length of the telomeres becomes shorter and this is linked to cell ageing and a decrease in cell health.
There is a product called TA-65MD® that has been shown

E.2.2

Secondary objectives of the trial

•This study will also investigate the effect of TA-65MD® on the small blood vessels that play an important role in the health of the heart.
•We will investigate whether cytomegalovirus exposure in participants has an effect on the immune system or the heart
•Investigate the effect of TA-65MD® on overall inflammation levels
•Investigate the effect of TA-65MD® on heart strain/heart failure and how well the heart is functioning
•Investigate the effect of TA-65MD® on length of telomeres , as the way that TA-65MD® works is by making telomeres longer, we want to check that the length of telomeres is increased in people who take TA-65MD®.
•Investigate the effect of TA-65MD® on telomerase activity- as TA-65MD® is supposed to increase telomerase activity we want to check this
•We will look at the rates of adherence to the study drugs
•We will also look at the adverse events profile for both placebo and intervention arms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Able to give written informed consent
• Patients aged 65 or over with an index presentation of an acute coronary syndrome* within the previous 6 months
• Successfully completed revascularisation** or managed medically following ACS
• Angiographic evidence of coronary heart disease (at least one major epicardial vessel stenosis ≥70%)
• More than 24 hours after presentation with the index event
*Acute coronary syndrome (ACS) defined as either a non ST elevation acute coronary syndrome (NSTEMI), or ST elevation MI (STEMI) only.
**PCI/angioplasty (eligible the following day) or surgery (eligible 3 months later)

E.4

Principal exclusion criteria

• Patients with any disorder associated with immunological dysfunction (acute or chronic inflammatory or neoplastic co-existing disease, known positive serology for HIV, or hepatitis)
• Clinically unstable patients (haemodynamically unstable, cardiogenic shock, unconscious)
• Severe, uncontrolled hypertension (Blood Pressure >170/110mmHg, or ambulatory BP of 150/95mmHg);
• Severe comorbidity that has an impact on outcome over next 2 years
• Taking immunosuppressants
• Known malignancy
• Insulin-controlled diabetes
• Judgment by the Investigator that the patient should not participate in the study, for example, if the patient is unlikely to comply with study procedures, restrictions, and requirements
• Participation in any other interventional medicinal studies in the past 6 months

E.5 End points

E.5.1

Primary end point(s)

Immunosenescence at 1 year following start of treatment with the study drug (TA-65MD®/placebo) will be determined by flow cytometry (FACS). The proportion of terminally differentiated CD8+ effector memory cells (%CD8+ TEMRA 'aged') will be calculated from the total number of peripheral blood CD8+ T-lymphocytes in each blood sample.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, 6 and 12 months

E.5.2

Secondary end point(s)

•Leukocyte Telomere Length will be measured at baseline, 6 months and 1 year; short leukocyte telomere length is a predictor of cardiovascular mortality
•CD8 T-cell telomere length will be measured at baseline, 6 months and 1 year; short telomere length is a predictor of cardiovascular mortality, and CD8 telomere length is significantly reduced in patients with coronary heart disease and post myocardial infarction. Isolated peripheral blood mononuclear cells (PBMCs) will be FACS sorted to purify CD8 cells.
•The proportion of senescent (CD28-) CD4+ T-lymphocytes will be measured at baseline, 6 months and 1 year and calculated from the total number of CD4+ T-lymphocytes in each PBMC sample. CD28- CD4+ T-lymphocytes have been shown to be significantly increased in patients with acute coronary syndrome
•The proportion of senescent (CD28-) CD8+ T-lymphocytes will be measured at baseline, 6 months and 1 year and calculated from the total number of CD8+ T-lymphocytes in each PBMC sample
•Microvascular Endothelial Function will be assessed by measuring flow-mediated dilation (FMD) using finger plethysmography (EndoPat) at baseline, 6 months and 1 year. Using plethysmography at the fingertips of both hands, the EndoPAT system (Itamar Medical Ltd., Caesarea, Israel) will calculate an index of pulse wave amplitude after cuff occlusion to before occlusion of the test arm divided by the same ratio of the control limb, namely the reactive hyperemic index (RHI). FMD has been shown to be compromised in patients with diabetes as well as with coronary artery disease. It is a predictor of adverse clinical outcome. Endothelial dysfunction is seen as the initial step in atherogenesis.
•Systemic Inflammation will be measured by high sensitivity C-reactive protein (hsCRP) at baseline, 6 months and 12 months of treatment. We expect TA-65MD® to reduce systemic inflammation, and this should be reflected in a reduction in hsCRP.
•Heart failure and cardiac function will be assessed by transthoracic echocardiography (TTE) at baseline and 12 months of treatment, and the pronatriuretic peptide NT-proBNP biomarker at baseline, 6 months and 12 months of treatment. Together these measures will determine myocardial function, hypertrophy (left ventricular wall thickness), strain (NT-proBNP), and global longitudinal strain, reflecting the pathophysiological targets of heart failure. TA-65MD® may reduce NT-proBNP levels or improve left ventricular function. Lack of telomerase and shortened telomeres in cardiomyocytes from preclinical models (mice) have been shown to be critical in the development of heart failure in that species
•Telomerase activity will be assessed at baseline, 6 and 12 months following treatment using the TRAP assay. This provides an indication of drug effect: TA-65MD® is expected to increase telomerase activity in PBMCs.
•Oxidative stress will be measured at baseline, 6 and 12 months following treatment with the TBARS colorimetric assay (Oxford Biomedical Research) with frozen plasma. TBARS is an established assay to quantify lipid peroxides. Additionally, we will evaluate whether treatment with TA-65MD® leads to parallel activation of canonical and non-canonical pathways. By measuring oxidative stress and endothelial function over time and correlating this with telomere length dynamics and telomerase activity.
•The effect of CMV seropositivity at baseline will be correlated with study outcomes using an exploratory analysis. We have previously shown that individuals who are seropositive have a much higher proportion of CD8+ TEMRA cells and have a greater risk of heart attacks
•Adherence to the study drugs will be determined by pill counts at baseline, 1, 3, 6, 9 and 12 months
•Adverse events will be recorded from the time of randomisation to withdrawal or the last study visit. All cause death, stroke and myocardial infarction will also be combined to provide a composite outcome.

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, 1, 3, 6, 9 and 12 months (individual endpoint evaluation points are listed in the secondary end points section)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1