Clinical Trials Register

Summary
EudraCT Number:	2015-005469-22
Sponsor's Protocol Code Number:	TEMPO-2
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-08-08
Trial 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

Austria - BASG

A.2

EudraCT number

2015-005469-22

A.3

Full title of the trial

Multi-Centre, prosepective randomised open label, blinded-endpoint (PROBE) controlled trial of thrombolysis with low dose Tenecteplase (TNK-tPA) versus standard of care in the prevention of disability at 3 months in minor ischemic stroke with proven acute symptomatic occlusion.

A.3.1

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

A randomised controlled trial of TNK-tPA versus standard of care for minor ischemic stroke with proven occlusion.

A.3.2

Name or abbreviated title of the trial where available

TEMPO-2

A.4.1

Sponsor's protocol code number

TEMPO-2

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 Calgary
B.1.3.4	Country	Canada
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	University of Calgary
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Calgary
B.5.2	Functional name of contact point	Dr Shelagh B. Coutts
B.5.3	Address:
B.5.3.1	Street Address	C1242, Foothills Medical Centre, 1403 29th St NW
B.5.3.2	Town/ city	Calgary, AB
B.5.3.3	Post code	T2N 2T9
B.5.3.4	Country	Canada
B.5.4	Telephone number	14039441594
B.5.5	Fax number	14039443079
B.5.6	E-mail	scoutts@ucalgary.ca

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	Metalyse 10, 000 U Powder and solvent for solution for injection Tenecteplase (TNK-tPA)
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingleheim International GmbH
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.3.1	Product name	Metalyse 10,000 U
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TENECTEPLASE
D.3.9.1	CAS number	191588-94-0
D.3.9.4	EV Substance Code	SUB04718MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10 000
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	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

To demonstrate the efficacy of using TNK-tPA (tenecteplase), a thrombolytic agent that is relatively novel to the treatment ischemic stroke but well-established in the treatment of myocardial infarction, to treat minor ischemic stroke patients with proven acute symptomatic occlusions or perfusion abnormalities.

E.1.1.1

Medical condition in easily understood language

To demonstrate the efficacy of using TNK-tPA to treat minor ischemic stroke with proven arterial occlusion.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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

The primary objective: to demonstrate the efficacy of using TNK-tPA to treat minor ischemic stroke with proven arterial occlusion.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Acute ischemic stroke in an adult patient (18 years of age or older)
2. Onset (last-seen-well) time to treatment time ≤ 12 hours.
3. Transient Ischemic Attack or minor stroke defined as a baseline National Institutes of Health Stroke Scale (NIHSS) ≤ 5 at the time of randomization. Patients do not have to have persistent demonstrable neurological deficit on physical neurological examination.
4. Any acute intracranial occlusion or near occlusion (Thrombolysis in cerebral ischemia (TICI) 0 or 1) (Middle Cerebal Artery, Anterior Cerebral Artery, Posterior Cerebral Artery, Vertebrobasilar territories) defined by non-invasive acute imaging Computed Tomography Angiography (CTA) or Magnetic Resonance angiography (MRA) ) that is neurologically relevant to the presenting symptoms and signs. Multiphase Computed Tomographic Angiography (CTA) or Computed Tomography (CT) perfusion are required for this study. An acute occlusion is defined as TICI 0 or TICI 1 flow.1 Practically this can include a small amount of forward flow in the presence of a near occlusion
AND,
Delayed washout of contrast with pial vessels on multiphase CTA in a region of brain concordant
with clinical symptoms and signs OR,
Any area of focal perfusion abnormality identified using CT or MR perfusion – e.g. transit delay (Time To Peak (TTP), Mean Transit Time (MTT) or Time to Peak of the impulse response (T Max) ), in a region of brain concordant with clinical symptoms and signs.
5. Pre-stroke independent functional status-structured Modified Rankin Scale mRS ≤2.
6. Informed consent from the patient or surrogate.
7. Patients can be treated within 90 minutes of the first slice of CT or MRI. Scans can be repeated
to meet this requirement; if there is no change neurologically then only a CT head need be repeated
for assessment of extent and depth of ischemia.

