Clinical Trials Register

Summary
EudraCT Number:	2015-003200-23
Sponsor's Protocol Code Number:	2013DR3084
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:	2016-01-27
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

2015-003200-23

A.3

Full title of the trial

Biomarkers and antithrombotic treatment in cervical artery dissection
(TREAT-CAD)

Biomarker und antithrombotische Therapie bei Dissektion der hirnzuführenden Gefässe

A.3.1

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

Anticoagulant medication for the treatment of patients with teared brain supplying vessels

Blutgerinnungshemmende Medikamente in der Behandlung von Patienten mit Einrissen hirnversorgender Gefässe

A.3.2

Name or abbreviated title of the trial where available

TREAT-CAD

A.4.1

Sponsor's protocol code number

2013DR3084

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02046460

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 Hospital Basel; Neurology
B.1.3.4	Country	Switzerland
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	Swiss National Science Foundation
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Swiss Heart Foundation
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	University Hospital Basel
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Basel
B.5.2	Functional name of contact point	Stefan Engelter, MD, PI TREA-CAD
B.5.3	Address:
B.5.3.1	Street Address	Petersgraben 4
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4031
B.5.3.4	Country	Switzerland
B.5.6	E-mail	stefan.engelter@usb.ch

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	Aspirin protect 300
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer
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.3.4	Pharmaceutical form	Gastro-resistant tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Acetylsalicylsäure
D.3.9.3	Other descriptive name	ASPIRIN PH. EUR
D.3.9.4	EV Substance Code	SUB76180
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	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	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	Marcumar
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDA Pharma GmbH; Germany
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	Marcoumar
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)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PHENPROCOUMON
D.3.9.1	CAS number	435-97-2
D.3.9.4	EV Substance Code	SUB09781MIG
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	3
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

cervical artery dissection

Dissektion hirnversorgender Gefässe

E.1.1.1

Medical condition in easily understood language

patients with teared brain supplying vessels

Patienten mit Einrissen hirnversorgender Gefässe

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 demonstrate the non-inferiority of acetylsalicylic acid (ASA) to anti- coagulant treatment (vitamin K antagonists) in patients with cervical artery dissection (CAD) with regard to outcome and complication measures

E.2.2

Secondary objectives of the trial

not appicable

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Transcranial doppler monitoring (TCD)-sub-study: All TREAT-CAD- participants will be asked to accept a 6 hour TCD recording in between day 1 and day 4 of study treatment (aspirin or anticoagulation). Recording times can be split in up to 3 episodes if this will comfort the patient. In patients with internal carotid artery dissection (ICAD), the ipislateral middle cerebral artery will be investigated. In patients with vertebral artery dissection (VAD), the ipsilateral posterior cerebral artery will be chosen. The presence of MES and their number will be compared with a) the presence of stroke/TIA (at 3 months) b) the presence of new ischemic lesion (DWI) or c) microbleeds (SWI) at the first follow-up-MRI (14 +/- 10 days after treatment onset), not present on the "baseline MRI" (by which diagnosis was established). Participation in this sub-study is optional. The target sample size for this sub-study is 60 patients.
The objectives of the TCD-sub-study are to (i) detect the frequency of
MES in CAD-patients, stratified to the type of treatment (aspirin
versus) anticoagulation – in the setting of a randomized-controlled trial
- and (ii) evaluate the meaning of MES by addressing the following questions:
a) Is there an association of MES (presence or number) with the occurrence of clinical and/or surrogate MR outcome measures
b) Is there an interaction between MES, type of treatment and outcome events
The TCD-Substudy is mentioned in the TREAT-CAD protocol version 3.3 18.12.17.

E.3

Principal inclusion criteria

1. Acute ischemic or non-ischemic symptoms within 2 weeks
2. Verification of CAD-diagnosis (carotid and/or vertebral) by MR-techniques (at least one):
• mural hematoma or
• pseudo-aneurysm or
• long filiform stenosis or
• intimal flap or
• double lumen or
• occlusion situated more than 2 cm above the bifurcation of the carotid artery, revealing a pseudo aneurysm or a long filiform stenosis after recanalisation.
3. Written informed consent by patient or next-to-kin
4. 24h latency period in case of thrombolysis
5. Age > 18 years by time of inclusion (no upper age limit)

