Clinical Trials Register

Summary
EudraCT Number:	2020-001982-36
Sponsor's Protocol Code Number:	AcT_CZE
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-07-17
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

Czechia - SUKL

A.2

EudraCT number

2020-001982-36

A.3

Full title of the trial

Alteplase compared to tenecteplase in patients with acute ischemic stroke: Registry-based pragmatic randomized controlled trial

Porovnání alteplasy s tenecteplasou u pacientů s akutní ischemií mozku: pragmatická randomizovaná kontrolovaná klinická studie založená na registru

A.3.1

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

Alteplase compared to tenecteplase in patients with acute ischemic stroke: Registry-based pragmatic randomized controlled trial

Porovnání alteplasy s tenecteplasou u pacientů s akutní ischemií mozku: pragmatická randomizovaná kontrolovaná klinická studie založená na registru

A.3.2

Name or abbreviated title of the trial where available

AcT

A.4.1

Sponsor's protocol code number

AcT_CZE

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	Fakultní nemocnice u sv. Anny
B.1.3.4	Country	Czech Republic
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	Fakultní nemocnice u sv. Anny
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Masarykova univerzita - Lékařská fakulta
B.5.2	Functional name of contact point	Farmakologický ústav
B.5.3	Address:
B.5.3.1	Street Address	Kamenice 5
B.5.3.2	Town/ city	Brno
B.5.3.3	Post code	625 00
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	00420549 496 526
B.5.6	E-mail	demlova@med.muni.cz

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
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.3.4	Pharmaceutical form	Powder and solution 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	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	range
D.3.10.3	Concentration number	8000 to 10000
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.2.1.1.1	Trade name	Actilyse
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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 solution 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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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

Acute ischemic stroke

Akutní ischemická mozková příhoda

E.1.1.1

Medical condition in easily understood language

Acute ischemic stroke

Akutní ischemická mozková příhoda

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	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10055221
E.1.2	Term	Ischemic stroke
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
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 main hypothesis of this clinical trial is that tenecteplase is non-inferior to alteplase in efficacy in patients with acute ischemic stroke eligible for i.v. thrombolysis as per current guidelines.

Hlavní hypotézou tohoto klinického hodnocení je: tenecteplasa je stejně účinná jako alteplasa u pacientů s akutní ischemií mozku, kteří jsou způsobilí pro i.v. trombolýzu podle současných guidelines.

E.2.2

Secondary objectives of the trial

not applicable

neaplikovatelné

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Clinical diagnosis of ischemic stroke (iCMP) with sudden and clear neurological deficit.
• Onset of iCMP symptoms within the last 4.5 hours, with the exception of acute basilar artery occlusion, where IVT administration is accepted even after 4.5 hours from the onset of symptoms.
• Age ≥18 years.

• Klinická diagnóza ischemické cévní mozkové příhody (iCMP) s náhle vzniklým a jasným neurologickým deficitem.
• Začátek příznaků iCMP v posledních 4,5 hodinách, s výjimkou akutního uzávěru arteria basilaris, kdy je akceptováno podání IVT i po 4,5 hodinách od začátku příznaků.
• Věk > 18 let

