Clinical Trials Register

Summary
EudraCT Number:	2011-005906-32
Sponsor's Protocol Code Number:	WAKE-UP
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-04
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

Spain - AEMPS

A.2

EudraCT number

2011-005906-32

A.3

Full title of the trial

Efficacy and safety of MRI-based thrombolysis in wake-up
stroke: a randomised, double-blind, placebo-controlled trial

A.3.1

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

Efficacy and safety of MRI-based thrombolysis in wake-up
stroke

A.3.2

Name or abbreviated title of the trial where available

WAKE-UP

A.4.1

Sponsor's protocol code number

WAKE-UP

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 Medical Center Hamburg-Eppendorf
B.1.3.4	Country	Germany
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	European Union
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Hamburg-Eppendorf
B.5.2	Functional name of contact point	Götz Thomalla
B.5.3	Address:
B.5.3.1	Street Address	Martinistr. 52
B.5.3.2	Town/ city	Hamburg
B.5.3.3	Post code	20246
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4940741050137
B.5.5	Fax number	+4940741056721
B.5.6	E-mail	thomalla@uke.de

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	Actilyse
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim Pharma 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.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ALTEPLASE
D.3.9.1	CAS number	105857-23-6
D.3.9.4	EV Substance Code	SUB05378MIG
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	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Lyophilisate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with acute ischemic stroke proven by MRI and unknown time from symptom onset which otherwise fulfil the approval criteria for intravenous thrombolysis in acute stroke

E.1.1.1

Medical condition in easily understood language

Patients with acute ischemic stroke

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10061256
E.1.2	Term	Ischaemic stroke
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

The objective is to test efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with unknown symptom onset.

E.2.2

Secondary objectives of the trial

no secondary objectives

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Clinical Inclusion Criteria
- Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on
awakening)
- Last known well (without neurological symptoms) >4.5 hours of treatment initiation
- Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor
function, cognition, gaze, vision, neglect)
- Age 18-80 years
-Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening)
- Written informed consent by patient or proxy

Imaging Inclusion Criteria:
- Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR)
completed and showing a pattern of ?DWI-FLAIR-mismatch?, i.e. acute ischemic lesion visibly on DWI (?positive
DWI?) but no marked parenchymal hyperintensity visible on FLAIR (?negative FLAIR?) indicative of an acute ischemic
lesion ?4.5 hours of age

E.4

Principal exclusion criteria

Clinical Exclusion Criteria
- Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis,
mechanical recanalization techniques)
- Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability
corresponding to an MRS score >1)
- Participation in any investigational study in the previous 30 days
- Severe stroke by clinical assessment (e.g. NIHSS >25)
- Hypersensitivity to Alteplase or any of the excipients
- Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed
in women up to 55 years of age)
- Significant bleeding disorder at present or within past 6 months
- Known haemorrhagic diathesis
- Manifest or recent severe or dangerous bleeding
- Known history of or suspected intracranial haemorrhage
- Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from
aneurysm
- History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)
- Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a
non-compressible blood-vessel
- Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current
use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed)
- Platelet count <100.000/mm3 (<100G/l)
- Blood glucose <50 or >400 mg/dl (<2.8 or 22.2 mmol/l)
- Severe uncontrolled hypertension, i.e. systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg
or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)
- Manifest or recent bacterial endocarditis, pericarditis
- Manifest or recent acute pancreatitis
- Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations
- Neoplasm with increased bleeding risk
- Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis
- Major surgery or significant trauma in past 3 months
- Stroke within 30 days
- Life expectancy 6 months or less by judgement of the investigator
- Any condition associated with a significantly increased risk of severe bleeding not mentioned above
- Any contraindication to MRI (e.g. cardiac pacemaker)

Imaging Exclusion Criteria:
- Poor MRI quality precluding interpretation according to the study protocol
- Any sign of intracranial haemorrhage on baseline MRI
- FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion inidicative of
an acute ischemic lesion with a high likelihood of being > 4.5 hours old
- Large DWI lesion volume > 1/3 of the MCA or >50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or >100 ml
- Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint
? ?Favourable outcome? defined by a score of 0-1 on the modified Rankin Scale (MRS) 90 (±10) days after stroke
Primary Safety Endpoints
? Mortality 90( ±)10 days after stroke
? Death or dependency 90 (±10) days after stroke (MRS 4-6)

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary Efficacy Endpoint
? 90 ±10 days after stroke
Primary Safety Endpoints
? 90 ±10 days after stroke
? 90 ±10 days after stroke

E.5.2

Secondary end point(s)

Secondary Efficacy Endpoints
- Global Outcome Score (combination of MRS 0-1, NIHSS 0-1, Barthel Index [BI] 95-100, Glasgow Outcome Scale [GOS] 1) 90 (±10) days after stroke
- Categorical shift in MRS 90 (±10) days after stroke
- Responder analysis relating MRS 90 (±10) days after stroke to baseline NIHSS score: ?response? defined by NIHSS
<7 = MRS 0; NIHSS 8-14 = MRS 0-1; NIHSS >14 = MRS 0-2
- Infarct volume after 22-36 hours
- Depressive symptoms 90 (±10) days after stroke (Beck Depression Inventory [BDI])
- Functional health status and quality of life 90 (±10) days after stroke (EQ-5D)
- Use of health care system resources
- 90 +/- 10 days after stroke

Secondary Safety Endpoints
- Symptomatic intracranial haemorrhage (SICH) as defined in SITS-MOST
- SICH as defined ECASS II
- SICH as defined in NINDS
- Parenchymal haemorrhage type 2 (PH-2)
- 22-36 hours after treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

90 (±10) days after stroke

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

We expect that 20-40% pf the patients will be unable to give informed consent. Excluding this group from the clinical trial would entail severe scientific and clinical drawbacks.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

800

F.4.2.2

In the whole clinical trial

800

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)

Post medical treatment at the study sites according to 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

2012-12-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-09-21

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