E.4

Principal exclusion criteria

1. Hyperdensity on NCCT consistent with intracranial hemorrhage.
2. Large acute stroke ASPECTS < 7 visible on baseline CT scan.
3. Core of established infarction. No large area (estimated >10 cc) of grey matter hypodensity at a similar density to white matter or in the judgment of the enrollingneurologist is consistent with a subacute ischemic stroke.
4. Patient has a severe or fatal or disabling illness that will prevent improvement or follow-up or such that the
treatment would not likely benefit the patient.
5. Pregnancy.
6. Planned thrombolysis with intravenous tPA or endovascular acute treatment.
7. In-hospital stroke unless these patients are at their baseline prior to the stroke.
8. Commonly accepted exclusions for medical thrombolytic treatment that potentially put the patient at an increased risk of bleeding. Country specific product monographs and stroke thrombolysis guidelines should be consulted. These are commonly relative contraindications (i.e. the final decision is at the discretion of the treating physician) but for the purposes of TEMPO-2 include the following:
a. Significant bleeding disorder either at present or within the past 6 months
b. International normalized ratio > 1.7 or known full anticoagulation with use of any standard or direct oral anticoagulant therapy with full anticoagulant dosing. [DVT prophylaxis dosing shall not prohibit enrolment]. For low molecular weight heparins (LMWH) more than 48 hours off drug will be considered sufficient to allow trial enrollment. For direct oral anticoagulants; in patients with normal renal function more than 48 hours off drug will be considered sufficient to allow trial enrollment. Patients on direct oral anticoagulants who have
any degree of renal impairment should not be enrolled in the trial unless they have not taken a dose of the drug in the last 5 days.
c. Dual antiplatelet therapy does not prohibit enrolment. [For patients who are known not to be
taking anticoagulant therapy it is not necessary to wait for coagulation lab results (e.g. PT, PTT) prior
to treatment]
d. Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
e. Acute pericarditis and/or subacute bacterial endocarditis
f. Acute pancreatitis
g. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal
varices) and active hepatitis
h. Neoplasm with increased bleeding risk
i. Arterial aneurysm and known arterial/venous malformation
j. Patients who have been acutely treated with GP2b3a inhibitors.
k. Arterial puncture at a non-compressible site in the previous seven days
l. Clinical stroke or serious head or spinal trauma in the preceding three months that would normally
preclude use of a thrombolytic agent.
m. History of intracranial hemorrhage, subarachnoid hemorrhage or other brain hemorrhage that would
normally preclude use of a thrombolytic agent.
n. Major surgery within the last 3 months that the treating physician considers a contraindication to
thrombolytic therapy.
o. Severe hypo- (< 50 mg/dL or 2.8mmol/l )or hyperglycemia (>400 or 22.2mmol/l)
p. Hypertension refractory to anti-hypertensive medication such that target blood pressure <185/110 cannot be achieved before treatment.
q. Known platelet count below 100,000 per cubic millimeter. [Treatment should not be delayed to
wait for platelet count unless thrombocytopenia is known or suspected]
r. Gastrointestinal or genitourinary bleeding within the past 3 months that would normally preclude
use of a thrombolytic agent.

E.5 End points

E.5.1

Primary end point(s)

Primary outcome: Return to baseline neurological functioning as measured by the mRS.
Analysis will be a responder analysis where return to baseline level of neurological functioning is
defined as follows:
If pre-morbid mRS is 0-1 then mRS 0-1 at 90 days is a good outcome.
If pre-morbid mRS is 2 then mRS 0-2 is a good outcome.

Pre-morbid mRS is assessed using the structured mRS prior to randomization.
Outcomes will be assessed by an individual blinded to the treatment assignment. The 90day mRS will
be rated using the structured mRS questionnaire. The 90 day mRS will be completed
in person where possible and by telephone otherwise. The structured questionnaire has been showed
to improve reliability in assessing the mRS both in person and by telephone.

E.5.1.1

Timepoint(s) of evaluation of this end point

At day 90 day mRS will be completed in person where possible and by telephone otherwise. The structured questionnaire has been showed to improve reliability in assessing the mRS both in person and by telephone.

E.5.2

Secondary end point(s)

Secondary outcomes: Safety, recanalization, ordinal shift
analysis of mRS, NIHSS 0 at day 5 (or discharge), Euroqol, everyday activities sub-question on
Euroqol, Lawton Instrumental Activities of Daily Living Scale (IADL), all cause mortality,
recurrent stroke or progression, mRS 0-1 at 90days, mRS 0-2 at 90 days, mean mRS using linear
regression,
composite of recanalization or mRS 0-1 at 90days and mortality.

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments at Day 1, Day 5 or discharge and Day 90

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

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

Prospective Randomised Open Label Blinded Endpoint Assessment

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard Usual Care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Australia

Austria

Canada

Ireland

New Zealand

Spain

United Kingdom

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)

F.1.2.1

Number of subjects for this age range:

425

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

849

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-08-08.

Yes

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

All patients or legally authorized surrogate will provide written informed consent.

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

200

F.4.2.2

In the whole clinical trial

1274

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)

All patients will be treated with the best practice usual care as deemed appropriate by their treating physician.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Irish Stroke Clinical Trial Network
G.4.3.4	Network Country	Ireland

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-08-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-09

P. End of Trial
P.	End of Trial Status	Ongoing

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