Clinical Trials Register

Summary
EudraCT Number:	2007-006749-42
Sponsor's Protocol Code Number:	31350
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2008-10-20
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

UK - MHRA

A.2

EudraCT number

2007-006749-42

A.3

Full title of the trial

Safety and efficacy of clopidogrel when added to aspirin and dipyridamole in high risk patients with recent ischaemic stroke or TIA: a randomised controlled trial

A.3.1

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

Is intensive blood thinning with three antiplatelet drugs better than the current guideline treatment in reducing recurrence after acute stroke?

A.3.2

Name or abbreviated title of the trial where available

TARDIS

A.4.1

Sponsor's protocol code number

31350

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN47823388

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	University of Nottingham
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	British Heart Foundation
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Nottingham
B.5.2	Functional name of contact point	TARDIS Trial Office
B.5.3	Address:
B.5.3.1	Street Address	Div Stroke, Cl.Sci.Bldg, Hucknall Rd
B.5.3.2	Town/ city	Nottingham
B.5.3.3	Post code	NG5 1PB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4401158230210
B.5.5	Fax number	+4401158230273
B.5.6	E-mail	tardis@nottingham.ac.uk

D. IMP Identification
D.IMP: 1
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.2.5	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	Clopidogrel
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent) Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOPIDOGREL
D.3.9.1	CAS number	113665-84-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	75 to 300
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.2.5	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	Dipyridamole
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent) Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DIPYRIDAMOLE
D.3.9.1	CAS number	58-32-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 400
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: 3
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.2.5	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	Aspirin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent) Oral use Rectal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ASPIRIN
D.3.9.1	CAS number	50-78-2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	75 to 300
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

Ischaemic stroke and TIA (transient ischaemic attack)

E.1.1.1

Medical condition in easily understood language

Stroke due to blood clot.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10042244
E.1.2	Term	Stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10044390
E.1.2	Term	Transient ischaemic attack
E.1.2	System Organ Class	10029205 - Nervous 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

To assess the safety of short-term administration (1 month) of intensive antiplatelet therapy (aspirin, dipyridamole and clopidogrel) versus current guideline therapy (dual aspirin and dipyridamole, or clopidogrel monotherapy) in patients with very recent ischaemic stroke or TIA.

E.2.2

Secondary objectives of the trial

1. To assess the safety of short-term administration (1 month) of intensive antiplatelet therapy versus guideline therapy in patients with very recent ischaemic stroke or TIA.

2. To further assess, in high risk patients with stroke/TIA, whether:
ii. it is feasible to administer intensive therapy acutely and is tolerable to take for 1 month,
iii. intensive therapy is superior in respect of surrogate markers such as platelet function.
iv. intensive therapy improves functional outcome

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Adults at high risk of recurrent ischaemic stroke:
1. Acute high risk TIAs <48 hours of onset All TIAs must have limb weakness and/or dysphasia lasting at least 10 minutes.
2. Ischaemic, non cardioembolic stroke with limb weakness, dysphasia or hemianopia ≤48 hours of onset with neuroimaging to rule out alternative causes.
3. Meaningful consent, or consent from a relative, carer or legal representative if the patient is unable to give consent (e.g. in cases of dysphasia, confusion, or reduced conscious level).

E.4

Principal exclusion criteria

1. Age<50
2. Isolated sensory symptoms or vertigo/dizziness or facial weakness
3. Isolated hemianopia without positive neuroimaging evidence
4. Intracranial haemorrhage
5. Baseline neuroimaging showing parenchymal haemorrhagic transformation (PH I/II) of infarct, subarachnoid haemorrhage or other non ischaemic cause for symptoms
6. Presumed cardioembolic stroke (e.g. history or current AF, myocardial infarction within 3 months)
7. Participants with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole.
8. Participants with definite need for treatment with aspirin, clopidogrel or dipyridamole individually or in combination (e.g. aspirin and clopidogrel for recent MI/acute coronary syndrome)
9. Participant has taken clopidogrel or dipyridamole after the index event but prior to randomisation (aspirin is allowed between ictus onset and randomisation)
10. Definite need for full dose oral (e.g. warfarin, dabigatran) or medium to high dose parenteral (e.g. heparin) anti-coagulation. NB Low dose heparin for DVT prophylaxis is allowed
11. Definite need for glycoprotein IIb-IIIa inhibitors
12. Received thrombolysis within the last 24 hours
13. No enteral access
14. Pre-morbid dependency (mRS>2).
15. Severe high BP (BP>185/110 mmHg).
16. Haemoglobin less than 10g/dL
17. Platelet count more than 600 x 109 /L or less than 100 x 109 /L
18. White cell count more than 30 x 109 /L or less than 3.5 x 109 /L
19. Major bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage).
20. Planned surgery during 3 month follow-up (e.g. carotid endarterectomy)
21. Concomitant STEMI or NSTEMI.
22. Stroke secondary to a procedure (e.g. carotid or coronary intervention)
23. Coma (GCS<8)
24. Non-stroke life expectancy<6 months
25. Dementia
26. Participation in another drug or devices trial concurrently or within 30 days. (participants may take part in observational studies or non-drug or devices trials)
27. Geographical or other factors that may interfere with follow-up e.g. no fixed address or telephone contact number, not registered with a GP, or overseas visitor.
28. Females of childbearing potential, pregnancy or breastfeeding

E.5 End points

E.5.1

Primary end point(s)

The trial will assess ordinal stroke severity: 5-level ordinal stroke and TIA scale with stroke ordered by its severity using the modified Rankin Scale (mRS): fatal stroke / severe non-fatal stroke (mRS 2-5) / mild stroke (mRS 0,1) / TIA / no stroke-TIA, measured at 90 days.

E.5.1.1

Timepoint(s) of evaluation of this end point

8 years 3 months

E.5.2

Secondary end point(s)

1. Safety outcome - bleeding at 35 days (end of treatment).
2. Functioning, cognition and quality of life.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Safety outcome - bleeding. Interim analysis at 4 years and end of trial at 8 years and 3 months.
2. Functional cognition, QUOL outcomes - 8 years 3 months.

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

Yes

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Outcome assessment blinded

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

100

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

As per protocol

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.1.1.1

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:

1435

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2665

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with a stroke may be incapable of giving consent due to confusion and speech difficulties. Consent may be obtained from the patient's relative or legal representative. This is standard practice in all acute stroke trials. (We exclude coma).

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Elderly patients

F.4 Planned number of subjects to be included

F.4.1

In the member state

4100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

4100

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 go back to Standard Care as per local and national guidelines.

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

2008-10-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-01-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-04-12

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