Hunting for the Off-Target Properties of Ticagrelor on Endothelial Function in Humans (HI-TECH) (HI-TECH)

February 10, 2017 updated by: Marco Valgimigli, Erasmus Medical Center

Hunting for the Off-Target Properties of Ticagrelor on Endothelial Function and Other Circulating Biomarkers in Humans

The purpose of this randomized, cross-over study, is to ascertain if ticagrelor, but not prasugrel or clopidogrel, is associated to an improved endothelial function as assessed with peripheral arterial tonometry and markers of endothelial function measurement in post-ACS patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Extensive literature documents that endothelial dysfunction is associated with almost every condition predisposing to atherosclerosis and cardiovascular disease. Hence, endothelial dysfunction is significantly associated with the burden of cardiovascular risk and can be considered a barometer of the total risk burden. Importantly, microvascular dysfunction has been shown to increase risk of future cardiovascular events.

This study aims to clarify if ticagrelor, but not prasugrel or clopidogrel is associated to an improved reactive hyperemia index (RHI) and circulating levels of specific biomarkers of endothelial function, at treatment steady state. Ticagrelor has previously been demonstrated to increase adenosine levels by inhibiting adenosine reuptake in red blood cells, by inhibiting the equilibrative nucleoside transporter (ENT)-1. Furthermore, ticagrelor can induce adenosine triphosphate (ATP) release from human red blood cells. Interestingly, ticagrelor, but not clopidogrel or prasugrel have been recently shown to be associated to an improved endothelial function as evaluated with peripheral arterial tonometry after forearm ischemia.

Post-ACS patients (who experienced an acute coronary syndrome and thereby started therapy with an oral P2Y12 inhibitor at least 30 days before) will be consecutively screened for possible inclusion. Patients will then be randomised to receive in a sequential manner the three oral P2Y12 blockers (i.e.) ticagrelor, prasugrel or clopidogrel for at least 30 days each, according to a balanced cross-over study design including the sequences below:

Seq\ Per P.I P.II P.III S.I T P C S.II T C P S.III P T C S.IV P C T S.V C T P S.VI C P T During the three months study period the therapy with the P2Y12 inhibitor will be switched as for randomization sequence scheme.

When started, each drug will be given with the corresponding loading dose of 600 mg for clopidogrel and then continued at 75 mg/day, 180 mg for ticagrelor and then continued at 90 mg b.i.d. and 60 mg for prasugrel and then continued at 10 mg/day (5 mg/day for patients ≥75 years or weighing ≤ 60 kg).

The main measurements, including reactive hypermedia index, PRU, aspirin reaction units, and circulating markers of endothelial function will be performed at baseline, after P2Y12-inhibitor loading dose, before and after P2Y12-inhibitor maintenance dose.

During the visit, blood pressure will be measured in the contralateral arm before examination. The EndoPAT probes will be placed on the index fingers. If the index finger will be missing or deformed, another finger will be used, using the same finger on both hands. Baseline registration will be conducted for 5 min. The test arm will be then occluded for 5 min, using a standard blood pressure cuff placed on the upper arm. Subsequently, the cuff was deflated and the registration continued for 5 more minutes. After EndoPAT, blood will be drawn to collect serum and plasma for biomarkers assessment [Asymmetrical dimethylarginine (ADMA), adenosine plasma concentration, von willebrand factor antigen, endothelin-1, C-reactive protein, soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), prothrombin fragment 1+2, fibrinopeptide A, and thrombin-antithrombin complex (TAT)]. To assess the relationship between residual platelet reactivity or percent inhibition and effect of P2Y12 oral blocker on endothelial function, platelet function testing will be also carried out acutely and at treatment steady state by means of the Verifynow system using both P2Y12 and aspirin assays.

Based on previous findings, we set mean RHI at 1.8 with a within subjects SD of 0.31. Hence, 36 patients completing all sequences (i.e. 6 pt/sequence) will provide 90% power to detect a 10% RHI relative change in the ticagrelor group with a two-sided alpha level at 5%. To account for drop outs as well as incomplete data assessment at all time points, a final sample size of 50 patients will be recruited.

Patients will be provided with a regular drug prescription (standard of care medication). At each follow-up the investigator will collect information about adherence to the study drug and register the charge number of the prescribed P2Y12.

Allocation of study treatment will be performed via a web-based interactive randomization system, based on a computer-generated random sequence with a random block size stratified according to the type of P2Y12 inhibitor (ticagrelor vs prasugrel vs clopidogrel) as well as for the presence of diabetes mellitus.

Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to study. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. Serious adverse events in this study are considered to be extremely rare.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Pavia, Italy, 27100
        • Policlinico San Matteo
  • Netherlands
      • Amsterdam, Netherlands, 1081 HZ
        • VU Medical Center
      • Rotterdam, Netherlands, 3015 CE
        • Erasmus MC
  • Spain
      • Barcelona, Spain, 08036
        • Hospital Clinic
  • Switzerland
      • Bern, Switzerland, 3010
        • Inselspitäl University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients older than 18 years.
  • Patients who experienced an Acute Coronary Syndrome (including STEMI or NSTEMI) at least 30 days before.
  • Patients on ongoing treatment for at least 30 days with dual anti-platelet therapy consisting of aspirin, at doses of 75-160 mg daily and one commercially available P2Y12 oral inhibitor , including ticagrelor, clopidogrel or prasugrel.
  • Patients who remained free from bleeding (defined as BARC type 2 or greater) or ischemic recurrences.
  • Signed informed consent All inclusion criteria are required.

Exclusion Criteria:

  • Administration of fibrinolytics or glycoprotein IIb/IIIa inhibitors in the previous 30 days.
  • Major surgery within 30 days or any planned surgical or percutaneous intervention.
  • Active bleeding or previous clinical relevant bleeding or stroke in the last 6 months.
  • Previous transient ischemic attack or intracranial bleeding.
  • Thrombocytopenia.
  • Oral anticoagulant therapy.
  • Vasculitis or any know immunological disorder.
  • Severe hepatic failure.
  • Uncontrolled hypertension (systolic or diastolic arterial pressure >180 mmHg or 120, respectively, despite medical therapy).
  • Known intolerance to aspirin or to clopidogrel or prasugrel or ticagrelor.
  • Limited life expectancy, e.g. neoplasms, others.
  • Inability to obtain informed consent.
  • Pregnancy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Sequence I
Ticagrelor in the period I Prasugrel in the period II Clopidogrel in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix
Active Comparator: Sequence II
Ticagrelor in the period I Clopidogrel in the period II Prasugrel in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix
Active Comparator: Sequence III
Prasugrel in the period I Ticagrelor in the period II Clopidogrel in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix
Active Comparator: Sequence IV
Prasugrel in the period I Clopidogrel in the period II Ticagrelor in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix
Active Comparator: Sequence V
Clopidogrel in the period I Ticagrelor in the period II Prasugrel in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix
Active Comparator: Sequence VI
Clopidogrel in the period I Prasugrel in the period II Ticagrelor in the period III
Drug: Ticagrelor
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Brilique
Drug: Prasugrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Efient
Drug: Clopidogrel
Comparison of ticagrelor with respect to prasugrel and clopidogrel in a different sequence
Other Names:
  • Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Improvement of endothelial function at steady state
Time Frame: After 30 days of therapy with assigned P2Y12-inhibitor
Evaluation if ticagrelor, at steady state (i.e. after 30 day therapy), will be associated to an improved endothelial function as compared to clopidogrel or prasugrel when assessed with endopath system 1-2 hour(s) after maintenance drug intake.
After 30 days of therapy with assigned P2Y12-inhibitor

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Improvement of endothelial function, both acutely and at steady state
Time Frame: One or 2 hour(s) after P2Y12-inhibitor loading dose administration and before and 1 or 2 hour(s) after maintenance dose administration
To assess if treatment with ticagrelor, both acutely and at steady state is associated to an improved endothelial function phenotype as compared to clopidogrel or prasugrel. The assessment is made with measurement of blood markers of endothelial function.
One or 2 hour(s) after P2Y12-inhibitor loading dose administration and before and 1 or 2 hour(s) after maintenance dose administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasmus Medical Center

Collaborators

Covance

Investigators

  • Principal Investigator: Marco Valgimigli, MD, PhD, Erasmus Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 17, 2015

Primary Completion (Actual)

February 10, 2017

Study Completion (Actual)

February 10, 2017

Study Registration Dates

First Submitted

October 23, 2015

First Submitted That Met QC Criteria

October 23, 2015

First Posted (Estimate)

October 27, 2015

Study Record Updates

Last Update Posted (Actual)

February 13, 2017

Last Update Submitted That Met QC Criteria

February 10, 2017

Last Verified

February 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL51124.078.14
  • 2014-004189-64 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Cardiovascular Diseases

Clinical Trials on Ticagrelor

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Senegal

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe