Clinical Trials Register

Summary
EudraCT Number:	2016-001642-26
Sponsor's Protocol Code Number:	LRD.2016.STREAM2
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-07-04
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

2016-001642-26

A.3

Full title of the trial

STREAM-2 (STrategic Reperfusion in elderly patients Early After Myocardial Infarction)

STREAM-2 (Reperfusión estratégica en pacientes de edad avanzada después del infarto de miocardio)

A.3.1

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

STREAM-2 (STrategic Reperfusion in elderly patients Early After Myocardial Infarction)

STREAM-2 (Reperfusión estratégica en pacientes de edad avanzada después del infarto de miocardio)

A.3.2

Name or abbreviated title of the trial where available

STREAM-2

A.4.1

Sponsor's protocol code number

LRD.2016.STREAM2

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02777580

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	Leuven Research & Development (LRD) at University of Leuven, Belgium
B.1.3.4	Country	Belgium
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	Boehringer Ingelheim
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Life Sciences Research Partners
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Fund for Clinical Cardiovascular Research at LRD
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leuven Coordinating Center
B.5.2	Functional name of contact point	Katleen Vandenberghe
B.5.3	Address:
B.5.3.1	Street Address	Herestraat 49
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	B-3000
B.5.3.4	Country	Belgium
B.5.6	E-mail	katleen.vandenberghe@kuleuven.be

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.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim
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 solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
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	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 25
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	Yes
D.3.11.13.1	Other medicinal product type	recombinant product, biotechnologically manufactured and isolated from hamster ovarian cells
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.2.1.2	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	Clopidogrel
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
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	Clopidogrel
D.3.9.3	Other descriptive name	CLOPIDOGREL
D.3.9.4	EV Substance Code	SUB13395MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
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.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

ST-elevation myocardial infarction within 3 hours of onset of symptoms

Infarto de miocardio con elevación del ST en las 3 horas posteriores a la aparición de los síntomas

E.1.1.1

Medical condition in easily understood language

Myocardial infarction within 3 hours of onset of symptoms

Infarto de miocardio en las 3 horas posteriores a la aparición de los síntomas

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10064345
E.1.2	Term	ST segment elevation myocardial infarction
E.1.2	System Organ Class	100000011652

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In elderly patients ≥ 70yrs with acute ST-elevation myocardial infarction randomised within 3 hours of onset of symptoms the efficacy and safety of a strategy of early fibrinolytic treatment with half-dose tenecteplase and additional antiplatelet therapy with a loading dose of 300 mg clopidogrel, aspirin and coupled with antithrombin therapy followed by catheterisation within 6-24 hours or rescue coronary intervention as required, will be compared to a strategy of primary PCI with a P2Y12 antagonist and antithrombin treatment according to local standards.

Eficacia y seguridad de una estrategia de tratamiento fibrinolítico temprano (mitad de dosis de tenecteplase y terapia antiplaquetaria con una dosis de carga de 300 mg de clopidogrel, junto a terapia de antitrombina seguida de cateterización dentro de 6-24 horas o intervención coronaria de rescate según se requiera, se comparará con una estrategia de PCI primaria con un antagonista de P2Y12 y tratamiento de antitrombina según las normas locales), en pacientes ancianos ≥ 70 años con infarto agudo de miocardio con elevación del ST aleatorizados dentro de las 3 horas del comienzo de los síntomas.

E.2.2

Secondary objectives of the trial

not applicable

no aplica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age equal or greater than 70 years
2. Onset of symptoms < 3 hours prior to randomisation
3. 12-lead ECG indicative of an acute STEMI (ST-elevation will be measured from the J point; scale: 1 mm per 0.1 mV):
* >=2 mm ST-elevation across 2 contiguous precordial leads (V1-V6) or leads I and aVL for a minimum combined total of >= 4 mm ST-elevation
or
* >=2 mm ST-elevation in 2 contiguous inferior leads (II, III, aVF) for a minimum combined total of >= 4 mm ST-elevation
4. Informed consent received

1. Edad igual o superior a 70 años
2. Inicio de los síntomas <3 horas antes de la asignación al azar
3. ECG de 12 derivaciones indicativo de un STEMI agudo (la elevación del ST se medirá desde el punto J, escala: 1 mm por 0,1 mV):
*> = 2 mm Elevación de ST a través de 2 conductores precordiales contiguos (V1-V6) o conductores I y aVL para un total combinado mínimo> = 4 mm Elevación de ST
o
*> = 2 mm Elevación de ST en 2 derivaciones inferiores contiguas (II, III, aVF) para un total combinado mínimo de> = 4 mm Elevación de ST
4. Consentimiento informado recibido

E.4

Principal exclusion criteria

1. Expected performance of PCI < 60 minutes from diagnosis (qualifying ECG) or inability to arrive at the catheterisation laboratory within 3 hours
2. Previous CABG
3. Left bundle branch block or ventricular pacing
4. Patients with cardiogenic shock - Killip Class 4
5. Patients with a body weight < 55 kg (known or estimated)
6. Uncontrolled hypertension, defined as sustained blood pressure >= 180/110 mm Hg (systolic BP >= 180 mm Hg and/or diastolic BP >= 110 mm Hg) prior to randomisation
7. Known prior stroke or TIA
8. Recent administration of any i.v. or s.c. anticoagulation within 12 hours, including unfractionated heparin, enoxaparin, and/or bivalirudin or current use of oral anticoagulation (i.e. warfarin or a NOACs)
9. Active bleeding or known bleeding disorder/diathesis
10. Known history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) or recent trauma to the head or cranium (i.e. < 3 months)
11. Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current myocardial infarction)
12. Clinical diagnosis associated with increased risk of bleeding including known active peptic ulceration and/or neoplasm with increased bleeding risk
13. Known severe renal insufficiency
14. Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
15. Known acute pericarditis and/or subacute bacterial endocarditis
16. Known acute pancreatitis or known severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
17. Dementia
18. Previous enrolment in this study or treatment with an investigational drug or device under another study protocol in the past 7 days
19. Known allergic reactions to tenecteplase, clopidogrel, enoxaparin and aspirin
20. Inability to follow the protocol and comply with follow-up requirements or any other reason that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

1. Rendimiento esperado de ICP <60 minutos desde el diagnóstico (ECG) o incapacidad para llegar al laboratorio de cateterización en 3 horas
2. CABG previa
3. Bloqueo de rama izquierda o estimulación ventricular
4. Pacientes con shock cardiogénico - Killip Clase 4
5. Los pacientes con un peso corporal <55 kg (conocido o estimado)
6. Hipertensión no controlada, definida como presión arterial sostenida> = 180/110 mm Hg (PA sistólica> = 180 mm Hg y / o PA diastólica> = 110 mm Hg) antes de la asignación al azar
7. Ictus anterior conocido o TIA
8. Administración reciente de cualquier anticoagulación i.v. o s.c. dentro de las 12 horas, incluyendo heparina no fraccionada, enoxaparina, y / o bivalirudina o uso actual de anticoagulación oral (es decir, warfarina o NOACs)
9. Sangrado activo o enfermedad conocida de sangrado / diátesis
10. Antecedentes conocidos de daño en el sistema nervioso central (por ejemplo, neoplasia, aneurisma, cirugía intracraneal o espinal) o trauma reciente en la cabeza o en el cráneo (es decir. <3 meses)
11. Cirugía mayor, biopsia de un órgano parenquimatoso o trauma significativo en los últimos 2 meses (esto incluye cualquier trauma asociado con el infarto de miocardio actual)
12. Diagnóstico clínico asociado con un mayor riesgo de hemorragia, incluyendo ulceración y / o neoplasia péptica activa conocida con aumento del riesgo de sangrado
13. Insuficiencia renal grave conocida
14. Reanimación cardiopulmonar prolongada (> 2 minutos) en las últimas 2 semanas
15. Pericarditis aguda conocida y / o endocarditis bacteriana subaguda
16. Pancreatitis aguda conocida o disfunción hepática grave conocida, incluyendo insuficiencia hepática, cirrosis, hipertensión portal (varices esofágicas) y hepatitis activa
17. Demencia
18. Participación anterior en este estudio o tratamiento con un fármaco en investigación o dispositivo bajo otro protocolo de estudio en los últimos 7 días
19. Reacciones alérgicas conocidas a tenecteplase, clopidogrel, enoxaparina y aspirina
20. Incapacidad para seguir el protocolo y cumplir con los requisitos de seguimiento o cualquier otra razón que el investigador perciba que ponga al paciente en mayor riesgo si se inicia la terapia de investigación

E.5 End points

E.5.1

Primary end point(s)

Number of patients achieving ≥ 50 % ST-segment resolution before and after PCI in lead with maximal ST elevation at baseline; % rescue PCI; TIMI flow grades

Número de pacientes que alcanzan ≥ 50% de la resolución del segmento ST antes y después de la PCI en el línea con la elevación máxima del ST en la línea de base; % de rescate PCI; grado de flujo TIMI

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days post randomisation

30 dias post aleatorión

E.5.2

Secondary end point(s)

Clinical events of interest i.e. death, shock, heart failure, recurrent MI and aborted MI will be recorded and assessed as single or composite endpoints for evaluation as noted in the statistical analytical plan.
Total stroke, intracranial haemorrhage, ischaemic stroke, haemorrhagic conversion.
Non-intracranial bleeds (total, major, minor, and blood transfusions).
Serious cardiac events (e.g. death , congestive heart failure, reinfarction, resuscitated ventricular fibrillation, repeat target vessel recanalization, stent thrombosis, total AV block etc).

Los eventos clínicos de interés, es decir, la muerte, el shock, la insuficiencia cardiaca, el IM recurrente y el IM fallido se registrarán y evaluarán como resultados finales individuales o compuestos, tal como se indica en el plan analítico estadístico.
Ictus total, hemorragia intracraneal, ictus isquémico, conversión hemorrágica.
Hemorragias no intracraneales (total, mayor, menor y transfusiones de sangre).
Eventos cardíacos graves (por ejemplo, muerte, insuficiencia cardíaca congestiva, reinfarto, fibrilación ventricular reanudada, repetición de la recanalización del vaso objetivo, trombosis del stent, bloqueo AV total, etc.).

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days post randomisation

30 días post aleatorización

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

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

comparative

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

PCI primaria según los estándares locales

Primary PCI according to local standards

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

Australia

Brazil

Canada

Chile

France

Romania

Russian Federation

Serbia

Spain

Ukraine

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

End of trial: 30 days after randomisation
1 year follow-up to obtain vital status/all-cause mortality

Fin del ensayo: 30 días después de la asignación al azar
1 año de seguimiento para obtener datos de estado vital / mortalidad

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.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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

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

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

300

F.4.2.2

In the whole clinical trial

600

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)

None

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

2017-10-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-04

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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