Clinical Trials Register

Summary
EudraCT Number:	2019-002226-79
Sponsor's Protocol Code Number:	AUGEAS
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-09-09
Trial results	View 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

Sweden - MPA

A.2

EudraCT number

2019-002226-79

A.3

Full title of the trial

A 30-day, randomized, evalUator-blind, controlled, multi-centre, parallel Group, phase III study to evaluate the Effect of a Low Maintenance Dose TicAgrelor Regimen versus Standard Dose Clopidogrel on Coronary Flow Reserve in Diabetes Mellitus Patients with impaired microvascular function without Prior Myocardial Infarction or Stroke Undergoing Elective Percutaneous Coronary Intervention

A.3.1

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

Study in diabetic patients undergoing elective Percutaneous Coronary Intervention (PCI) to investigate whether the blood clotting inhibitor ticagrelor can improve the blood flow in the heart instead of the standard treatment with clopidogrel.

A.4.1

Sponsor's protocol code number

AUGEAS

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	Region Skåne
B.1.3.4	Country	Sweden
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	AstraZeneca
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Region Skåne
B.5.2	Functional name of contact point	Ulf Malmqvist
B.5.3	Address:
B.5.3.1	Street Address	Kliniska Studier Sverige – Forum Söder, Skåne University Hospital
B.5.3.2	Town/ city	Lund
B.5.3.3	Post code	SE-221 85
B.5.3.4	Country	Sweden
B.5.4	Telephone number	004646173333
B.5.6	E-mail	ulf.malmqvist@skane.se

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	Ticagrelor
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	Ticagrelor
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	60
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
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Clir SNC
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	Plavix, Clopidogrel
D.3.9.1	CAS number	113665-84-2
D.3.9.3	Other descriptive name	CLOPIDOGREL HYDROGEN SULFATE
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

Coronary Artery Disease (CAD)

E.1.1.1

Medical condition in easily understood language

Impaired blood flow in the arteries of the heart.

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10011078
E.1.2	Term	Coronary artery disease
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10072685
E.1.2	Term	Microvascular coronary artery disease
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10065608
E.1.2	Term	Percutaneous coronary intervention
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 assess the effect of Ticagrelor on change from baseline in Coronary Flow Velocity Reserve (CFR) at 30 days.

E.2.2

Secondary objectives of the trial

To assess the effect of Ticagrelor on coronary flow parameters at 30 days.
To assess the safety and tolerability of Ticagrelor at 30 days.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Provision of informed consent prior to any study specific procedures
2. Men or women ≥18 years of age
3. Diagnosed with T2DM defined as treatment with ongoing glucose lowering drug (oral
medications and/or insulin) for at least 1 month
4. Presence of CAD undergoing elective PCI
5. Impaired coronary microvascular function post PCI as defined by a CFR ≤2.5 (as per local
reading)
6. TIMI 3 flow post PCI

E.4

Principal exclusion criteria

1. Previous MI defined as a documented hospitalization with a final diagnosis of spontaneous
MI (with the exception of definite secondary MI [e.g., due to coronary revascularization
procedure, profound hypotension, hypertensive emergency, tachycardia, or profound
anemia]).
2. Previous stroke (transient ischemic attack [TIA] is not included in the stroke definition)
3. Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI
4. On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV event
(MI or stroke) (on treatment with clopidogrel due to prior vascular intervention not
secondary to a major CV event is allowed)
5. Planned use of aspirin treatment at doses >150 mg od
6. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4
(CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be
stopped for the course of the study:
a. Strong CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin,
clarithromycin (but not erythromycin or azithromycin), nefazodone, ritonavir,
saquinavir, nelfinavir, indinavir, atazanavir
b. CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40
mg daily or lovastatin at doses >40 mg daily
7. Hypersensitivity to ticagrelor or any of its excipients
8. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin
9. Patients with known bleeding diathesis or coagulation disorder
10. History of intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6
months prior to randomization, or major surgery within 30 days prior to randomization
11. Increased risk of bradycardic events (e.g., known sick sinus syndrome, second or thirddegree
AV block or previous documented syncope suspected to be due to bradycardia)
unless treated with a pacemaker
12. Known severe liver disease (e.g., ascites and/or clinical signs of coagulopathy)
13. Renal failure requiring dialysis
14. Known platelet count <145 x109 platelets/L
15. Known hemoglobin <9 g/dL
16. Women of child-bearing potential (WOCBP)*, who are not willing to use a method of
contraception that is considered highly reliable** per CTFG (Clinical Trial Facilitation
Group), OR who have a positive pregnancy test at enrolment or randomization OR women
who are breast-feeding
17. Inability of the patient to understand and/or comply with study procedures and/or follow
up, in the opinion of the investigator, OR any conditions that, in the opinion of the
investigator, may render the patient unable to complete the study
18. Life expectancy of less than 6 month based on investigator’s judgement
19. Participation in another clinical study with an investigational (defined as non-approved)
product, if taken within five half-lives or 28 days prior to the first administration of the trial
medication, whichever is longer
20. Previous randomization in the present study
21. Severe asthma
22. Hypersensitivity to adenosine or mannitol
23. Long QT syndrome
24. Chronic obstructive lung disease, with evidence of bronchospasm
25. Severe low blood pressure
26. Unstable angina pectoris
27. Severe heart failure
28. Hypovolemia
29. Treatment with dipyradimol
30. Increased intracranial pressure
* fertile, following menarche until becoming post-menopausal, unless permanently sterile (permanent sterilisation
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy)
** estrogen/progestogen or progestogen (oral, intravaginal or transdermal administration); intrauterine device
(IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual
abstinence

E.5 End points

E.5.1

Primary end point(s)

Difference in mean of individual absolute change from baseline to 30
days in Coronary Flow Velocity Reserve (CFR) in the mid-distal
segment of the left anterior descending (LAD) coronary artery under
adenosine infusion measured by Transthoracic Doppler
Echocardiography (TDE) between the two arms.

E.5.1.1

Timepoint(s) of evaluation of this end point

The Endpoint for the study is at day 30+/- 3 days after Patient was randomized, got initital CFR measurement and medication was handed over

E.5.2

Secondary end point(s)

Difference in mean of individual absolute change from baseline at 30 days in:
- LAD resting mean diastolic flow velocity
- LAD hyperemic mean diastolic flow velocity

- Bleeding complications (BARC 2, 3 and 5)
- Mortality
- Myocardial Infarction
- Definite and probable stent thrombosis
- Serious Adverse Events (SAEs)

E.5.2.1

Timepoint(s) of evaluation of this end point

The Endpoint for the study is at day 30+/- 3 days after Patient was randomized, got initital CFR measurement and medication was handed over

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

114

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.4.2

For a multinational trial

F.4.2.1

In the EEA

314

F.4.2.2

In the whole clinical trial

314

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)

Patients will be switched to current standard of care.

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

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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