E.4

Principal exclusion criteria

• Known hypersensitivity to the drug or to any of the excipients.
• Demonstration of intracranial haemorrhage on CT or MR.
• Demonstration of a brain disease other than ischemia as a cause of acute neurological deficit.
• Presence of clear hypodense changes corresponding to acute cerebral ischemia in more than 1/3 of the cerebral media artery basin (ACM) on CT of the brain.
• Suspected subarachnoid haemorrhage or clinical signs suggestive of subarachnoid haemorrhage, even if a negative CT scan is performed.
• Acute internal bleeding.
• Uncontrollable systolic blood pressure above 185 mm Hg or diastolic blood pressure above 110 mm Hg. Uncontrollable BP is considered to be a condition in which, despite adequate antihypertensive treatment, it is not possible to maintain BP values <185/110 mm Hg before the onset of IVT. Single, bolus administration of antihypertensives and subsequent continuous administration are not a contraindication to IVT if the BP is <185/110 mm Hg at the time of IVT initiation.
• Ischemic CMP or craniocerebral or spinal injuries in the last 3 months in patients with severe residual clinical or radiological findings.
• Intracranial haemorrhage in the last 6 months.
• Manifest or severe or dangerous bleeding in the last 21 days, including bleeding into the gastrointestinal or urogenital tract.
• Known haemorrhagic diathesis.
• Known arteriovenous malformation or known arterial aneurysm.
• Intracranial or intraspinal surgery in the last 4 weeks.
• Arterial puncture at an uncompressible site in the last 7 days.
• Pregnancy
• Childbirth in the last 10 days or the third trimester with iminent childbirth.
• Other known serious conditions with a high risk of severe or life-threatening bleeding.
• Glycaemia less than 2.7 mmol/l.
• INR> 1.7. It also applies to patients taking coumarin anticoagulants. Patients taking warfarin do not have an increased risk of symptomatic intracranial haemorrhage if the INR is below 1.7. Warfarin use is an absolute contraindication to IVT if the INR is above 1.7.
• Platelet count below 100,000/μl; in patients without known thrombocytopenia, it is possible to initiate IVT without knowing the platelet count if their determination and evaluation would lead to a delay in the initiation of IVT; if a platelet count is found below 100,000/μl, IVT must be stopped immediately.
• Heparin or low molecular weight heparin (LMWH) therapy in the last 48 hours and with an increased aPTT above the upper limit of the laboratory.
• Abnormal specific coagulation tests with apaxiban, rivaroxaban and endoxaban. Abnormal coagulation tests are prolonged thrombin time (TT) or increased value of a specific anti-Xa test according to the laboratory standard
• Parallel participation in any other trial involving investigational medication or medical devices

• Známá přecitlivělost na léčebnou nebo na některou z pomocných látek.
• Průkaz intrakraniálního krvácení na CT nebo MR.
• Průkaz jiného onemocnění mozku než ischémie jako příčiny akutního neurologického deficitu.
• Přítomnost jasných hypodenzních změn, které odpovídají akutní mozkové ischémii ve více než 1/3 povodí arteria cerebri media (ACM) na CT mozku.
• Podezření na subarachnoidální krvácení nebo klinické příznaky naznačující subarachnoidální krvácení, a to i v případě negativního nálezu na CT mozku.
• Akutní vnitřní krvácení.
• Nekontrolovatelný systolický TK nad 185 mm Hg nebo diastolický TK nad 110 mm Hg. Za nekontrolovatelný TK, se považuje takový stav, kdy i přes adekvátní antihypertenzní léčbu není možno udržet hodnoty TK < 185/110 mm Hg před zahájením IVT. Jednorázové, bolusové podání antihypertenziv i následná kontinuální aplikace není kontraindikací IVT, pokud je TK < 185/110 mm Hg v době zahájení IVT.
• Ischemická CMP nebo kraniocerebrální či spinální poranění v posledních 3 měsících u pacientů se závažným reziduálním klinickým nebo radiologickým nálezem.
• Intrakraniální krvácení v posledních 6 měsících.
• Manifestní nebo silné či nebezpečné krvácení v posledních 21 dnech, včetně krvácení do gastrointestinálního nebo urogenitálního traktu.
• Známá hemoragická diatéza.
• Známá arteriovenózní malformace nebo známé tepenné aneurysma.
• Intrakraniální nebo intraspinální operace v posledních 4 týdnech.
• Arteriální punkce na nekomprimovatelném místě v posledních 7 dnech.
• Těhotenství
• Porod v posledních 10 dnech nebo třetí trimestr s iminentním porodem.
• Ostatní známé závažné stavy s vysokým rizikem vážného nebo život ohrožujícího krvácení.
• Glykémie méně než 2,7 mmol/l.
• INR > 1,7. Platí i pro pacienty, kteří užívají kumarinová antikoagulancia. Pacienti, kteří užívají warfarin, nemají zvýšené riziko symptomatického intrakraniálního krvácení, pokud INR je pod 1,7. Užívání warfarinu je absolutní kontraindikací IVT, pokud INR je nad 1,7.
• Počet trombocytů pod 100 000/μl; u pacientů bez známé trombocytopénie je možné zahájit IVT i bez znalosti počtu trombocytů, pokud by jejich stanovení a vyhodnocení vedlo k prodlevě zahájení IVT; při zjištění počtu trombocytů pod 100 000/μl musí být IVT okamžitě ukončena.
• Terapie heparinem nebo nízkomolekulárním heparinem (LMWH) v posledních 48 hodinách a se zvýšenou hodnotou aPTT nad horní limit laboratoře.
• Abnormní specifické koagulační testy při léčbě apaxibanem, rivaroxabanem a endoxabanem. Abnormními koagulačními testy jsou prodloužený trombinový čas (TT) nebo zvýšená hodnota specifického anti-Xa testu dle normy laboratoře.
• Paralelní účast na jakémkoli jiném klinickém hodnocení zahrnujícím hodnocené léčivé přípravky nebo zdravotnické prostředky

