Clinical Trials Register

Summary
EudraCT Number:	2015-005630-21
Sponsor's Protocol Code Number:	D5130C00173
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-04-18
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

Greece - EOF

A.2

EudraCT number

2015-005630-21

A.3

Full title of the trial

A Prospective, Multicentre, Randomized, Open Label, Blinded Endpoint, Phase 3 Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr with Acetylsalicylic Acid versus CLopidogrel with Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events during Transcatheter Aortic Valve Implantation (TAVI) OperationS

A.3.1

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

Study comparing the action of drugs : ticagrelor, clopidogrel combined with acetylsalicylic acid in preventing ischemic strokes during transcatheter aortic valve implantation operations.

A.3.2

Name or abbreviated title of the trial where available

PTOLEMAIOS Study

A.4.1

Sponsor's protocol code number

D5130C00173

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	National and Kapodistrian University of Athens
B.1.3.4	Country	Greece
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	ELKE EKPA (University of Athens)
B.4.2	Country	Greece
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ass. Prof. Emmanouil Vavouranakis
B.5.2	Functional name of contact point	Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	114 Vasilissis Sofias
B.5.3.2	Town/ city	Athens
B.5.3.3	Post code	11527
B.5.3.4	Country	Greece
B.5.4	Telephone number	+302132088 286
B.5.5	Fax number	+302132088 676
B.5.6	E-mail	vavouran@otenet.gr

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	Yes
D.2.1.1.1	Trade name	Brilique 90 mg film-coated tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Film-coated tablet
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	Τicagrelor
D.3.9.1	CAS number	274693-27-5
D.3.9.3	Other descriptive name	TICAGRELOR
D.3.9.4	EV Substance Code	SUB30898
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	90
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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	No
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	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Plavix 75 mg film-coated tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Film-coated tablet
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	Clopidogrel Bisulfate
D.3.9.1	CAS number	113665-84-2
D.3.9.3	Other descriptive name	CLOPIDOGREL BISULFATE
D.3.9.4	EV Substance Code	SUB12483MIG
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	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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	No
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	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Preventing cerebrovascular embolic events during the TAVI procedure

E.1.1.1

Medical condition in easily understood language

Prevention of ischemic stroke

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10002918
E.1.2	Term	Aortic valve stenosis
E.1.2	System Organ Class	10007541 - Cardiac 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

To identify any potential differences between the two treatment groups, subjects receiving Ticagrelor with ASA vs. those receiving Clopidogrel with ASA, in preventing cerebrovascular embolic events during the TAVI procedure, as assessed by measuring the number of HITS with an operative transcranial continuous-function Doppler.

E.2.2

Secondary objectives of the trial

•To assess the safety of Ticagrelor by assessment of all AEs, physical examination and vital signs.
•To evaluate the differences between the two treatment groups, in the incidence in bleeding events of each of the three grades, as defined by VARC-2, perioperatively and at 90 days.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects eligible for study inclusion must meet all of the following criteria:
1.The subject (or where unable to do so, their legally acceptable representative) must be able to provide written informed consent prior to any study specific criteria, stating that he or she understands the purpose of and the procedures required for the study and is willing to participate in the study.
2.Female and/or male subjects aged 18 years or older.
3.High risk (EuroSCORE ≥18, or considered inoperable) for surgical aortic valve replacement.
4.Is expected to benefit from the placement of TAVI.
5.Does not suffer from any disease or condition that would limit his/her life expectancy of <6 months.
6.The subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
7.Subjects must meet the following laboratory results from Visit 0 for study inclusion :
a. Hemoglobin ≥ 10 g/dL
b. Platelets ≥ 100 X 103 cells/μL
c. Absolute neutrophil count (ANC) ≥ 1000 cells/μL
d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels must be within 1.5 times the upper limit of normal (ULN) range for the laboratory conducting the test.
e. Total bilirubin ≤ 2x ULN.