E.4

Principal exclusion criteria

1. MR-contraindications (claustrophobia precluding MRI: patients agreeing to undergo MRI scanning with mild sedation may be entered into the study)
2. Contraindications to the use of ASA or vitamin K-antagonists (see below)
3. Pregnancy
4. Gegenanzeigen gegen eine der IMPs
Aspirin protect 300 mg darf nicht
angewendet werden:
– bei Überempfindlichkeit gegen Acetylsalicylsäure,
anderen Salicylaten oder einem
der sonstigen Bestandteile von Aspirin
protect 100 mg/-300 mg
– bei Asthmaanfällen in der Vergangenheit,
die durch die Verabreichung von Salicylaten
oder Substanzen mit ähnlicher
Wirkung, insbesondere nichtsteroidalen
Antiphlogistika ausgelöst wurden
– bei akuten gastrointestinalen Ulzera
– bei hämorrhagischer Diathese
– bei Leber- und Nierenversagen
– bei schwerer, nicht eingestellter Herzinsuffizienz
– in Kombination mit Methotrexat in einer
Dosierung von 15 mg oder mehr pro Woche

Marcumar darf nicht angewendet werden
– bei Überempfindlichkeit gegen den Wirkstoff
oder einen seiner sonstigen Bestandteile.
– bei Erkrankungen, bei denen das Blutungsrisiko
den möglichen therapeutischen Benefit überwiegt, z. B. hämorrhagische Diathesen, schweren Leberparenchymerkrankungen, manifeste Niereninsuffizienz, schwere Thrombozytopenie
– bei Erkrankungen, bei denen der Verdacht
auf eine Läsion des Gefäßsystems
besteht, z. B.:
– bei frischem apoplektischem Insult
– bei Endocarditis
– bei Perikarditis
– bei Hirnarterienaneurysma
– bei disseziierendem Aortenaneurysma
– bei Ulzera im Magen-Darm-Trakt
– bei einer Operation am Auge
– bei Retinopathien mit Blutungsrisiko
– bei Traumen oder chirurgischen Eingriffen
am Zentralnervensystem
– bei fortgeschrittener Arteriosklerose
– bei fixierter und behandlungsrefraktärer
Hypertonie (> 200/105 mmHg)
– bei kavernöser Lungentuberkulose
– nach urologischen Operationen solange
Blutungsneigung (Makrohämaturie) besteht
– bei ausgedehnten offenen Wunden (auch
nach chirurgischen Eingriffen)

E.5 End points

E.5.1

Primary end point(s)

Primary composite outcome measure – labeled Cerebrovascular Ischemia, major Hemorrhagic events or Death (CIHD) – includes the following efficacy and safety outcome measures during the treatment period: (i) occurrence of any stroke, new acute lesions on diffusion- weighted MRI (ii) any major extracranial hemorrhage, any symptomatic intracranial hemorrhage and any asymptomatic micro- or macrobleeds, (iii) death.

E.5.1.1

Timepoint(s) of evaluation of this end point

14 +/- 10 days after baseline
90 +/- 30 days after baseline

E.5.2

Secondary end point(s)

1. New ischemic strokes;
2. new acute lesions on diffusion-weighted MRI
3. any major extracranial hemorrhage
4. any symptomatic intracranial hemorrhage
5. any asymptomatic micro- or macrobleeds
6. any death
7. any increase in volume of the vessel wall hematoma at the follow- up cervical MRI as compared to the baseline MR-scan.
8. independence in activity of daily living (modified Rankin scale 0-2)
at 3 months and at 6 months
9. excellent functional outcome (modified Rankin scale 0,1) at 3 month and at 6 months
10. any TIA (classical Definition)
11. recurrent cervical artery dissection

E.5.2.1

Timepoint(s) of evaluation of this end point

14 +/- 10 days after baseline
90 +/- 30 days after baseline

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

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Rand. controlled, open labeled, non-inferiority trial with blinded assessment of outcomes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

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

31. September 2019

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:

194

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients unable to understand or unable to express their will due to CAD-related stroke can participate if a next of kin and a physician not involved in the study declare that participation is in line with his/her interests.

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

F.4.2.2

In the whole clinical trial

194

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)

the treatment after the trial will be render by the general practioner

Eine Betreuung nach dem Ende der klinischen Prüfung erfolgt durch den Hausarzt

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-04-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-21

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