E.5 End points

E.5.1

Primary end point(s)

1) Non-inferiority of tenecteplase in efficacy terms, i.e. in the degree of functional independence at 90−120 days after stroke
• Modified Rankin scale (mRS) – comparison of the proportion of patients with mRS 0−1 during 90−120 days after stroke in both study arms

1) Noninferiorita tenekteplázy z hlediska účinnosti tj. ve stupni funkční nezávislosti 90−120 dnů po mozkové příhodě
• Modifikovaná škála Rankin (mRS) – porovnání podílů pacientů s mRS 0−1 během 90−120 dnů po mozkové příhodě v obou studijních ramenech

E.5.1.1

Timepoint(s) of evaluation of this end point

90−120 days after stroke in both study arms

90−120 dní po mozkové příhodě v obou studijních ramenech

E.5.2

Secondary end point(s)

1) Discharge destination (home, early supported discharge, rehabilitation facility, long term care, death)
2) Home time (defined as number of days subject spends at home after index stroke event)
3) Actual mRS score 90−120 day
4) Door to needle (DTN) time
5) Door-in-door-out (DIDO) times at Primary Stroke Centers
6) Recanalization status (mTICI score) at first angiographic acquisition in patients taken to the angio-suite for the purpose of administering endovascular thrombectomy (EVT)
7) Proportion of patients administered EVT
8) Door-to-groin puncture time in patients undergoing EVT
9) CT-to-puncture time in patients undergoing EVT
10) Return to baseline level of functioning

1) Místo po propuštění (domov, předčasné propuštění, rehabilitační centrum, dlouhodobá péče, smrt)
2) Čas doma (definovaný jako počet dnů, které subjekt strávil doma po události mozkové mrtvice)
3) Aktuální skóre mRS 90−120 den
4) Čas Door to needle (DTN)
5) Čas Door-in-door-out (DIDO) v hlavních neurologických centrech
6) Status rekanalizace (skóre mTICI) při první angiografii pacientů odebraných na sál za účelem provedení endovaskulární trombektomie (EVT)
7) Poměr pacientů obdržených EVT
8) Čas Door-to-groin puncture u pacientů podstupujících EVT
9) Čas CT-to-puncture u pacientů podstupujících EVT
10) Návrat k základní úrovni fungování

E.5.2.1

Timepoint(s) of evaluation of this end point

hospitalisation phase;90−120 days after stroke in both study arms

období hospitalizace; 90−120 dní po mozkové příhodě v obou studijních ramenech

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

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

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

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

Last visit last patient

Poslední vizita posledního pacienta

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.1.2.1

Number of subjects for this age range:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

250

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 2020-07-17.

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

Yes

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

Due to the underlying disease (ischemic stroke), patients will be include in study according to physician decision. After recovery the informed consent with continuation in the study will be sign by patient or their relatives.

Vzhledem k základnímu onemocnění (akutní ischemická mozková příhoda), budou pacienti zařazeni do studie na základě rozhodnutí lékaře. Po zotavení bude informovaný souhlas s pokračováním ve studii podepsán pacientem nebo osobou blízkou.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

500

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)

Standard medical care

Standardní péče

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

2020-08-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-12

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-01-24

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