Clinical Trials Register

Summary
EudraCT Number:	2006-004870-28
Sponsor's Protocol Code Number:	9.182
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-04-02
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

Germany - BfArM

A.2

EudraCT number

2006-004870-28

A.3

Full title of the trial

Prospective, randomized, national, multi-centre, open-label, blinded endpoint study to compare Aggrenox® b.i.d. (200 mg dipyridamole MR + 25 mg acetylsalicylic acid) when started within 24 hours of stroke onset on an acute stroke unit, and Aggrenox® b.i.d. when started after a 7-day therapy with ASA 100 mg once daily outside off an acute stroke unit, in symptomatic ischaemic stroke patients over a three months treatment period (EARLY) – An exploratory study

German title:
Prospektive, randomisierte, nationale, offene Multicenterstudie mit verblindeter Endpunktanalyse zum Vergleich von Aggrenox® Retardkapseln (200 mg Dipyridamol + 25 mg Acetylsalicylsäure) 2x täglich, Behandlungsbeginn innerhalb von 24 Stunden nach einem ischämischem Schlaganfall auf einer Stroke unit, versus Aggrenox® Retardkapseln b.i.d., Behandlungsbeginn außerhalb einer Stroke unit nach einer 7-tägigen Therapie mit 100 mg Acetylsalicylsäure pro Tag bei symptomatischen Patienten für einen Behandlungszeitraum von drei Monaten (EARLY) – Phase IV Studie

A.3.2

Name or abbreviated title of the trial where available

EARLY

A.4.1

Sponsor's protocol code number

9.182

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Boehringer Ingelheim Pharma GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Aggrenox®
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim Pharma GmbH & Co. KG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Aggrenox®
D.3.4	Pharmaceutical form	Prolonged-release capsule*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	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	equal
D.3.10.3	Concentration number	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Acetylic salicylic acid
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	equal
D.3.10.3	Concentration number	25
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	ASS Stada 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Stada GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	ASS Stada 100 mg
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Acetylic Salicylic Acid
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	100
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Information not present in EudraCT

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Level	LLT
E.1.2	Classification code	10023027
E.1.2	Term	Ischaemic stroke NOS

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of the trial is to investigate the tolerability and efficacy of a secondary stroke prevention treatment with Aggrenox when initiated within 24 hours of stroke onset on a stroke unit compared to initiation after a 7-day ASA treatment outside off an acute stroke unit.

E.2.2

Secondary objectives of the trial

Secondary efficacy endpoints
1.) Tele-mRS on day 8 and 90 – centralised, blinded assessment
2.) Change in mRS and NIHSS from baseline to day 8 and 90 – assessment by investigator
3.) Time to first relevant event (vascular or non-vascular death, non-fatal stroke, non-fatal myocardial infarction, bleeding complications) – centralised, blinded assessment by an adjudicating committee
4.) Neuroanatomical and neurofunctional changes from baseline to day 8 as assessed by MRI parameters – centralised, blinded assessment by a central radiology centre
5.) Changes of special biochemical laboratory values (MMP-9, MCP-1 and CRP) from baseline to day 8 – centralised, blinded assessment by a specialised central clinical laboratory
6.) Premature study discontinuations due to AEs

Secondary safety endpoints
7.) Number and kind of adverse events (AEs)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria
To be eligible, the following inclusion criteria must be met:
1.) Adult inpatient
2.) Clinical diagnosis of ischaemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition and/or gaze, vision or neglect. Symptoms must be distinguishable from an episode of generalized ischaemia (i.e. syncope), seizure, or migraine disorder.
3.) Time of stroke onset is known. Symptoms of ischaemic attack began at a time point what makes the start with study medication within 24 hours possible. When a stroke happened during sleep, bedtime is assumed as time of onset.
4.) NIHSS assessment equal or below 20 points (at pre-screening).
5.) Treatment indication is given either to valid German SPC of Aggrenox capsules or to ASS STADA 100 mg tablets.
6.) A contraindication for stroke lysis is given
7.) Patients are able to swallow either medication or administration of the substances via a nasogastral tube is possible.
8.) Signed and witnessed written informed consent obtained prior to the first study intervention. Patients who are unable to sign but who are able to understand the meaning of participation in the study may give an oral, witnessed (preferably by relatives) informed consent. These patients have to make clear without doubt that they are willing to participate voluntarily and must be able to understand an explanation of the contents of the information sheet.

E.4

Principal exclusion criteria

Exclusion criteria
1.) Intracranial haemorrhage on CT-scan present.
2.) A contraindication for Aggrenox or ASA is given:
· Hypersensitivity to any of the components of the product or salicylates
· Active gastric or duodenal ulcers
· Bleeding disorders
· Pregnancy during the third trimester
· Hereditary problems of fructose intolerance and / or galactose intolerance, e.g. galactosaemia
3.) As to the discretion of the investigator, precautions and warnings for ASA and Aggrenox may lead to exclusion of patients as there are:
· Dipyridamole should be used with caution in patients with severe coronary artery disease, including unstable angina and recent myocardial infarction, left ventricular outflow obstruction, or haemodynamic instability (e.g. decompensated heart failure).
· In patients with myasthenia gravis readjustment of therapy may be necessary after changes in dipyridamole dosage.
· Long-term treatment of elderly patients suffering from ascending cholangitis should be considered with caution. A small number of cases has been reported in which unconjugated dipyridamole was incorporated into gallstones to a variable extent (up to 70% by dry weight of stone).
· Due to the ASA component, Aggrenox should be used with caution in patients with asthma, allergic rhinitis, nasal polyps, chronic or recurring gastric or duodenal complaints, impaired renal or hepatic function or glucose-6-phosphate dehydrogenase deficiency.
· Caution is advised in patients hypersensitive to NSAIDs.
· Dipyridamole and salicylates are excreted in breast milk. Aggrenox should only be administered during early pregnancy or lactation if considered essential by the physician in terms of benefit and risk.
· Caution should be advised in patients receiving concomitant medication which may increase the risk of bleeding, such as anti-platelet agents (e.g. clopidogrel, ticlopidine) or selective serotonin reuptake inhibitors (SSRIs). See section 4.2.2 for restrictions on concomitant medication.
4.) Patient underwent any thrombolysis therapy (e. g. for stroke, myocardial infarct, deep vein thrombosis) within 24 hours before medication.
5.) Any antithrombotic treatment has been planned or started (Note: low-dose thrombosis prevention which is permitted in combination with ASA treatment is acceptable).
6.) A platelet inhibiting therapy with ASA doses of more than 100 mg per day, or with Clopidogrel at any dose has been planned or started.
7.) Current or recent (within 3 months) participation in another clinical study with a non-registered drug.

E.5 End points

E.5.1

Primary end point(s)

The study is powered on tele-mRS on day 90 – centralised, blinded assessment. But since this study has an exploratory character and does not serve for regulatory purposes, no primary endpoint is defined. All endpoints that will be investigated are described in the protocol in section 2.3.1.

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

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

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

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.8.3

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

Information not present in EudraCT

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

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

Information not present in EudraCT

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

468

F.4.2

For a multinational trial

F.4.2.1

In the EEA

468

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)

After a patient has ended his/her participation in the trial the respective family doctor will take care on the patient. All further decisions on diagnostic and thrapy will be his/her responsibility.

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

2007-04-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-05-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2009-02-05

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