E.4

Principal exclusion criteria

Subjects will not enter the study if any of the following exclusion criteria are fulfilled:
1.Have scheduled any elective surgery in the next 4 months following screening procedures.
2.History of hypocoagulopathies.
3.Previous thromboembolism or known hypercoagulopathy (acquired or congenital).
4.Antiplatelet therapy, other than ASA, within 7 days before randomization that cannot be discontinued due to the underlying disease.
5.History of gastric or duodenal ulcer disease verified by endoscopy or barium meal double-contrast technique within the 3 months.
6.Moderate or severe hepatic impairment.
7.Known hypersensitivity to any of the investigational products or their components.
8.Presence of any other clinically significant disease or disorder which, in the opinion of the Investigator (by its nature or by being inadequately controlled), might put the subject at risk due to participation in the study, or may influence the conduct or the interpretation of the results of the study or the subject’s ability to complete the study.
9.Any identified contraindication for using Ticagrelor, Clopidogrel or ASA.
10.History or recent findings of atrial fibrillation.
11.Significant carotid artery disease on either internal carotid artery, as defined by a >50 % diameter reduction on carotid ultrasonography.
12.Unwillingness to receive or intolerant to any blood products.
13.Previous trauma or surgery to either femoral vein.
14.Major surgical procedure or trauma within the 30 days prior to enrolment.
15.Mechanical heart valve (any location).
16.Mitral or aortic bioprosthetic valve.
17.The subject is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
18.Reproductive status:
a.Women who are pregnant or planning a pregnancy within 1 month of the end of study;
b.Women who are breastfeeding;
c.Women of childbearing potential who are unwilling or unable to use two highly effective methods of birth control to avoid pregnancy for the entire study period, as evaluated by the Investigator. Women who are not of childbearing potential are those that have a history of hysterectomy, bilateral oophorectomy, or are postmenopausal with no history of menstrual flow for ≥ 12 months prior to the screening Visit.
19.International normalized ratio (INR) ≥ 2 on the day before the TAVI procedure.
20.History of hemorrhagic stroke, intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular hemorrhage, intracerebral mass or aneurysm, or arteriovenous malformation.
21.Severe left ventricular dysfunction (left ventricular ejection fraction<15%).
22.Severe aortic regurgitation or mitral regurgitation, according to the 2012 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery guidelines (See Appendix 2)
23.Hemodynamic instability (e.g. requiring inotropic or intra-aortic balloon pump support) within 2 hours of the procedure.
24.Subject is dialysis dependent.
25.Any condition requiring the use of anticoagulants that cannot be stopped for the duration of the study.
26.Acute myocardial infarction, major surgery or any therapeutic cardiac procedure (other than balloon aortic valvuloplasty) within 30 days.
27.Gastrointestinal or genitourinary bleed within 30 days.
28.Absolute contraindications or allergy to iodinated contrast that cannot be pre-medicated.
29.Treatment with other investigational drugs (including investigational vaccines) or devices within the 30 days preceding enrolment or planned use of other investigational drugs or devices before the end of the study.
30.Known alcohol or drug abuser.
31.The subject has received any prohibited therapies, as defined in Section 5.7 before the planned first dose of investigational product or is scheduled to receive during the study period. These include, but are not limited to: strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, erythromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, over 1 litre daily of grapefruit juice), CYP3A substrates with a narrow therapeutic index (cyclosporine, quinidine, simvastatin at doses >40 mg daily, lovastatin at doses >40 mg daily), and strong CYP3A inducers (rifampin/rifampicin, phenytoin, carbamazepine, phenobarbital).

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the number of confirmed HITS, as assessed by TCD, between the two treatment groups during the TAVI procedure.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 0

E.5.2

Secondary end point(s)

The differences in the incidence of cerebral embolic events between the two treatment groups, as assessed by HITS measured by TCD at subject discharge. Days 4-7

The differences in the incidence of cerebral embolic events in each treatment group, as assessed by HITS measured by TCD preoperatively, during the TAVI procedure, and at subject discharge. Days -10 to -1, Day 0, Days 4-7

The differences between the two treatment groups in induced platelet inhibition, as assessed by the use of the P2Y12 VerifyNow® assay at the day of the procedure. Day 0

The differences between the two treatment groups in induced platelet inhibition, as assessed by the use of the P2Y12 VerifyNow® assay at subject discharge. Days 4-7

E.5.2.1

Timepoint(s) of evaluation of this end point

See E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-30

P. End of Trial
P.	End of Trial Status	Ongoing

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